"Publication Type"	"Authors"	"Author Full Names"	"Group Authors"	"Methodology/Application"	"Article Title"	"Source Title"	"Language"	"Document Type"	"Author Keywords"	"Keywords Plus"	"Abstract"	"Addresses"	"Reprint Addresses"	"Email Addresses"	"Researcher Ids"	"ORCIDs"	"Funding Orgs"	"Funding Text"	"Cited Reference Count"	"Times Cited, WoS Core"	"Times Cited, All Databases"	"180 Day Usage Count"	"Since 2013 Usage Count"	"Publisher"	"Publisher City"	"Publisher Address"	"ISSN"	"eISSN"	"ISBN"	"Journal Abbreviation"	"Journal ISO Abbreviation"	"Publication Date"	"Publication Year"	"Volume"	"Issue"	"Start Page"	"End Page"	"Article Number"	"DOI"	"Number of Pages"	"WoS Categories"	"Research Areas"	"IDS Number"	"UT (Unique WOS ID)"	"Pubmed Id"	"Open Access Designations"	"Highly Cited Status"	"Hot Paper Status"	"Date of Export"
"J"	"Knibbe, CAJ; Krekels, EHJ; van den Anker, JN; DeJongh, J; Santen, GWE; van Dijk, M; Simons, SHP; van Lingen, RA; Jacqz-Aigrain, EM; Danhof, M; Tibboel, D"	"Knibbe, Catherijne A. J.; Krekels, Elke H. J.; van den Anker, Johannes N.; DeJongh, Joost; Santen, Gijs W. E.; van Dijk, Monique; Simons, Sinno H. P.; van Lingen, Richard A.; Jacqz-Aigrain, Evelyne M.; Danhof, Meindert; Tibboel, Dick"	"NA"	"A"	"Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"GLUCURONOSYLTRANSFERASE 2B7 UGT2B7; RANDOMIZED CONTROLLED-TRIAL; NEWBORN-INFANTS; POPULATION PHARMACOKINETICS; MAJOR SURGERY; MORPHINE-6-GLUCURONIDE; CLEARANCE; MORPHINE-3-GLUCURONIDE; METABOLITES; PREMATURE"	"Background and objective: A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug. Methods: A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM (R) V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors. Results: Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight. Conclusions: Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in mu g/kg and a maintenance dose expressed in mu g/kg(1.5)/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made."	"[Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands; [Knibbe, Catherijne A. J.; Krekels, Elke H. J.; DeJongh, Joost; Santen, Gijs W. E.; Danhof, Meindert] Leiden Amsterdam Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Knibbe, Catherijne A. J.; Krekels, Elke H. J.; van den Anker, Johannes N.; van Dijk, Monique; Simons, Sinno H. P.; Tibboel, Dick] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [DeJongh, Joost] LAP&P Consultants, Leiden, Netherlands; [van Lingen, Richard A.] Isala Clin, Div Neonatol, Princess Amalia Dept Pediat, Zwolle, Netherlands; [Jacqz-Aigrain, Evelyne M.] Hop Robert Debre, Dept Pediat Pharmacol & Pharmacogenet, F-75019 Paris, France"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"simons, sinno/AAC-7442-2019; van Dijk, Monique/B-6327-2009"	"DeJongh, Joost/0000-0003-3034-4712; van Dijk, Monique/0000-0002-9856-0318; Simons, Sinno/0000-0001-5219-5696; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"Sophia Foundation for Scientific Research; Erasmus Medical Center; Sophia's Children's Hospital, Rotterdam, the Netherlands; Dutch Organisation for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); NICHDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HD45993, HD48689]; NCRRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [RR19729]"	"This study was supported by a grant from the Sophia Foundation for Scientific Research, Erasmus Medical Center, Sophia's Children's Hospital, Rotterdam, the Netherlands. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni Grant, July 2006) of the Dutch Organisation for Scientific Research (NWO). The clinical research of J.N. Van den Anker is supported by grants HD45993 (NICHD), RR19729 (NCRR) and HD48689 (NICHD). All authors have no conflicts of interest that are directly relevant to the contents of this study."	45	104	104	0	7	"ADIS INT LTD"	"AUCKLAND"	"41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND"	"0312-5963"	"NA"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2009	48	6	371	385	"NA"	"10.2165/00003088-200948060-00003"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"491GE"	"WOS:000269565700003"	19650676	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Abboud, I; Lerolle, N; Urien, S; Tadie, JM; Leviel, F; Fagon, JY; Faisy, C"	"Abboud, Imad; Lerolle, Nicolas; Urien, Saik; Tadie, Jean-Marc; Leviel, Francoise; Fagon, Jean-Yves; Faisy, Christophe"	"NA"	"A"	"Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status"	"CRITICAL CARE"	"English"	"Article"	"NA"	"SEPSIS FORUMS CONTROVERSIES; INITIAL VASOPRESSOR AGENT; NOREPINEPHRINE; PLASMA; DOPAMINE; CATECHOLAMINES; NORADRENALINE; INACTIVATION; DOBUTAMINE; ADRENALINE"	"Introduction In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock. Methods Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C-0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C-1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM. Results Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 mu g/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 x (BW/70)(0.60) x (SAPS II/50)(-0.67). The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1-56.7) at C-0 vs. 4.5 (0.3 - 38.9) nmol/L at C-1, P < 0.001). Conclusions Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients."	"[Abboud, Imad; Lerolle, Nicolas; Tadie, Jean-Marc; Fagon, Jean-Yves; Faisy, Christophe] Univ Paris 05, Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Med Intens Care Unit, Paris, France; [Urien, Saik] Univ Paris 05, Tarnier Hosp, Assistance Publ Hop Paris,EA 3620, Unite Rech Clin,Cochin Necker Paris Descartes CIC, Paris, France; [Leviel, Francoise] Univ Paris 05, Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Physiol, Paris, France"	"Lerolle, N (corresponding author), Univ Paris 05, Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Med Intens Care Unit, Paris, France."	"nilerolle@chu-angers.fr"	"Urien, Saik/G-3240-2013"	"ABBOUD, Imad/0000-0003-4352-1968"	"NA"	"NA"	36	25	26	0	9	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1466-609X"	"1364-8535"	"NA"	"CRIT CARE"	"Crit. Care"	"NA"	2009	13	4	"NA"	"NA"	"R120"	"10.1186/cc7972"	8	"Critical Care Medicine"	"General & Internal Medicine"	"525OL"	"WOS:000272225600017"	19622169	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Mazoit, JX; Le Guen, R; Beloeil, H; Benhamou, D"	"Mazoit, Jean-Xavier; Le Guen, Regine; Beloeil, Helene; Benhamou, Dan"	"NA"	"A"	"Binding of Long-lasting Local Anesthetics to Lipid Emulsions"	"ANESTHESIOLOGY"	"English"	"Article"	"NA"	"SUCCESSFUL RESUSCITATION; CARDIOVASCULAR COLLAPSE; INDUCED ASYSTOLE; PLEXUS BLOCK; BUPIVACAINE; ROPIVACAINE; TOXICITY; INFUSION; PATIENT; MODEL"	"Background Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. Methods: Using the shake-flask method, the authors measured die solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France). Results: The apparent distribution coefficient expressed as the ratio of mole fraction was 823 � 198 and 320 � 65 for racemic bupivacaine and levobtipivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 � 92 and 1,240 � 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 � 3.8 to 46 � 2.8 for bupivacaine, and to a lesser extent from 51 � 4.0 to 31 � 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 pm for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 mu M for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. increasing the temperature from 20 to 37 degrees C led to It greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the PH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics. Conclusions: The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding (if these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to he about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacainelevobupivacaine seem to clear more rapidly than ropivacaine."	"[Mazoit, Jean-Xavier; Le Guen, Regine; Beloeil, Helene; Benhamou, Dan] Univ Paris Sud, Fac Med, Lab Anesthesie, F-94276 Le Kremlin Bicetre, France"	"Mazoit, JX (corresponding author), Univ Paris Sud, Fac Med, Lab Anesthesie, F-94276 Le Kremlin Bicetre, France."	"jean-xavier.mazoit@u-psud.fr"	"beloeil, helene/AAD-4404-2020"	"NA"	"University Paris-Sud, Orsay Cedex, France; Association Mises au point en Anesthesie et Reanimation, Hopital Bicetre, Bicetre Cedex, France; Astra-Zeneca LaboratoriesAstraZeneca; Abbott LaboratoriesAbbott Laboratories"	"Supported by grants from the University Paris-Sud, Orsay Cedex, France, and from Association Mises au point en Anesthesie et Reanimation, Hopital Bicetre, Bicetre Cedex, France. Association Mises au Point en Anesthesie et Reanimation received funding from Astra-Zeneca Laboratories (Rucil-Malmaison France) and from Abbott Laboratories (Rungis France). Presented in part at the American Society of Anesthesiologists annual meeting, San francisco, California, October 13-17, 2007."	25	126	140	0	4	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0003-3022"	"1528-1175"	"NA"	"ANESTHESIOLOGY"	"Anesthesiology"	"FEB"	2009	110	2	380	386	"NA"	"NA"	7	"Anesthesiology"	"Anesthesiology"	"400ZI"	"WOS:000262907500026"	19194164	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Kumar, VVP; Oscarsson, S; Friberg, LE; Isbister, GK; Hackett, LP; Duffull, SB"	"Kumar, V. V. P.; Oscarsson, S.; Friberg, L. E.; Isbister, G. K.; Hackett, L. P.; Duffull, S. B."	"NA"	"A"	"The Effect of Decontamination Procedures on the Pharmacokinetics of Venlafaxine in Overdose"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"TOXICITY; CITALOPRAM"	"The aim of this work was to investigate the pharmacokinetics (PK) of venlafaxine in overdose and the effects of single-dose activated charcoal (SDAC) and whole-bowel irrigation (WBI), alone or in combination, as methods of decontamination. The data included 339 concentration-time points from 76 venlafaxine overdose events (median dose 2,625 (150-13, 500 mg)); 69 were slow-release doses. SDAC, WBI, a combination of both, or no decontamination were administered to patients as decided by the treating clinician. The data were modeled using WinBUGS (Windows Bayesian Inference Using Gibbs Sampling). A one-compartment model with first-order input and elimination provided an adequate description of the data. SDAC increased clearance (CL) of venlafaxine by 35%, and SDAC and WBI combined reduced the fraction absorbed by 29%. However, the latter produced a greater reduction in maximum plasma concentration (C-max) for a similar drop in area under the plasma concentration-time curve (AUC). Both SDAC alone, and a combination of SDAC and WBI, decreased the AUC after venlafaxine overdose, but the combination may be more beneficial because it reduces peak concentrations to a greater extent."	"[Kumar, V. V. P.; Duffull, S. B.] Univ Otago, Sch Pharm, Dunedin, New Zealand; [Oscarsson, S.; Friberg, L. E.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Isbister, G. K.] Newcastle Mater Hosp, Dept Clin Toxicol & Pharmacol, Newcastle Upon Tyne, Tyne & Wear, England; [Isbister, G. K.] Charles Darwin Univ, Menzies Sch Hlth Res, Trop Toxinol Unit, Darwin, NT 0909, Australia; [Hackett, L. P.] PathWest Lab Med WA, Perth, WA, Australia"	"Kumar, VVP (corresponding author), Univ Otago, Sch Pharm, Dunedin, New Zealand."	"pavan.kumar@otago.ac.nz"	"Isbister, Geoffrey K/G-8052-2015"	"Isbister, Geoffrey K/0000-0003-1519-7419; Friberg, Lena/0000-0002-2979-679X; Duffull, Stephen/0000-0002-6545-9408"	"NA"	"NA"	21	17	17	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"OCT"	2009	86	4	403	410	"NA"	"10.1038/clpt.2009.114"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"500LO"	"WOS:000270303500018"	19606091	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Brendel, K; Comets, E; Laffont, C; Mentre, F"	"Brendel, Karl; Comets, Emmanuelle; Laffont, Celine; Mentre, France"	"NA"	"M"	"Evaluation of different tests based on observations for external model evaluation of population analyses"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Model evaluation; Population pharmacokinetics; Predictive distribution; VPC; NPC; Predictive check; Prediction error"	"GLICLAZIDE"	"To evaluate by simulation the statistical properties of normalized prediction distribution errors (NPDE), prediction discrepancies (pd), standardized prediction errors (SPE), numerical predictive check (NPC) and decorrelated NPC (NPCdec) for the external evaluation of a population pharmacokinetic analysis, and to illustrate the use of NPDE for the evaluation of covariate models. We assume that a model M-B has been built using a building dataset B, and that a separate validation dataset, V is available. Our null hypothesis H-0 is that the data in V can be described by M-B. We use several methods to test this hypothesis: NPDE, pd, SPE, NPC and NPCdec. First, we evaluated by simulation the type I error under H-0 of different tests applied to the four methods. We also propose and evaluate a single global test combining normality, mean and variance tests applied to NPDE, pd and SPE. We perform tests on NPC and NPCdec, after a decorrelation. M-B was a one compartment model with first order absorption (without covariate), previously developed from two phase II and one phase III studies of the antidiabetic drug, gliclazide. We simulated 500 external datasets according to the design of a phase III study. Second, we investigated the application of NPDE to covariate models. We propose two approaches: the first approach uses correlation tests or mean comparisons to test the relationship between NPDE and covariates; the second evaluates NPDE split by category for discrete covariates or quantiles for continuous covariates. We generated several validation datasets under H-0 and under alternative assumptions with a model without covariate, with one continuous covariate (weight), or one categorical covariate (sex). We calculated the powers of the different tests using simulations, where the covariates of the phase III study were used. The simulations under H-0 show a high type I error for the different tests applied to SPE and an increased type I error for pd. The different tests present a type I error close to 5% for the global test appied to NPDE. We find a type I error higher than 5% for the test applied to classical NPC but this test becomes close to 5% for NPCdec. For covariate models, when model and validation dataset are consistent, type I error of the tests are close to 5% for both effects. When validation datasets and models are not consistent, the tests detect the correlation between NPDE and the covariate. We recommend to use NPDE over SPE for external model evaluation, since they do not depend on an approximation of the model and have good statistical properties. NPDE represent a better approach than NPC, since in order to perform tests on NPC, a decorrelation step must be applied before. NPDE, in this illustration, is also a good tool to evaluate model with or without covariates."	"[Brendel, Karl; Laffont, Celine] Inst Rech Int Servier, F-92415 Courbevoie, France; [Brendel, Karl; Comets, Emmanuelle; Mentre, France] INSERM, U738, Paris, France; [Brendel, Karl; Comets, Emmanuelle; Mentre, France] Univ Paris Diderot, UFR Med, Paris, France"	"Brendel, K (corresponding author), Inst Rech Int Servier, 6 Pl Pleiades, F-92415 Courbevoie, France."	"karl.brendel@fr.netgrs.com"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"NA"	"NA"	18	50	52	0	4	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"FEB"	2010	37	1	49	65	"NA"	"10.1007/s10928-009-9143-7"	17	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"556IW"	"WOS:000274585300003"	20033477	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Royer, B; Yin, W; Pegram, M; Ibrahim, N; Villanueva, C; Mir, D; Erlandsson, F; Pivot, X"	"Royer, B.; Yin, W.; Pegram, M.; Ibrahim, N.; Villanueva, C.; Mir, D.; Erlandsson, F.; Pivot, X."	"NA"	"A"	"Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer"	"BRITISH JOURNAL OF CANCER"	"English"	"Article"	"HuHMFG1; AS1402; population pharmacokinetic; antibody; linear two-compartment; breast cancer"	"CONCENTRATION-CONTROLLED TRIAL; AIRWAYS OBSTRUCTION; MUC1; PREDICTION; MODEL"	"BACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16mg kg(-1). Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody. British Journal of Cancer (2010) 102, 827-832. doi: 10.1038/sj.bjc.6605560 www.bjcancer.com Published online 16 February 2010 (C) 2010 Cancer Research UK"	"[Royer, B.] Hop Jean Minjoz, Lab Pharmacol Clin, CHU Besancon, F-25030 Besancon, France; [Royer, B.; Pivot, X.] INSERM, UMR645, F-25020 Besancon, France; [Royer, B.] Univ Franche Comte, IFR133, F-25030 Besancon, France; [Royer, B.] EFS Bourgogne Franche Comte, Besancon, France; [Royer, B.] CHU Besancon, CIC Integre Biotherapies 506, Besancon, France; [Yin, W.; Mir, D.; Erlandsson, F.] Antisoma Res Ltd, London W4 5YF, England; [Pegram, M.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA; [Ibrahim, N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA; [Villanueva, C.; Pivot, X.] Hop Jean Minjoz, CHU Besancon, Serv Oncol, F-25030 Besancon, France"	"Royer, B (corresponding author), Hop Jean Minjoz, Lab Pharmacol Clin, CHU Besancon, F-25030 Besancon, France."	"broyer@chu-besancon.fr"	"NA"	"NA"	"NA"	"NA"	24	12	12	0	1	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"0007-0920"	"NA"	"NA"	"BRIT J CANCER"	"Br. J. Cancer"	"MAR 2"	2010	102	5	827	832	"NA"	"10.1038/sj.bjc.6605560"	6	"Oncology"	"Oncology"	"563XH"	"WOS:000275170300007"	20160731	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Blasco, H; Senecal, D; Le Gouge, A; Pinard, E; Benz-de Bretagne, I; Colombat, P; Hulot, JS; Chatelut, E; Le Guellec, C"	"Blasco, Helene; Senecal, Delphine; Le Gouge, Amelie; Pinard, Emmanuelle; Benz-de Bretagne, Isabelle; Colombat, Philippe; Hulot, Jean-Sebastien; Chatelut, Etienne; Le Guellec, Chantal"	"NA"	"A"	"Influence of methotrexate exposure on outcome in patients treated with MBVP chemotherapy for primary central nervous system lymphoma"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"dose-response relationship; methotrexate; pharmacokinetics; primary central nervous system lymphoma"	"HIGH-DOSE METHOTREXATE; PHARMACOKINETIC INTERACTION; PHASE-II; EUROPEAN ORGANIZATION; CNS; PIPERACILLIN; RADIOTHERAPY; DISPOSITION; PROTEIN"	"Although treated using the same high-dose methotrexate (HD-MTX)-based multiagent chemotherapy, patients with primary central nervous system lymphoma (PCNSL) have significant differences in outcome. However, little information has been published about factors influencing outcome in PCNSL. As it is known that the pharmacokinetics of MTX vary considerably between subjects leading to different exposure in patients receiving the same dose, it is important to evaluate its role in response to chemotherapy. WHAT THIS STUDY ADDS This study is the first to evaluate the exposure-response relationship in patients treated with MBVP chemotherapy. We found that patients who were early non-responders to MBVP chemotherapy had poor survival, whatever the salvage regimen. Tumour response at early evaluation was not associated with MTX pharmacokinetics and increasing the dose would probably not improve results. AIMS Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles. METHODS We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients. RESULTS Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n = 12) than in those who received three cycles (8.04 years) (group 2, n = 25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles. CONCLUSIONS We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome."	"[Le Guellec, Chantal] Univ Tours, CHRU Tours, Dept Pharmacol, F-37044 Tours, France; [Le Gouge, Amelie] Univ Tours, CHRU Tours, INSERM, CIC 202, F-37044 Tours, France; [Hulot, Jean-Sebastien] Univ Paris 06, F-75252 Paris 05, France; [Chatelut, Etienne] Univ Toulouse 3, Ctr Claudius Regaud, F-31062 Toulouse, France"	"Le Guellec, C (corresponding author), Univ Tours, CHRU Tours, Dept Pharmacol, 2 Blvd Tonnelle, F-37044 Tours, France."	"leguellec@med.univ-tours.fr"	"Hulot, Jean-Sebastien/A-2278-2016; LE GUELLEC, Chantal/P-8704-2014; , Chatelut/I-7916-2014; Hulot, Jean-Sebastien/AAM-6490-2020"	"Hulot, Jean-Sebastien/0000-0001-5463-6117; LE GUELLEC, Chantal/0000-0001-5846-8616; , Chatelut/0000-0002-7740-9096; Hulot, Jean-Sebastien/0000-0001-5463-6117; blasco, helene/0000-0001-6107-0035"	"NA"	"NA"	33	8	8	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2010	70	3	367	375	"NA"	"10.1111/j.1365-2125.2010.03712.x"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"639PV"	"WOS:000280987600009"	20716237	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Mould, DR; Frame, B"	"Mould, Diane R.; Frame, Bill"	"NA"	"A"	"Population Pharmacokinetic-Pharmacodynamic Modeling of Biological Agents: When Modeling Meets Reality"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Biological pharmaceuticals; population pharmacokinetic pharmacodynamic modeling; 2-part model; indescribable model; adaptive dosing"	"THERAPY; DISEASE"	"The pharmacokinetics (PK) and pharmacodynamics (PD) of many biological agents (biologics) have inherent complexities requiring specialized approaches to develop reliable, unbiased models. Three cases are covered: preponderance of zero values, nonresponder subpopulations, and adaptive dosing. Engineered biologics exhibit high affinity for target receptors. Biologics can saturate receptors, abolishing free receptor levels for protracted periods. Consequently, the distribution of observations can be heavy at, and near, the boundary. A 2-part model (ie, a truncated delta log-normal distribution) may be appropriate. Mixture models identify subpopulations based on bimodal or multimodal distributions of. values. With biologics, PD may be compromised because of lack of receptors, or the PD may be affected because of other events resulting in erratic excursions. Nonresponders exhibit a random walk-around placebo trajectory, resulting in high residual variability. The distributions of etas are often badly skewed or polymodal. An indescribable mixture model separates subjects who are nonresponders, providing diagnostic pharmacologic information on the drug. Many biologics use PD-based adaptive dosing. During model development, data used for model development include adaptive dosing. For simulation, adaptive dosing must be implemented. Failure to account for dose adjustments results in biased or inflated prediction intervals because subjects in the simulated data undergo inappropriate dose adjustments."	"[Mould, Diane R.] Project Res, Phoenixville, PA USA; [Mould, Diane R.; Frame, Bill] Wolverine Pharmacometr, Ann Arbor, MI USA"	"Mould, DR (corresponding author), FCP Project Res Inc, 535 Springview Lane, Phoenixville, PA 19460 USA."	"drmould@pri-home.net"	"NA"	"NA"	"American Conference on Pharmacometrics"	"The articles in this supplement are sponsored by the American Conference on Pharmacometrics."	24	10	10	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"SEP"	2010	50	9	"91S"	"100S"	"NA"	"10.1177/0091270010376965"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"650OZ"	"WOS:000281860400012"	20881222	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bulitta, JB; Kinzig, M; Jakob, V; Holzgrabe, U; Sorgel, F; Holford, NHG"	"Bulitta, Juergen B.; Kinzig, Martina; Jakob, Verena; Holzgrabe, Ulrike; Soergel, Fritz; Holford, Nicholas H. G."	"NA"	"A"	"Nonlinear pharmacokinetics of piperacillin in healthy volunteers - implications for optimal dosage regimens"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"healthy volunteers; Monte Carlo simulation; piperacillin population pharmacokinetics; pharmacodynamics; saturable elimination; within subject variability; between occasion variability"	"BETA-LACTAM ANTIBIOTICS; CRITICALLY-ILL PATIENTS; SINGLE-DOSE PHARMACOKINETICS; SERUM BACTERICIDAL ACTIVITY; MONTE-CARLO-SIMULATION; SUCTION BLISTER FLUID; CONTINUOUS-INFUSION; POPULATION PHARMACOKINETICS; PSEUDOMONAS-AERUGINOSA; CYSTIC-FIBROSIS"	"center dot Despite the clinical use of piperacillin for more than two decades, there are still contradictory reports whether or not the elimination of piperacillin is saturable at clinically relevant concentrations. center dot Two recent studies that applied population pharmacokinetic (PK) modelling found evidence for a saturable component of piperacillin elimination, whereas other published population PK analyses found non-saturable elimination of piperacillin. center dot There is limited information on the between occasion variability of beta-lactams (including piperacillin) and such data might be important to maximize the effectiveness by individualizing beta-lactam dosage regimens. WHAT THIS STUDY ADDS center dot Saturable and non-saturable components of renal elimination were identified for piperacillin and the unbound non-saturable renal clearance of piperacillin was similar to the glomerular filtration rate. center dot Between occasion variability of clearance and volume of distribution at steady-state of piperacillin was below 20% which indicated that the PK of piperacillin was predictable from one dosing interval to the next. center dot Monte Carlo simulation predicted 5 h infusions every 8 h and continuous infusion of piperacillin would be able to successfully treat infections by pathogens with a 2 to 4-fold (5 to 8-fold) higher MIC compared with 30 min infusions given every 6 h (every 8 h) at the same daily dose. AIMS (i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens. METHODS We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4 g piperacillin as a single 5 min intravenous infusion in each study period. Drug analysis was performed by HPLC. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and Monte Carlo simulation to predict the probability of target attainment (PTA) with a target time of non-protein bound concentration above MIC > 50% of the dosing interval. RESULTS A model with first-order nonrenal elimination and parallel first-order and mixed-order renal elimination had the best predictive performance. For a 70 kg subject we estimated 4.40 l h-1 for nonrenal clearance, 5.70 l h-1 for first-order renal clearance, 170 mg h-1 for V-max, and 49.7 mg l-1 for K-m for the mixed-order renal elimination. The BOV was 39% for V-max, 117% for K-m, and 8.5% for total clearance. A 30 min infusion of 4 g every 6 h achieved robust (>= 90%) PTAs for MICs < 12 mg l-1. As an alternative mode of administration, a 5 h infusion of 6 g every 8 h achieved robust PTAs for MICs < 48 mg l-1. CONCLUSIONS Part of the renal elimination of piperacillin is saturable at clinically used doses. The BOV of total clearance and volume of distribution were low. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 12 and 48 mg l-1."	"[Bulitta, Juergen B.; Kinzig, Martina; Jakob, Verena; Soergel, Fritz] Inst Biomed & Pharmaceut Res, D-90562 Nurnberg, Germany; [Holzgrabe, Ulrike] Univ Wurzburg, Inst Pharm & Food Chem, Wurzburg, Germany; [Soergel, Fritz] Univ Duisburg Essen, Dept Pharmacol, Essen, Germany; [Holford, Nicholas H. G.] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland 1, New Zealand"	"Sorgel, F (corresponding author), Inst Biomed & Pharmaceut Res, Paul Ehrlich Str 19, D-90562 Nurnberg, Germany."	"ibmp@osn.de"	"Bulitta, Jurgen B/P-3355-2018; Holford, Nick/B-9774-2008"	"Bulitta, Jurgen B/0000-0001-7352-3097; Holford, Nick/0000-0002-4031-2514; Holzgrabe, Ulrike/0000-0002-0364-7278"	"NA"	"NA"	77	18	18	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"NOV"	2010	70	5	682	693	"NA"	"10.1111/j.1365-2125.2010.03750.x"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"663IS"	"WOS:000282877500007"	21039762	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Sun, B; Li, XY; Gao, JW; Rui, JZ; Guo, YK; Peng, ZH; Liu, GL"	"Sun, Bo; Li, Xiao-Yu; Gao, Jun-Wei; Rui, Jian-Zhong; Guo, Yan-Kun; Peng, Zhi-Hai; Liu, Gao-Lin"	"NA"	"A"	"Population Pharmacokinetic Study of Cyclosporine Based on NONMEM in Chinese Liver Transplant Recipients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"cyclosporine (CsA); population pharmacokinetic; nonlinear mixed effects modeling (NONMEM); liver transplantation; therapeutic drug monitoring"	"ORAL CYCLOSPORINE; BAYESIAN-ESTIMATION; INTEROCCASION VARIABILITY; MICROEMULSION FORMULATION; HEART-TRANSPLANTATION; WHOLE-BLOOD; MODEL; KIDNEY; ABSORPTION; PERFORMANCE"	"A population pharmacokinetic study of cyclosporine (CsA) was performed in liver transplant recipients. A total of 3731 retrospective drug monitoring data points at predose (C-0) and 2 hours postdose (C-2) were collected from 124 liver transplant recipients receiving CsA micromulsion. Population pharmacokinetic analysis was performed using the program NONMEM (nonlinear mixed-effect modeling). Various covariates potentially related to CsA pharmacokinetics were explored, and the final modelwas validated by a bootstrap method and by assessing the predictive performance using empiric Bayesian estimates. A one-compartment model with first-order absorption was considered. Population parameters of apparent clearance (CL/F) and volume of distribution were estimated as 23.1 L/h and 105 L, respectively. CL/F was influenced by four covariates: duration of CsA therapy (DT), hematocrit (HCT), and concurrent prednisone dose (PR). The final model for CL/F was fitted as follows: CL/F = 23.1 broken vertical bar 0.5 x (DT/200) - 0.07 x HCT broken vertical bar 0.04 x PR. The interindividual variability in CL/F, volume of distribution, and K-a calculated as coefficient of variation were 15.1%, 9.3%, and 66.0%, respectively. The intraindividual variability was 18.6%. The model fitted well with the observed data, and the bootstrap method guaranteed robustness of the population pharmacokinetic study model. Model validation was performed by a visual predictive check. Moreover, simulation was conducted to facilitate the individualized treatment based on patient information and the final model. The model to characterize population pharmacokinetic study of CsA provided better clinical individualization of CsA dosing in liver transplant recipients based on patient information and to assess patients' suitability for CsA therapy."	"[Sun, Bo; Li, Xiao-Yu; Gao, Jun-Wei; Guo, Yan-Kun] Shanghai Jiao Tong Univ, Dept Pharmacol, Peoples Hosp Affiliated 1, Shanghai 200030, Peoples R China; [Peng, Zhi-Hai] Shanghai Jiao Tong Univ, Dept Surg, Peoples Hosp Affiliated 1, Shanghai 200030, Peoples R China; [Peng, Zhi-Hai] Shanghai Jiao Tong Univ, Shanghai Organ Transplantat Clin Med Ctr, Peoples Hosp Affiliated 1, Shanghai 200030, Peoples R China; [Rui, Jian-Zhong] Jinling Hosp, Dept Clin Pharmacol, Nanjing, Peoples R China"	"Liu, GL (corresponding author), Shanghai Jiao Tong Univ, Dept Pharmacol, Peoples Hosp Affiliated 1, 100 Haining Rd, Shanghai 200030, Peoples R China."	"liugaolin@gmail.com"	"NA"	"NA"	"Foundation of Shanghai Clinical Center [QY040101]"	"This work was supported by the Foundation of Shanghai Clinical Center (No. QY040101)."	53	12	13	0	3	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"DEC"	2010	32	6	715	722	"NA"	"10.1097/FTD.0b013e3181fb6ce3"	8	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"678TI"	"WOS:000284103400008"	21068646	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Conil, JM; Georges, B; Ruiz, S; Rival, T; Seguin, T; Cougot, P; Fourcade, O; Pharmd, GH; Saivin, S"	"Conil, Jean-Marie; Georges, Bernard; Ruiz, Stephanie; Rival, Thomas; Seguin, Thierry; Cougot, Pierre; Fourcade, Olivier; Pharmd, Georges Houin; Saivin, Sylvie"	"NA"	"A"	"Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"ICU patients; population pharmacokinetics; tobramycin"	"ALTERED AMINOGLYCOSIDE PHARMACOKINETICS; TARGET CONCENTRATION INTERVENTION; CRITICALLY-ILL PATIENTS; CREATININE CLEARANCE; DOSING REGIMEN; BURN PATIENTS; AMIKACIN; VARIABILITY; THERAPY; PHARMACODYNAMICS"	"center dot It is well known that tobramycin given as an once daily dose according to the usual recommendations needs therapeutic drug monitoring by measurement of peak and trough concentrations. In the literature, there are only few published studies on the population pharmacokinetics of once daily tobramycin in critically ill patients. Glomerular filtration rate and bodyweight were identified as covariates contributing to the inter-individual variability in the disposition of aminoglycosides. The study, by Peris-Marti et al. [24], only evaluated the pharmacodynamic effectiveness of a 4 mg kg-1 dose of tobramycin given once daily in critically ill patients. The authors concluded with a simulation showing that for a theoretical MIC of 1 or 2 mg l-1, a 7 mg kg-1 dose was required. WHAT THIS STUDY ADDS? center dot Our results confirm the high variability of tobramycin disposition in intensive care patients and consequently the possible lack of effectiveness. center dot By using a population pharmacokinetic approach, two explicative covariates (height and Cockcroft creatinine clearance) added to a two-compartment model with proportional error, explained much of the inter-individual variability of tobramycin disposition in the critically ill patient population. center dot In a median ICU patient, simulations were performed at various dosage regimens and peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Drug monitoring is required to manage efficacy and toxicity. AIM The aim of this study was to evaluate the disposition of tobramycin (TOB) in critically ill patients (ICU) by a population pharmacokinetic approach, to determine the covariates involved, and to simulate tobramycin dosage regimens. METHODS Forty-nine adult ICU patients received TOB (5 mg kg-1) once daily. NonMem modelling was performed on 32 patients. The 17 other patients were used for the qualification process by normalized prediction distribution error. Then Monte Carlo simulations (MCS) were performed. RESULTS A two-compartment model with a proportional error best fitted the data. TOB total clearance (CLTOB) was significantly correlated with Cockcroft creatinine clearance (COCK) and height. TOB clearance was 4.8 � 1.9 l h-1 (range 1.22-8.95), the volume of distribution of the central compartment was 24.7 � 3.7 l (range 17.34-32.83) and that of the peripheral compartment and the inter-compartmental clearance were 30.6 l and 4.74 l h-1, respectively. Only 29% of the patients presented a target AUC between 80 and 125 mg l-1 h and 61% were lower than 80 mg l-1 h. After considering COCK and height, MCS showed that only 50% of the population could achieve the target AUC for the 375 and 400 mg dosages. CONCLUSION Even after taking into account COCK and height, for strains with an MIC < 1 mg l-1, MCS doses evidenced that peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Combination therapy in addition to drug monitoring are required to manage efficacy and toxicity."	"[Saivin, Sylvie] Inst Federatif Biol, Lab Pharmacocinet & Toxicol Clin, TSA 40031, F-31059 Toulouse 9, France; [Conil, Jean-Marie; Georges, Bernard; Fourcade, Olivier; Saivin, Sylvie] Univ Toulouse 3, Inst Federatif Rech Biomed Toulouse, IFR 150, GRCB 48, F-31062 Toulouse 9, France; [Conil, Jean-Marie; Georges, Bernard; Ruiz, Stephanie; Rival, Thomas; Seguin, Thierry; Cougot, Pierre; Fourcade, Olivier] Hop Rangueil, F-31059 Toulouse 9, France"	"Saivin, S (corresponding author), Inst Federatif Biol, Lab Pharmacocinet & Toxicol Clin, TSA 40031, 330 Ave Grande Bretagne, F-31059 Toulouse 9, France."	"saivin.s@chu-toulouse.fr"	"NA"	"NA"	"NA"	"NA"	61	26	27	0	11	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JAN"	2011	71	1	61	71	"NA"	"10.1111/j.1365-2125.2010.03793.x"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"692KR"	"WOS:000285152200009"	21143502	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Krekels, EHJ; DeJongh, J; van Lingen, RA; van der Marel, CD; Choonara, I; Lynn, AM; Danhof, M; Tibboel, D; Knibbe, CAJ"	"Krekels, Elke H. J.; DeJongh, Joost; van Lingen, Richard A.; van der Marel, Caroline D.; Choonara, Imti; Lynn, Anne M.; Danhof, Meindert; Tibboel, Dick; Knibbe, Catherijne A. J."	"NA"	"A"	"Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"EXTRACORPOREAL MEMBRANE-OXYGENATION; RANDOMIZED CONTROLLED-TRIAL; NEWBORN-INFANTS; POSTOPERATIVE INFANTS; INTRAVENOUS MORPHINE; MAJOR SURGERY; CLEARANCE; PREMATURE; INFUSION; AGE"	"Background and Objective: Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model. Methods: Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model. Results: The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH. Conclusion: The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated."	"[Krekels, Elke H. J.; DeJongh, Joost; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Amsterdam Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Krekels, Elke H. J.; van der Marel, Caroline D.; Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [DeJongh, Joost] LAP&P Consultants BV, Leiden, Netherlands; [van Lingen, Richard A.] Isala Clin, Div Neonatol, Princess Amalia Dept Pediat, Zwolle, Netherlands; [Choonara, Imti] Univ Nottingham, Derbyshire Childrens Hosp, Acad Div Child Hlth, Derby, England; [Lynn, Anne M.] Univ Washington, Sch Med, Seattle Childrens Hosp, Dept Anesthesiol & Pain Med, Seattle, WA USA; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Choonara, Imti/I-3559-2019"	"Choonara, Imti/0000-0002-3069-6323; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Dutch Top Institute [D2-104]; Dutch Organisation for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO)"	"We would like to thank Dr Monique van Dijk for her valuable input on this project. This study was performed within the framework of the Dutch Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organisation for Scientific Research (NWO). All authors declare no conflict of interest."	40	38	40	0	7	"ADIS INT LTD"	"AUCKLAND"	"41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND"	"0312-5963"	"NA"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2011	50	1	51	63	"NA"	"10.2165/11536750-000000000-00000"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"704IR"	"WOS:000286045300004"	21142267	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"van den Broek, MPH; Huitema, ADR; van Hasselt, JGC; Groenendaal, F; Toet, MC; Egberts, TCG; de Vries, LS; Rademaker, CMA"	"van den Broek, Marcel P. H.; Huitema, Alwin D. R.; van Hasselt, Johan G. C.; Groenendaal, Floris; Toet, Mona C.; Egberts, Toine C. G.; de Vries, Linda S.; Rademaker, Catharine M. A."	"NA"	"A"	"Lidocaine (Lignocaine) Dosing Regimen Based upon a Population Pharmacokinetic Model for Preterm and Term Neonates with Seizures"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"INTRAVENOUS LIDOCAINE; DRUG DISPOSITION; NEWBORN-INFANTS; PHARMACODYNAMICS; INFUSION; ONTOGENY; BRAIN; METABOLISM; OVERDOSAGE; GRAPHICS"	"Background and Objective: The application of lidocaine (lignocaine) as an anticonvulsant in neonates originated more than 40 years ago in Scandinavia. Lidocaine has been shown to be an effective anticonvulsant for the treatment of neonatal seizures that persist in spite of first-line anticonvulsant therapy. However, lidocaine toxicity, mainly in the form of cardiac arrhythmias, can be life threatening. Therapeutic drug monitoring can be useful to prevent toxicity. In a previous study, a dosing regimen was developed for term neonates, but it was not evaluated for preterm neonates. Extrapolation of the previously developed dosing regimen to premature neonates without accounting for differences in pharmacokinetics because of immaturity of phase I metabolism and body fat/water ratio may result in serious toxicity or therapy failure. The objective of this study was to develop an optimized dosing regimen for lidocaine in preterm as well as term neonates, using population pharmacokinetic modelling and simulation. Methods: The requirements for this dosing regimen were simplicity of implementation, equal initial doses for all weight categories and avoidance of plasma concentrations >9 mg/L. After lidocaine administration, blood samples were collected from an arterial line from a total of 46 preterm and term neonates with convulsion, within 10 days after birth. Lidocaine concentrations were measured in plasma using a fluorescence polarization immunoassay. Population pharmacokinetic modelling started with assessment of two important aspects of paediatric pharmacokinetics: relation to body size and the effects of maturation. Results: In the studied neonatal population (term and preterm neonates with gestational ages up to 10 days), gestational age and bodyweight were closely related. Therefore, the effects of allometry and maturation on lidocaine pharmacokinetics could not be described independently and were described by a combined power estimate of bodyweight on clearance and volume of distribution. Based on this pharmacokinetic model, a dosing strategy for lidocaine for neonatal seizure control was developed, which allows rapid and safe administration of lidocaine in this population. When prospective validation confirms our model, routinely performed therapeutic drug monitoring should no longer be necessary and would only be advised in cases of (suspected) clinical symptoms of over- or underdosing. Conclusion: A lidocaine dosing regimen for seizure control in preterm and term neonates has been developed using population pharmacokinetic modelling and simulation. Allometry and maturation exponents were combined into one exponent for each pharmacokinetic parameter and could not be described independently. Based on this model, this regimen allows rapid and safe administration of lidocaine in this population."	"[van den Broek, Marcel P. H.; Egberts, Toine C. G.; Rademaker, Catharine M. A.] Univ Med Ctr Utrecht, Dept Clin Pharm, Div Lab Med & Pharm, NL-3508 GA Utrecht, Netherlands; [Huitema, Alwin D. R.; van Hasselt, Johan G. C.] Slotervaart Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands; [Groenendaal, Floris; Toet, Mona C.; de Vries, Linda S.] Wilhelmina Childrens Hosp, Univ Med Ctr Utrecht, Dept Neonatol, Utrecht, Netherlands; [Egberts, Toine C. G.] Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands"	"van den Broek, MPH (corresponding author), Univ Med Ctr Utrecht, Dept Clin Pharm, Div Lab Med & Pharm, POB 85500, NL-3508 GA Utrecht, Netherlands."	"m.p.h.vandenbroek@umcutrecht.nl"	"Egberts, Toine/K-4579-2019; Groenendaal, Floris/P-6872-2019; van Hasselt, Coen/H-5593-2019; Egberts, Toine/A-6625-2012"	"Egberts, Toine/0000-0003-1758-7779; Groenendaal, Floris/0000-0002-9284-1637; Egberts, Toine/0000-0003-1758-7779"	"NA"	"NA"	42	24	24	0	4	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2011	50	7	461	469	"NA"	"10.2165/11589160-000000000-00000"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"793AM"	"WOS:000292792800004"	21651313	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kumar, VVP; Duffull, SB"	"Kumar, Venkata V. Pavan; Duffull, Stephen B."	"NA"	"M"	"Evaluation of graphical diagnostics for assessing goodness of fit of logistic regression models"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Logistic regression; Model diagnostics; Random binning; Simplified Bayes marginal model plots"	"NA"	"The aim of the current work was to evaluate graphical diagnostics for assessment of the fit of logistic regression models. Assessment of goodness of fit of a model to the data set is essential to ensure the model provides an acceptable description of the binary variables seen. For logistic regression the most common diagnostic used for this purpose is binning the data and comparing the empirical probability of the occurrence of a dependent variable with the model predicted probability against the mean covariate value in the bin. Although intuitively appealing this method, which we term simple binning, may not have consistent properties for diagnosing model problems. In this report we describe and evaluate two different diagnostic procedures, random binning and simplified Bayes marginal model plots. These procedures were assessed via simulation under three different designs. Design 1: studies which were balanced on binary variables and a continuous covariate. Design 2: studies that were balanced on binary variables but unbalanced on the continuous covariate. Design 3: studies that were unbalanced on both the binary variables and the covariate. Each simulated study consisted of 500 individuals. Thirty studies were simulated. The covariate of interest was dose which could range from 0 to 20 units. The data were simulated with the dose being related to the outcome according to an E (max) model on the logit scale. A logit E (max) model (correct model) and a logit linear model (wrong model) were fitted to all data sets. The performance of the above diagnostics, in addition to simple binning, was compared. For all designs the proposed diagnostics performed at least as well and in many instances better than simple binning. In case of design 1 random binning and simple binning are identical. In the case of designs 2 and 3 random binning and simplified Bayes marginal model plots were superior in assessing the model fit when compared to simple binning. For the examples tested, both random binning and simplified Bayesian marginal model plots performed acceptably."	"[Kumar, Venkata V. Pavan; Duffull, Stephen B.] Univ Otago, Sch Pharm, Dunedin, New Zealand"	"Kumar, VVP (corresponding author), Univ Otago, Sch Pharm, Dunedin, New Zealand."	"pavan.kumar@otago.ac.nz"	"NA"	"Duffull, Stephen/0000-0002-6545-9408"	"NA"	"NA"	19	6	6	0	6	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"APR"	2011	38	2	205	222	"NA"	"10.1007/s10928-010-9189-6"	18	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"733LC"	"WOS:000288263200003"	21153868	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Krekels, EHJ; van Hasselt, JGC; Tibboel, D; Danhof, M; Knibbe, CAJ"	"Krekels, Elke H. J.; van Hasselt, Johan G. C.; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Systematic Evaluation of the Descriptive and Predictive Performance of Paediatric Morphine Population Models"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"model evaluation; morphine; paediatric pharmacokinetic population modeling"	"DRUG CLEARANCE; MAJOR SURGERY; PHARMACOKINETICS; INFANTS; CHILDREN; PHARMACODYNAMICS; PRETERM; SIZE"	"A framework for the evaluation of paediatric population models is proposed and applied to two different paediatric population pharmacokinetic models for morphine. One covariate model was based on a systematic covariate analysis, the other on fixed allometric scaling principles. The six evaluation criteria in the framework were 1) number of parameters and condition number, 2) numerical diagnostics, 3) prediction-based diagnostics, 4) eta-shrinkage, 5) simulation-based diagnostics, 6) diagnostics of individual and population parameter estimates versus covariates, including measurements of bias and precision of the population values compared to the observed individual values. The framework entails both an internal and external model evaluation procedure. The application of the framework to the two models resulted in the detection of overparameterization and misleading diagnostics based on individual predictions caused by high shrinkage. The diagnostic of individual and population parameter estimates versus covariates proved to be highly informative in assessing obtained covariate relationships. Based on the framework, the systematic covariate model proved to be superior over the fixed allometric model in terms of predictive performance. The proposed framework is suitable for the evaluation of paediatric (covariate) models and should be applied to corroborate the descriptive and predictive properties of these models."	"[Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands; [Krekels, Elke H. J.; van Hasselt, Johan G. C.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Amsterdam Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Krekels, Elke H. J.; Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"van Hasselt, Coen/H-5593-2019"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NA"	"NA"	36	48	48	0	3	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"APR"	2011	28	4	797	811	"NA"	"10.1007/s11095-010-0333-1"	15	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"740OW"	"WOS:000288805300012"	21153913	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Urien, S; Firtion, G; Anderson, ST; Hirt, D; Solas, C; Peytavin, G; Faye, A; Thuret, I; Leprevost, M; Giraud, C; Lyall, H; Khoo, S; Blanche, S; Treluyer, JM"	"Urien, Saik; Firtion, Ghislaine; Anderson, Suzanne T.; Hirt, Deborah; Solas, Caroline; Peytavin, Gilles; Faye, Albert; Thuret, Isabelle; Leprevost, Marthe; Giraud, Carole; Lyall, Hermione; Khoo, Saye; Blanche, Stephane; Treluyer, Jean-Marc"	"NA"	"A"	"Lopinavir/ritonavir population pharmacokinetics in neonates and infants"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"children; lopinavir; ritonavir; neonates; population pharmacokinetics"	"LOPINAVIR; CHILDREN; MODELS; BIRTH; AGE"	"AIMS Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg. METHODS Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach. RESULTS A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h-1 70 kg-1 and 91.7 l 70 kg-1. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks. CONCLUSIONS Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h-1, 80 mg 12 h-1 and 120 mg 12 h-1 in the 1-2 kg, 2-6 kg and 6-10 kg group, respectively."	"[Urien, Saik; Hirt, Deborah; Giraud, Carole; Blanche, Stephane; Treluyer, Jean-Marc] Univ Paris 05, EA 3620, Paris, France; [Urien, Saik; Hirt, Deborah; Giraud, Carole; Treluyer, Jean-Marc] Grp Hosp Cochi St Vincent de Paul, AP HP, Unite Rech Clin Paris Ctr Descartes, Paris, France; [Urien, Saik; Hirt, Deborah; Giraud, Carole; Blanche, Stephane; Treluyer, Jean-Marc] INSERM, CIC 0901, Paris, France; [Anderson, Suzanne T.] Brighton & Sussex Med Sch, Dept Med, Falmer BN1 9PS, Sussex, England; [Leprevost, Marthe] NW London Hosp NHS Trust, Northwick Pk Hosp, London, Middx, England; [Solas, Caroline] Hop La Timone, Lab Pharmacocinet, Marseille, France; [Peytavin, Gilles] Hop Bichat Claude Bernard, AP HP, Serv Pharm Clin, F-75877 Paris 18, France; [Faye, Albert] Hop Robert Debre, AP HP, F-75019 Paris, France; [Anderson, Suzanne T.; Lyall, Hermione] Imperial Coll Healthcare NHS Trust, London, England; [Khoo, Saye] Univ Liverpool, Dept Pharmacol, Liverpool L69 3BX, Merseyside, England; [Blanche, Stephane] Hop Necker Enfants Malad, AP HP, Paris, France; [Treluyer, Jean-Marc] Grp Hosp Cochin St Vincent de Paul, AP HP, Pharmacol Clin, Paris, France"	"Urien, S (corresponding author), Hop Tarnier, Grp Hosp Cochin St Vincent de Paul, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"saik.urien@svp.aphp.fr"	"treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013"	"NA"	"AbbottAbbott Laboratories; Boehringer-IngelheimBoehringer Ingelheim; Bristol-Myers-SquibbBristol-Myers Squibb; Gilead SciencesGilead Sciences; VuV Healthcare; JanssenJohnson & Johnson USAJanssen Biotech Inc; MerckMerck & Company; RocheRoche Holding; Abbott LaboratoriesAbbott Laboratories"	"GP has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, VuV Healthcare, Janssen, Merck and Roche. The hospital institution of SU, CG, DH and J-MT, Cochin Hospital, received a grant of 5000 euros from Abbott for research funding. There are no other competing interests to declare.; The authors thank Abbott Laboratories, which partially supported this study."	9	22	22	0	3	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUN"	2011	71	6	956	960	"NA"	"10.1111/j.1365-2125.2011.03926.x"	5	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"762CI"	"WOS:000290449500020"	21564164	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Bergstrand, M; Hooker, AC; Wallin, JE; Karlsson, MO"	"Bergstrand, Martin; Hooker, Andrew C.; Wallin, Johan E.; Karlsson, Mats O."	"NA"	"M"	"Prediction-Corrected Visual Predictive Checks for Diagnosing Nonlinear Mixed-Effects Models"	"AAPS JOURNAL"	"English"	"Article"	"mixed-effects modeling; model diagnostics; pcVPC; prediction correction; VPC"	"NONMEM; PSN"	"Informative diagnostic tools are vital to the development of useful mixed-effects models. The Visual Predictive Check (VPC) is a popular tool for evaluating the performance of population PK and PKPD models. Ideally, a VPC will diagnose both the fixed and random effects in a mixed-effects model. In many cases, this can be done by comparing different percentiles of the observed data to percentiles of simulated data, generally grouped together within bins of an independent variable. However, the diagnostic value of a VPC can be hampered by binning across a large variability in dose and/or influential covariates. VPCs can also be misleading if applied to data following adaptive designs such as dose adjustments. The prediction-corrected VPC (pcVPC) offers a solution to these problems while retaining the visual interpretation of the traditional VPC. In a pcVPC, the variability coming from binning across independent variables is removed by normalizing the observed and simulated dependent variable based on the typical population prediction for the median independent variable in the bin. The principal benefit with the pcVPC has been explored by application to both simulated and real examples of PK and PKPD models. The investigated examples demonstrate that pcVPCs have an enhanced ability to diagnose model misspecification especially with respect to random effects models in a range of situations. The pcVPC was in contrast to traditional VPCs shown to be readily applicable to data from studies with a priori and/or a posteriori dose adaptations."	"[Bergstrand, Martin; Hooker, Andrew C.; Wallin, Johan E.; Karlsson, Mats O.] Uppsala Univ, Dept Pharmaceut Biosci, S-75124 Uppsala, Sweden; [Wallin, Johan E.] Lilly PKPD&TS, Windlesham, Surrey, England"	"Bergstrand, M (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, POB 591, S-75124 Uppsala, Sweden."	"martin.bergstrand@farmbio.uu.se"	"Hooker, Andrew/A-7794-2015"	"Hooker, Andrew/0000-0002-2676-5912; Bergstrand, Martin/0000-0002-0295-1227"	"NA"	"NA"	27	638	640	0	26	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JUN"	2011	13	2	143	151	"NA"	"10.1208/s12248-011-9255-z"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"758LG"	"WOS:000290165700001"	21302010	"Green Published"	"Y"	"N"	"2020-10-01"
"J"	"Laffont, CM; Concordet, D"	"Laffont, Celine Marielle; Concordet, Didier"	"NA"	"M"	"A New Exact Test for the Evaluation of Population Pharmacokinetic and/or Pharmacodynamic Models Using Random Projections"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"GUD; model evaluation or diagnostics; nonlinear mixed effects models; normalised prediction distribution errors NPDE; weighted residuals"	"DRUG DEVELOPMENT; ERROR"	"Within-subject dependency of observations has a strong impact on the evaluation of population pharmacokinetic (PK) and/or pharmacodynamic (PD) models. To our knowledge, none of the current model evaluation tools correctly address this issue. We present a new method with a global test and easy diagnostic plot which relies on the use of a random projection technique that allows the analysis of dependent data. For each subject, the vector of standardised residuals is calculated and projected onto many random directions drawn uniformly from the unit sphere. Our test compares the empirical distribution of projections with their distribution under the model. Simulation studies assess the level of the test and compare its performance with common metrics including normalised prediction distribution errors and different types of weighted residuals. An application to real data is performed. In contrast to other evaluated methods, our test shows adequate level for all models and designs investigated, which confirms its good theoretical properties. The weakness of other methods is demonstrated and discussed. This new test appears promising and could be used in combination with other tools to drive model evaluation in population PK/PD analyses."	"[Laffont, Celine Marielle] Ecole Natl Vet Toulouse, Lab Biostat, F-31076 Toulouse 03, France; [Laffont, Celine Marielle; Concordet, Didier] INRA, UMR 1331, F-31027 Toulouse, France; [Laffont, Celine Marielle; Concordet, Didier] Univ Toulouse, INPT, ENVT, UPS,EIP, F-31076 Toulouse, France"	"Laffont, CM (corresponding author), Ecole Natl Vet Toulouse, Lab Biostat, 23 Chemin Capelles,BP 87614, F-31076 Toulouse 03, France."	"c.rousset@envt.fr"	"Concordet, Didier/AAT-1120-2020"	"Concordet, Didier/0000-0003-3916-577X"	"NA"	"NA"	25	2	2	0	0	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"NA"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"AUG"	2011	28	8	1948	1962	"NA"	"10.1007/s11095-011-0422-9"	15	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"789ME"	"WOS:000292518800014"	21491150	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Khachman, D; Conil, JM; Georges, B; Saivin, S; Houin, G; Toutain, PL; Laffont, CM"	"Khachman, Dalia; Conil, Jean-Marie; Georges, Bernard; Saivin, Sylvie; Houin, Georges; Toutain, Pierre-Louis; Laffont, Celine M."	"NA"	"A"	"Optimizing ciprofloxacin dosing in intensive care unit patients through the use of population pharmacokinetic-pharmacodynamic analysis and Monte Carlo simulations"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"intensive care unit patients; mutant selection window; pharmacokinetic-pharmacodynamic target attainment rate"	"MUTANT PREVENTION CONCENTRATION; CRITICALLY-ILL PATIENTS; VITRO DYNAMIC-MODEL; PSEUDOMONAS-AERUGINOSA; ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; SELECTION WINDOW; INTRAVENOUS CIPROFLOXACIN; STREPTOCOCCUS-PNEUMONIAE; STAPHYLOCOCCUS-AUREUS"	"Objectives: To explore different ciprofloxacin dosage regimens for the treatment of intensive care unit (ICU) patients with respect to clinical outcome and the development of bacterial resistance for the major Gram-negative pathogens. Methods: A population pharmacokinetic model was first developed on ciprofloxacin serum concentrations obtained in 102 ICU patients. Then, based on this model, pharmacokinetic-pharmacodynamic Monte Carlo simulations (MCSs) were carried out to explore the appropriateness of different ciprofloxacin dosage regimens in ICU patients. The defined targets were free AUC(24)/MIC >= 90 h (as a predictor of clinical outcome) and T(MSW) <= 20% (as a predictor of selecting resistance), where T(MSW) is the time spent within the mutant selection window over 24 h. Two simulation trials were conducted: Trial 1 took into account the whole MIC distribution for each causative pathogen in line with empirical antibiotherapy; Trial 2 used MIC breakpoints given by the Antibiogram Committee of the French Microbiology Society in order to treat the 'worst-case' scenario. Results: Trial 1 showed that for Pseudomonas aeruginosa and Acinetobacter baumannii, the common dosage regimens of 400 mg twice or three times a day did not achieve the desired target attainment rates (TARs) with respect to T(MSW), while suboptimal TARs were found for AUC(24)/MIC. Trial 2 showed that <= 18% of patients reached the target of T(MSW) <= 20% for MIC breakpoints of 0.5 and 1 mg/L, regardless of the administered dose. Conclusions: Based on the mutant selection window concept, our simulations truly question the use of ciprofloxacin for the treatment of P. aeruginosa and A. baumannii infections in ICU patients due to the potential for developing resistance."	"[Laffont, Celine M.] Univ Toulouse 1, ENVT, Lab Biostat, INPT,UPS,EIP, F-31076 Toulouse 03, France; [Khachman, Dalia; Toutain, Pierre-Louis; Laffont, Celine M.] INRA, UMR 1331, F-31027 Toulouse, France; [Khachman, Dalia; Saivin, Sylvie; Houin, Georges] Hop Purpan, Lab Pharmacocinet & Toxicol Clin, Inst Federatif Biol, TSA 40031, F-31059 Toulouse 9, France; [Conil, Jean-Marie; Georges, Bernard] Hop Rangueil, Pole Anesthesie Reanimat, TSA 50032, F-31059 Toulouse 9, France; [Conil, Jean-Marie; Georges, Bernard; Saivin, Sylvie] Univ Toulouse 3, GRCB 48, IFR Inst Federatif Rech Biomed Toulouse 150, Fac Med,Inst Louis Bugnard IFR 31, F-31062 Toulouse 9, France"	"Laffont, CM (corresponding author), Univ Toulouse 1, ENVT, Lab Biostat, INPT,UPS,EIP, 23 Chemin Capelles,BP 87614, F-31076 Toulouse 03, France."	"c.rousset@envt.fr"	"Toutain, Pierre Louis/G-4540-2011"	"Toutain, Pierre Louis/0000-0002-8846-8892"	"Lebanese National Council for Scientific Research (Beirut, Lebanon)"	"The pharmacokinetic study was supported by internal funding. D. K., who performed the population pharmacokinetic analysis and Monte Carlo simulations, was supported by a doctoral scholarship from the Lebanese National Council for Scientific Research (Beirut, Lebanon)."	66	28	31	0	6	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"NA"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"AUG"	2011	66	8	1798	1809	"NA"	"10.1093/jac/dkr220"	12	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"791VW"	"WOS:000292696400019"	21653603	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Bertrand, J; Laffont, CM; Mentre, F; Chenel, M; Comets, E"	"Bertrand, Julie; Laffont, Celine M.; Mentre, France; Chenel, Marylore; Comets, Emmanuelle"	"NA"	"A"	"Development of a Complex Parent-Metabolite Joint Population Pharmacokinetic Model"	"AAPS JOURNAL"	"English"	"Article"	"back-transformation mechanism; estimation algorithms; first-pass metabolism; genetic covariate; nonlinear mixed effects modeling"	"MIXED EFFECTS MODELS; RISPERIDONE; CYP2D6; AGENT"	"This study aimed to develop a joint population pharmacokinetic model for an antipsychotic agent in development (S33138) and its active metabolite (S35424) produced by reversible metabolism. Because such a model leads to identifiability problems and numerical difficulties, the model building was performed using the FOCE-I and the Stochastic Approximation Expectation Maximization (SAEM) estimation algorithms in NONMEM and MONOLIX, respectively. Four different structural models were compared based on Bayesian information criteria. Models were first written as ordinary differential equations systems and then in closed form (CF) to facilitate further analyses. The impact of polymorphisms on genes coding for the CYP2C19 and CYP2D6 enzymes, respectively involved in the parent drug and the metabolite elimination were investigated using permutation Wald test. The parent drug and metabolite plasma concentrations of 101 patients were analyzed on two occasions after 4 and 8 weeks of treatment at 1, 3, 6, and 24 h following daily oral administration. All configurations led to a two compartment model with back-transformation of the metabolite into the parent drug and a first-pass effect. The elimination clearance of the metabolite through other processes than back-transformation was decreased by 35% [9-53%] in CYP2D6 poor metabolizer. Permutation tests were performed to ensure the robustness of the analysis, using SAEM and CF. In conclusion, we developed a complex joint pharmacokinetic model adequately predicting the impact of CYP2D6 polymorphisms on the parent drug and its metabolite concentrations through the back-transformation mechanism."	"[Bertrand, Julie; Mentre, France; Comets, Emmanuelle] Univ Paris Diderot, INSERM, UMR 738, F-75018 Paris, France; [Laffont, Celine M.] ENVT, Physiol & Toxicol Expt INRA, UMR181, Toulouse, France; [Chenel, Marylore] Inst Rech Int Servier, F-92415 Courbevoie, France"	"Bertrand, J (corresponding author), Univ Paris Diderot, INSERM, UMR 738, 16 Rue Henri Huchard, F-75018 Paris, France."	"julie.bertrand@inserm.fr"	"Bertrand, julie/A-6989-2017; Comets, Emmanuelle/C-9328-2017"	"Bertrand, julie/0000-0002-6568-1041;"	"Institut de Recherches Internationales Servier (France)"	"The authors would like to thank Prof. N. Holford for his clever inputs on the choice of the parameter's notation to facilitate the understanding of the different structural models. We would also like to thank the MONOLIX development team for making the MLXTRAN tool available for this work. During this work, Julie Bertrand was supported by a grant from the Institut de Recherches Internationales Servier (France)."	34	14	14	0	3	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"SEP"	2011	13	3	390	404	"NA"	"10.1208/s12248-011-9282-9"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"798ES"	"WOS:000293186000010"	21618059	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Cella, M; Zhao, W; Jacqz-Aigrain, E; Burger, D; Danhof, M; Della Pasqua, O"	"Cella, Massimo; Zhao, Wei; Jacqz-Aigrain, Evelyne; Burger, David; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Paediatric drug development: are population models predictive of pharmacokinetics across paediatric populations?"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"dose adjustment; model-based research; paediatric drug development; paediatric drug prescription; pharmacokinetic bridging"	"SELECTION; CHILDREN; DOSAGE; COMBINATION; INFECTION; CLEARANCE; SIZE"	"AIMS To assess the predictive value of a model-based approach for dose selection across paediatric populations in early clinical drug development. METHODS Abacavir was selected as a paradigm compound using data across a wide age range. Abacavir pharmacokinetics (PK) in children were analysed separately from infants and toddlers. Two independent models were obtained, and systemic exposure (AUC) was then simulated across populations based on the estimates from each model. Drug exposures in infants and toddlers were predicted using pharmacokinetic parameter distributions obtained from children, and the other way around. RESULTS The pharmacokinetic models (a two-compartment PK model for infants and toddlers and a one compartment PK model for children) accurately described the exposure in the population from which they were built. However, neither model predicted exposure in a different population: in infants, the median AUC (95%-CI) was estimated at 7.03 (6.72, 7.48) mu g ml(-1) h, whilst it was predicted at 5.75 (4.82, 6.26) mu g ml(-1) h; in children, the estimated median AUC was 6.96 (5.85, 7.91) mu g ml(-1) h, whilst the predicted value was 6.45 (5.80, 7.01) mu g ml(-1) h. CONCLUSIONS These findings suggest that the assumption of an identical (linear or nonlinear) correlation between pharmacokinetic parameters and demographic factors may not hold true across age groups. Whilst the use of modelling enables accurate characterization of pharmacokinetic properties, extrapolations based on such parameter estimates may have limited value due to differences in the impact of developmental growth across populations."	"[Cella, Massimo; Danhof, Meindert; Della Pasqua, Oscar] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Pharmacol, NL-2300 RA Leiden, Netherlands; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Hop Robert Debre, Dept Paediat Pharmacol & Pharmacogenet, INSERM, Clin Invest Ctr CIC 9202, F-75019 Paris, France; [Burger, David] Radboud Univ Nijmegen Med Ctr, Dept Clin Pharm, Nijmegen, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol & Discovery Med, Stockley Pk, Middx, England"	"Della Pasqua, O (corresponding author), Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands."	"odp72514@gsk.com"	"Cella, Massimo/K-8375-2019; Burger, David/C-9929-2013; Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"GlaxoSmithKlineGlaxoSmithKline; European Commission (EC)European Commission Joint Research CentreEuropean Community (EC) [LSHP-CT-2006-018865, QLK2-2000-00150]; PENTA LABNET (EC)European Commission Joint Research Centre [201057]; GlaxoSmithKline, UKGlaxoSmithKline"	"DB has received fees for speaking, funds for research and fees for consulting from GlaxoSmithKline. There are no other competing interests to declare.; PENTA is a Co-ordinated Action of the European Commission (EC), supported by the Sixth Framework contract LSHP-CT-2006-018865 and Fifth Framework Program contract QLK2-2000-00150. PENTA activities are also supported by the PENTA Foundation and PENTA LABNET (EC Seventh Framework contract 201057). Financial support for PENTA 13 and 15 was also received from GlaxoSmithKline, UK."	39	32	35	1	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2011	72	3	454	464	"NA"	"10.1111/j.1365-2125.2011.03992.x"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"804LD"	"WOS:000293654400010"	21501213	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Foissac, F; Urien, S; Hirt, D; Frange, P; Chaix, ML; Treluyer, JM; Blanche, S"	"Foissac, Frantz; Urien, Saik; Hirt, Deborah; Frange, Pierre; Chaix, Marie-Laure; Treluyer, Jean-Marc; Blanche, Stephane"	"NA"	"A"	"Pharmacokinetics and Virological Efficacy after Switch to Once-Daily Lopinavir-Ritonavir in Treatment-Experienced HIV-1-Infected Children"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"TWICE-DAILY LOPINAVIR/RITONAVIR; REGIMEN; SAFETY"	"Lopinavir-ritonavir (LPV/r) is a protease inhibitor that is used twice daily (BID) in the treatment of HIV infection in children. In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4() T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4() T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (C-trough) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P = 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being < 50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4() T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower C-trough values and resulted in lower levels of virological control in these antiretroviral-experienced children."	"[Foissac, Frantz; Urien, Saik; Hirt, Deborah; Frange, Pierre; Chaix, Marie-Laure; Treluyer, Jean-Marc; Blanche, Stephane] Univ Paris 05, EA 3620, Paris, France; [Foissac, Frantz; Urien, Saik; Hirt, Deborah; Treluyer, Jean-Marc] Assistance Publ Hop Paris, Unite Rech Clin, Paris Ctr, Paris, France; [Urien, Saik; Hirt, Deborah; Treluyer, Jean-Marc] INSERM, CIC 0901, Paris, France; [Treluyer, Jean-Marc] Hop St Vincent de Paul, Pharmacol Lab, F-75674 Paris, France; [Frange, Pierre; Blanche, Stephane] Hop Necker Enfants Malad, APHP, Unite Immunol Hematotol, Paris, France; [Chaix, Marie-Laure] Hop Necker Enfants Malad, APHP, Lab Virol, Paris, France"	"Foissac, F (corresponding author), Hop Tarnier, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"frantz.foissac@cch.aphp.fr"	"Urien, Saik/G-3240-2013; treluyer, Jean-Marc/F-8036-2010"	"NA"	"Pediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET)"	"We acknowledge the Pediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET) for their financial support."	23	15	15	0	1	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"SEP"	2011	55	9	4320	4325	"NA"	"10.1128/AAC.00166-11"	6	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"808CW"	"WOS:000293953900051"	21746952	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Bouazza, N; Urien, S; Hirt, D; Frange, P; Rey, E; Benaboud, S; Foissac, F; Blanche, S; Treluyer, JM"	"Bouazza, Naim; Urien, Saik; Hirt, Deborah; Frange, Pierre; Rey, Elisabeth; Benaboud, Sihem; Foissac, Frantz; Blanche, Stephane; Treluyer, Jean-Marc"	"NA"	"A"	"Population Pharmacokinetics of Tenofovir in HIV-1-Infected Pediatric Patients"	"JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES"	"English"	"Article"	"children; HIV; population pharmacokinetics; tenofovir"	"VIRUS-INFECTED PATIENTS; DISOPROXIL FUMARATE; FANCONI-SYNDROME; RENAL-FAILURE; THERAPY; RITONAVIR; CHILDREN; ADULTS"	"Objectives: To evaluate the pharmacokinetics of tenofovir in children and the influence of covariates [body weight (BW), age, cotreatments]. The main goal was then to suggest for the first time the dose of tenofovir disoproxil fumarate (TDF) to give in children. Design/Methods: Tenofovir concentrations were monitored on a routine basis and measured in 93 children aged 5 to 18 years; 283 tenofovir plasma concentrations were used to perform a population pharmacokinetic analysis. Results: A 2-compartment model adequately described the data. A BW allometric scaling was used; and the typical population estimates (interindividual variability), standardized for 70 kg, for apparent clearance, central and peripheral volume of distribution, intercompartmental clearance, and absorption rate constant, were 59.8 L.h(-1) (0.48), 386 L (1.39), 666 L, 92.8 L.h(-1) and 0.43 h(-1), respectively. TDF clearance increased significantly with BW and decreased with lopinavir/ritonavir (LPV/r) coadministration, thus these factors were used to propose doses for children. Dosing scheme, according BW and LPV/r coadministration were simulated to produce the same 24-hr exposure as adults after 300-mg TDF dose. Conclusions: Children without LPV/r should receive: 150 mg TDF from 20 to 30 kg, 225 mg TDF from 30 to 40 kg, and the adult dosage of 300 mg TDF over 40 kg. To avoid risk of renal toxicity, TDF dose should be decreased when coadministrated with LPV/r, children should receive 150 mg TDF from 20 to 40 kg, 225 mg TDF from 40 to 55 kg, and the adult dosage of 300 mg TDF over 55 kg."	"[Bouazza, Naim; Urien, Saik; Hirt, Deborah; Benaboud, Sihem; Foissac, Frantz; Treluyer, Jean-Marc] Hop Tarnier, AP HP, Unite Rech Clin, F-75006 Paris, France; [Bouazza, Naim; Urien, Saik; Hirt, Deborah; Frange, Pierre; Benaboud, Sihem; Foissac, Frantz; Blanche, Stephane; Treluyer, Jean-Marc] Univ Paris 05, EA 3620, Sorbonne Paris Cite, France; [Urien, Saik; Treluyer, Jean-Marc] CIC 0901 Inserm, Paris, France; [Frange, Pierre; Blanche, Stephane] Hop Necker Enfants Malad, AP HP, Unite Immunol Hematol & Rhumatol Pediat, Paris, France; [Rey, Elisabeth; Treluyer, Jean-Marc] Hop Cochin St Vincent de Paul, AP HP, Serv Pharmacol Clin, Paris, France"	"Bouazza, N (corresponding author), Hop Tarnier, AP HP, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"naim.bouaz-za@cch.aphp.fr"	"Urien, Saik/G-3240-2013; treluyer, Jean-Marc/F-8036-2010"	"NA"	"Pediatric European Network Treatment AIDS Laboratory Network (PENTA-LABNET)"	"Financial support was received from the Pediatric European Network Treatment AIDS Laboratory Network (PENTA-LABNET)."	18	15	15	0	5	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA"	"1525-4135"	"1077-9450"	"NA"	"JAIDS-J ACQ IMM DEF"	"JAIDS"	"NOV 1"	2011	58	3	283	288	"NA"	"10.1097/QAI.0b013e3182302ea8"	6	"Immunology; Infectious Diseases"	"Immunology; Infectious Diseases"	"839QQ"	"WOS:000296383900019"	21857359	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Foissac, F; Blanche, S; Dollfus, C; Hirt, D; Firtion, G; Laurent, C; Treluyer, JM; Urien, S"	"Foissac, Frantz; Blanche, Stephane; Dollfus, Catherine; Hirt, Deborah; Firtion, Ghislaine; Laurent, Corinne; Treluyer, Jean-Marc; Urien, Saik"	"NA"	"A"	"Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"atazanavir; children; population pharmacokinetics; ritonavir"	"STEADY-STATE PHARMACOKINETICS; UNBOOSTED ATAZANAVIR; BOOSTED ATAZANAVIR; COMBINATION; RITONAVIR; EFFICACY; SAFETY"	"AIMS To investigate atazanavir (ATV) population pharmacokinetics in children and adolescents, establish factors that influence ATV pharmacokinetics and investigate the ATV exposure after recommended doses. METHODS Atazanavir concentrations were measured in 51 children/adolescents during a mean therapeutic monitoring follow up of 6.6 months. A total of 151 ATV plasma concentrations were obtained, and a population pharmacokinetic model was developed with NONMEM. Patients received ATV alone or boosted with ritonavir. RESULTS Atazanavir pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The effect of bodyweight was added on both apparent elimination clearance (CL/F) and volume of distribution using allometric scaling. Atazanavir CL/F was reduced by ritonavir by 45%. Tenofovir disoproxil fumarate (TDF) co-medication (300 mg) increased significantly by 25% the atazanavir/ritonavir (ATV/r) CL/F. Mean ATV/r CL/F values with or without TDF were 8.9 and 7.1 L h(-1) (70 kg)(-1), respectively. With the recommended 250/100 mg and 300/100 mg ATV/r doses, the exposure was higher than the mean adult steady-state exposure in the bodyweight range of 32-50 kg. CONCLUSIONS To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100 mg from 25 to 39 kg, 250/100 mg from 39 to 50 kg and 300/100 mg above 50 kg. When 300 mg TDF is co-administered, children should receive (ATV/r) at 250/100 mg between 35 and 39 kg, then 300/100 mg over 39 kg."	"[Foissac, Frantz; Blanche, Stephane; Hirt, Deborah; Treluyer, Jean-Marc; Urien, Saik] Univ Paris 05, EA 3620, Paris, France; [Foissac, Frantz; Hirt, Deborah; Treluyer, Jean-Marc; Urien, Saik] Hop Paris, AP HP, Clin Paris Ctr, Unite Rech, Paris, France; [Blanche, Stephane] Hop Necker Enfants Malad, AP HP, Unite Immunol Hematotol, Paris, France; [Dollfus, Catherine] Hop Trousseau, AP HP, Serv Hematol & Oncol Pediat, F-75571 Paris, France; [Firtion, Ghislaine] Grp Hosp CHU Cochin, AP HP, F-75571 Paris, France; [Laurent, Corinne] Hop Louis Mourier, AP HP, Serv Pediat & Neonatol, Paris, France; [Treluyer, Jean-Marc; Urien, Saik] INSERM, CIC 0901, Paris, France; [Treluyer, Jean-Marc] Hop St Vincent de Paul, Pharmacol Lab, F-75674 Paris, France"	"Foissac, F (corresponding author), Hop Tarnier, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"frantz.foissac@gmail.com"	"treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013"	"NA"	"BMSBristol-Myers Squibb; Paediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET)"	"CD has received fees for speaking at several conferences by BMS. There are no other competing interests to declare.; We acknowledge the Paediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET) for their financial support."	34	10	10	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2011	72	6	940	947	"NA"	"10.1111/j.1365-2125.2011.04035.x"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"846LK"	"WOS:000296901900010"	21649692	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Budha, NR; Kovar, A; Meibohm, B"	"Budha, Nageshwar R.; Kovar, Andreas; Meibohm, Bernd"	"NA"	"A"	"Comparative Performance of Cell Life Span and Cell Transit Models for Describing Erythropoietic Drug Effects"	"AAPS JOURNAL"	"English"	"Article"	"cell life span model; cell transit model; delayed response; pharmacodynamics; PK/PD modeling"	"RECOMBINANT-HUMAN-ERYTHROPOIETIN; HEALTHY-SUBJECTS; PHARMACODYNAMIC MODELS; MATHEMATICAL-MODEL; POPULATION PHARMACOKINETICS; NATURAL CELLS; RATS; MICE; MYELOSUPPRESSION; CHEMOTHERAPY"	"Prolonged time delay in response to drug action is a common feature of hematological responses to pharmacotherapy such as erythropoiesis. The objective of this study was to compare the performance of two competing modeling approaches for delayed drug effects, mechanistic cell life span models, and semi-mechanistic cell transit models. The comparison was performed with an experimental dataset from multiple dose administrations of an erythropoietin mimetic to Cynomolgus monkeys. Comparative performance measures include visual predictive checks, goodness-of-fit plots, model estimation time, estimation status, and estimation error. The analysis revealed that both models resulted in a similarly good description of the erythropoietic drug effect, with precision and bias of the model-based predictions of red blood cell counts of less than 11%. The cell transit model needed slightly longer time to converge compared to the cell life span model. The system and drug effect parameters were similar in both models indicating that the models can be interchangeably used to describe the current data. Thus, model selection would be dependent on the purpose of the modeling exercise, the available data, and the time allocated for model development."	"[Budha, Nageshwar R.; Meibohm, Bernd] Univ Tennessee, Dept Pharmaceut Sci, Coll Pharm, Hlth Sci Ctr, Memphis, TN USA; [Kovar, Andreas] Merck KGaA, Global Exploratory Med, Darmstadt, Germany; [Budha, Nageshwar R.] Genentech Inc, San Francisco, CA 94080 USA"	"Meibohm, B (corresponding author), Univ Tennessee, Dept Pharmaceut Sci, Coll Pharm, Hlth Sci Ctr, 881 Madison Ave,Rm 444, Memphis, TN USA."	"bmeibohm@uthsc.edu"	"NA"	"Meibohm, Bernd/0000-0003-3923-3648"	"NA"	"NA"	38	9	9	0	1	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"DEC"	2011	13	4	650	661	"NA"	"10.1208/s12248-011-9302-9"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"852KZ"	"WOS:000297358100012"	22005901	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ternant, D; Mulleman, D; Lauferon, F; Vignault, C; Ducourau, E; Wendling, D; Goupille, P; Paintaud, G"	"Ternant, David; Mulleman, Denis; Lauferon, Francine; Vignault, Celine; Ducourau, Emilie; Wendling, Daniel; Goupille, Philippe; Paintaud, Gilles"	"NA"	"A"	"Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"ankylosing spondylitis; infliximab; methotrexate; pharmacokinetics"	"POPULATION PHARMACOKINETICS; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; CLINICAL-RESPONSE; DISEASE-ACTIVITY; CROHNS-DISEASE; MAINTENANCE; EFFICACY; TRIAL; ALPHA"	"AIMS Infliximab, an anti-tumour necrosis factor a monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases. The objective was to assess the influence of methotrexate on the variability of infliximab pharmacokinetics and concentrationeffect relationship in axial ankylosing spondylitis (AAS) patients. METHODS Twenty-six patients with AAS were included in a prospective study. They were treated by infliximab 5mg kg-1 infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured before, and 2 and 4 h after each infusion, and at each intermediate visit (weeks 1, 3, 4, 5, 8, 10 and 14). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at each visit. Infliximab pharmacokinetics was described using a two-compartment model with first-order distribution and elimination constants. A population approach was used. Infliximab pharmacodynamics was described using the area under the BASDAI curve. RESULTS A total of 507 blood samples and 329 BASDAI measurements were collected. The following pharmacokinetic parameters were obtained (interindividual coefficient of variation): volumes of distribution for the central compartment = 2.4 l (9.6%) and peripheral compartment = 1.8 l (26%), systemic clearance = 0.23 l day(-1) (22%) and intercompartment clearance = 2.3 l day(-1). Methotrexate influenced neither pharmacokinetic nor BASDAI variability. CONCLUSIONS Using the present dosage, the clinical efficacy of infliximab is only weakly influenced by its serum concentrations. The results do not support the combination of methotrexate with infliximab in ankylosing spondylitis."	"[Ternant, David; Mulleman, Denis; Lauferon, Francine; Vignault, Celine; Ducourau, Emilie; Goupille, Philippe; Paintaud, Gilles] Univ Tours, 2 Blvd Tonnelle, Tours, France; [Ternant, David; Mulleman, Denis; Vignault, Celine; Ducourau, Emilie; Goupille, Philippe; Paintaud, Gilles] CNRS, UMR 6239, Tours, France; [Ternant, David; Vignault, Celine; Paintaud, Gilles] CHRU, Lab Pharmacol Toxicol, Tours, France; [Wendling, Daniel] CHRU Besancon, Dept Rheumatol, Besancon, France; [Goupille, Philippe] INSERM, CIC 202, Tours, France; [Mulleman, Denis; Lauferon, Francine; Ducourau, Emilie; Goupille, Philippe] CHRU, Dept Rheumatol, Tours, France"	"Ternant, D (corresponding author), Univ Tours, 2 Blvd Tonnelle, Tours, France."	"david.ternant@free.fr"	"Mulleman, Denis/K-5822-2012; Mulleman, Denis/O-3221-2019"	"Mulleman, Denis/0000-0003-4089-7513; PAINTAUD, Gilles/0000-0003-0158-1356"	"French Ministry of Health"	"This study was financed by the French Ministry of Health (regional PHRC 2004)."	37	34	34	1	3	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JAN"	2012	73	1	55	65	"NA"	"10.1111/j.1365-2125.2011.04050.x"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"858IP"	"WOS:000297790200009"	21692827	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, RFW; Allegaert, K; Schreuder, MF; Sherwin, CMT; de Hoog, M; van den Anker, JN; Danhof, M; Knibbe, CAJ"	"De Cock, Roosmarijn F. W.; Allegaert, Karel; Schreuder, Michiel F.; Sherwin, Catherine M. T.; de Hoog, Matthijs; van den Anker, Johannes N.; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Maturation of the Glomerular Filtration Rate in Neonates, as Reflected by Amikacin Clearance"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"RENAL DRUG CLEARANCE; SINGLE-INJECTION; INULIN-CLEARANCE; SERUM CREATININE; PRETERM INFANTS; DOSING CHART; PHARMACOKINETICS; GENTAMICIN; IBUPROFEN; INDOMETHACIN"	"Background and Objectives: During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin. Methods: Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally. Results: Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived. Conclusions: Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates."	"[Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 BE Nieuwegein, Netherlands; [De Cock, Roosmarijn F. W.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Allegaert, Karel] Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, Louvain, Belgium; [Schreuder, Michiel F.] Radboud Univ Nijmegen, Med Ctr, Dept Pediat Nephrol, NL-6525 ED Nijmegen, Netherlands; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Div Clin Pharmacol, Salt Lake City, UT USA; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Clin Trials Off, Salt Lake City, UT USA; [de Hoog, Matthijs; van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Intens Care, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 BE Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Sherwin, Catherine Mary Turner/B-2888-2012; Schreuder, Michiel/P-5465-2014; allegaert, karel/C-3611-2016; de Hoog, Matthijs/A-3882-2013"	"Sherwin, Catherine Mary Turner/0000-0002-0844-3207; Schreuder, Michiel/0000-0001-9725-4856; allegaert, karel/0000-0001-9921-5105;"	"Fund for Scientific Research, Flanders (Belgium) [FWO Vlaanderen]FWO [1800209 N]; US National Institutes of Health [NIH]United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01HD048689, 5K24DA027992, 5R01HD060543]; Dutch Organisation for Scientific Research [NWO]Netherlands Organization for Scientific Research (NWO)"	"The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) [FWO Vlaanderen] via a Fundamental Clinical Investigatorship (grant no. 1800209 N). The clinical research of J.N. van den Anker is supported by the US National Institutes of Health [NIH] (grant nos. 5R01HD048689; 5K24DA027992; 5R01HD060543). The clinical research of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organisation for Scientific Research [NWO] None of the other authors have any conflicts of interest to declare."	47	78	78	1	13	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2012	51	2	105	117	"NA"	"10.2165/11595640-000000000-00000"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"896AA"	"WOS:000300536600003"	22229883	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, DD; Zhang, SZ"	"Wang, Diane D.; Zhang, Shuzhong"	"NA"	"M"	"Standardized Visual Predictive Check Versus Visual Predictive Check for Model Evaluation"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"pharmacokinetics; pharmacodynamics; model evaluation; visual predictive check; standardized visual predictive check; prediction discrepancy; normalized prediction distribution error"	"COUMARIN ANTICOAGULANT DRUGS; WARFARIN"	"The visual predictive check (VPC) is a commonly used approach in model evaluation. However, it may not be feasible to conduct a VPC, or the results of a VPC could be misleading in certain situations. The objectives of the present study were to (1) examine the performance and applicability of the VPC and (2) propose the standardized visual predictive check (SVPC) as an alternative/complementary approach to the VPC. The difference between the SVPC and normalized prediction distribution error (npde) as visual tools for model evaluation is also discussed. The results of the simulation studies demonstrate that the VPC is not appropriate when stratification of covariate(s) in a model is difficult or arbitrary and may not be feasible when study design varies during a study/among participants. The SVPC addresses these issues by displaying the percentiles (P(i,j)) of each participant's observations in the marginal distribution of the corresponding model-simulated endpoints as a function of time (or any covariate of interest) based on that participant's own design template. Since the calculation of P(i),(j) factors out subject-specific design features, the difference between observation and simulated values is only caused by misspecification of the structure model and/or inadequate estimation of random effect. Thus, the SVPC can be used in any situation."	"[Wang, Diane D.; Zhang, Shuzhong] Pfizer Oncol, San Diego, CA 92121 USA"	"Wang, DD (corresponding author), Pfizer Oncol, 10646 Sci Ctr Dr, San Diego, CA 92121 USA."	"diane.wang@pfizer.com"	"NA"	"NA"	"NA"	"NA"	16	46	48	0	1	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"0091-2700"	"NA"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JAN"	2012	52	1	39	54	"NA"	"10.1177/0091270010390040"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"872ZZ"	"WOS:000298851400004"	21257797	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"van den Broek, MPH; Groenendaal, F; Toet, MC; van Straaten, HLM; van Hasselt, JGC; Huitema, ADR; de Vries, LS; Egberts, ACG; Rademaker, CMA"	"van den Broek, M. P. H.; Groenendaal, F.; Toet, M. C.; van Straaten, H. L. M.; van Hasselt, J. G. C.; Huitema, A. D. R.; de Vries, L. S.; Egberts, A. C. G.; Rademaker, C. M. A."	"NA"	"A"	"Pharmacokinetics and Clinical Efficacy of Phenobarbital in Asphyxiated Newborns Treated with Hypothermia A Thermopharmacological Approach"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"AMPLITUDE-INTEGRATED EEG; NEONATAL SEIZURES; BRAIN-INJURY; ENCEPHALOPATHY; INFANTS; TRIAL; BIRTH"	"Background and Objectives Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. Patients and Methods Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. Results and Conclusion A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66 %. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern."	"[van den Broek, M. P. H.; Egberts, A. C. G.; Rademaker, C. M. A.] Univ Med Ctr Utrecht, Dept Clin Pharm, Div Lab Med & Pharm, NL-3508 GA Utrecht, Netherlands; [Groenendaal, F.; Toet, M. C.; de Vries, L. S.] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Neonatol, NL-3508 GA Utrecht, Netherlands; [van Straaten, H. L. M.] Isala Clin, Dept Neonatol, Zwolle, Netherlands; [van Hasselt, J. G. C.; Huitema, A. D. R.] Slotervaart Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands; [Egberts, A. C. G.] Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands"	"van den Broek, MPH (corresponding author), Univ Med Ctr Utrecht, Dept Clin Pharm, Div Lab Med & Pharm, POB 85500, NL-3508 GA Utrecht, Netherlands."	"NA"	"Egberts, Toine/K-4579-2019; van Hasselt, Coen/H-5593-2019; Egberts, Toine/A-6625-2012; Groenendaal, Floris/P-6872-2019"	"Egberts, Toine/0000-0003-1758-7779; Egberts, Toine/0000-0003-1758-7779; Groenendaal, Floris/0000-0002-9284-1637"	"NA"	"NA"	31	44	44	0	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2012	51	10	671	679	"NA"	"10.1007/s40262-012-0004-y"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"012PF"	"WOS:000309248300004"	23018530	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Royer, B; Kalbacher, E; Onteniente, S; Jullien, V; Montange, D; Piedoux, S; Thiery-Vuillemin, A; Delroeux, D; Pili-Floury, S; Guardiola, E; Combe, M; Muret, P; Nerich, V; Heyd, B; Chauffert, B; Kantelip, JP; Pivot, X"	"Royer, B.; Kalbacher, E.; Onteniente, S.; Jullien, V.; Montange, D.; Piedoux, S.; Thiery-Vuillemin, A.; Delroeux, D.; Pili-Floury, S.; Guardiola, E.; Combe, M.; Muret, P.; Nerich, V.; Heyd, B.; Chauffert, B.; Kantelip, J-P; Pivot, X."	"NA"	"A"	"Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study"	"BRITISH JOURNAL OF CANCER"	"English"	"Article"	"biomarker; cisplatin; epinephrine; intraperitoneal perioperative chemotherapy; population pharmacokinetics"	"OVARIAN-CANCER PATIENTS; PERITONEAL CARCINOMATOSIS; INTRAOPERATIVE CHEMOTHERAPY; EPINEPHRINE; PENETRATION; MODEL; HYPERTHERMIA; TUMORS; SERUM; STAGE"	"BACKGROUND: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. METHODS: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n = 26) or without (n = 29) epinephrine were analysed using NONMEM. RESULTS: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity. CONCLUSION: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context. British Journal of Cancer (2012) 106, 460-467. doi: 10.1038/bjc.2011.557 www.bjcancer.com Published online 15 December 2011 (C) 2012 Cancer Research UK"	"[Royer, B.; Onteniente, S.; Montange, D.; Piedoux, S.; Muret, P.; Kantelip, J-P] CHU Jean Minjoz, Lab Pharmacol Clin, Dept Pharmacol, CHU Besancon, F-25030 Besancon, France; [Royer, B.; Montange, D.; Muret, P.; Pivot, X.] INSERM, UMR645, Besancon, France; [Royer, B.; Muret, P.; Pivot, X.] CHU Besancon, Clin Invest Ctr CIC, BT 506, F-25030 Besancon, France; [Royer, B.; Muret, P.; Pivot, X.] Univ Franche Comte, IFR133, F-25030 Besancon, France; [Kalbacher, E.; Thiery-Vuillemin, A.; Guardiola, E.; Pivot, X.] CHU Besancon, Dept Oncol, F-25030 Besancon, France; [Jullien, V.] Paris Descartes Univ, Cochin St Vincent de Paul Hosp, INSERM, Dept Pharmacol,U663, Paris, France; [Delroeux, D.; Heyd, B.] CHU Besancon, Dept Surg Oncol, F-25030 Besancon, France; [Pili-Floury, S.; Combe, M.] CHU Besancon, Dept Anesthesiol & Intens Care Med, F-25030 Besancon, France; [Nerich, V.] CHU Besancon, Dept Pharm, F-25030 Besancon, France; [Chauffert, B.] CHU Amiens, Dept Oncol, Amiens, France"	"Royer, B (corresponding author), CHU Jean Minjoz, Lab Pharmacol Clin, Dept Pharmacol, CHU Besancon, Bvd Fleming, F-25030 Besancon, France."	"broyer@chu-besancon.fr"	"THIERY-VUILLEMIN, Antoine/B-1876-2013"	"NA"	"Ligue contre le Cancer, Comite du Doubs"	"We are grateful to the technicians of the Pharmacology Department for their expert Pt determination and Ms F Sheppard (Inserm Clinical Investigation Center, Besancon) for her editorial assistance. This work was partly supported by the 'Ligue contre le Cancer, Comite du Doubs'."	43	9	9	0	6	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"0007-0920"	"NA"	"NA"	"BRIT J CANCER"	"Br. J. Cancer"	"JAN 31"	2012	106	3	460	467	"NA"	"10.1038/bjc.2011.557"	8	"Oncology"	"Oncology"	"892RC"	"WOS:000300302300006"	22173671	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Cella, M; Della Pasqua, O; Burger, D; Jacqz-Aigrain, E"	"Zhao, Wei; Cella, Massimo; Della Pasqua, Oscar; Burger, David; Jacqz-Aigrain, Evelyne"	"Pediat European Network Treatment"	"A"	"Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"abacavir; human immunodeficiency virus; maximum a posteriori probability Bayesian estimator; paediatrics; population pharmacokinetics"	"HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; CHILDREN; GLUCURONIDATION; OPTIMIZATION; VARIABILITY; PREDICTION; LAMIVUDINE; 1592U89; MODELS"	"AIMS To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h-1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h-1 (RSE 16.9%) and absorption rate constant 0.758 h-1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 (weight/12) 1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0-t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0-t was developed from the final model and can be used routinely to optimize individual dosing."	"[Della Pasqua, Oscar] Univ Paris 07, Hop Robert Debre, Dept Pediat Pharmacol & Pharmacogenet, Clin Investigat Ctr CIC Inserm 9202, F-75935 Paris 19, France; [Cella, Massimo; Della Pasqua, Oscar] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline Inc, Clin Pharmacol & Discovery Med, London, England; [Burger, David] Radboud Univ Nijmegen, Ctr Med, Dept Pharm, Nijmegen, Netherlands; [Burger, David] Radboud Univ Nijmegen, Med Ctr, N4i, Nijmegen, Netherlands"	"Jacqz-Aigrain, E (corresponding author), Univ Paris 07, Hop Robert Debre, Dept Pediat Pharmacol & Pharmacogenet, Clin Investigat Ctr CIC Inserm 9202, 48 Blvd Serurier, F-75935 Paris 19, France."	"evelyne.jacqz-aigrain@rdb.aphp.fr"	"Zhao, Wei/D-3322-2011; De Rossi, A./L-3128-2015; Cella, Massimo/K-8375-2019; Burger, David/C-9929-2013"	"Zhao, Wei/0000-0002-1830-338X; De Rossi, A./0000-0001-6435-7509; Gibb, Diana/0000-0002-9738-5490; GIAQUINTO, CARLO/0000-0001-9365-0413; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067; GARCIA-BERMEJO, ISABEL/0000-0001-9229-8905"	"PENTA Foundation; MRCMedical Research Council UK (MRC); Agence Nationale de Recherche sur le SidaANRSFrench National Research Agency (ANR); Istituto Superiore di Sanita - Progetto Terapia Antivirale; PENTA LABNET [201057]; GlaxoSmithKline, UKGlaxoSmithKline;  [LSHP-CT-2006-018865];  [QLK2-2000-00150]"	"PENTA is a Co-ordinated Action of the European Commission, supported by the Sixth Framework contract LSHP-CT-2006-018865 and Fifth Framework Program contract QLK2-2000-00150. The PENTA 15 study was sponsored by the PENTA Foundation and was co-ordinated by the Medical Research Council (MRC) Clinical Trials Unit, London (with support from the MRC) and INSERM SC10, Paris (supported by Agence Nationale de Recherche sur le Sida). UK clinical sites were supported by a grant from the MRC; those in Italy by a grant from the Istituto Superiore di Sanita - Progetto Terapia Antivirale 2004, 2005. PENTA activities are also supported by the PENTA Foundation and PENTA LABNET (EC Seventh Framework contract 201057). Financial support for PENTA 15 was also received from GlaxoSmithKline, UK."	31	7	7	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"APR"	2012	73	4	641	650	"NA"	"10.1111/j.1365-2125.2011.04121.x"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"906IX"	"WOS:000301339800014"	21988586	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Comets, E; Diquet, B; Legrain, S; Huisse, MG; Godon, A; Bruhat, C; Chauveheid, MP; Delpierre, S; Duval, X; Berrut, G; Verstuyft, C; Aumont, MC; Mentre, F"	"Comets, E.; Diquet, B.; Legrain, S.; Huisse, M-G; Godon, A.; Bruhat, C.; Chauveheid, M-P; Delpierre, S.; Duval, X.; Berrut, G.; Verstuyft, C.; Aumont, M-C; Mentre, F."	"NA"	"A"	"Pharmacokinetic and Pharmacodynamic Variability of Fluindione in Octogenarians"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"ELDERLY HOSPITALIZED-PATIENTS; ORAL ANTICOAGULANT-THERAPY; ATRIAL-FIBRILLATION; BLEEDING COMPLICATIONS; ANTITHROMBOTIC THERAPY; VENOUS THROMBOEMBOLISM; EUROPEAN-SOCIETY; RISK-FACTORS; TASK-FORCE; MANAGEMENT"	"In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients. Measurements of fluindione concentrations and international normalized ratio (INR) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLIX3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (IIV) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione."	"[Comets, E.; Duval, X.; Mentre, F.] Univ Paris Diderot, INSERM, UMR738, Paris, France; [Diquet, B.] Univ Angers PRES LUNAM, Dept Biol Infect Agents & Pharmacotoxicol, CHU Angers, Angers, France; [Legrain, S.; Huisse, M-G; Aumont, M-C] Univ Paris Diderot, Dept Med, Paris, France; [Legrain, S.; Delpierre, S.] Bretonneau Hosp, AP HP, Dept Geriatr, Paris, France; [Huisse, M-G] Hop Bichat Claude Bernard, AP HP, Dept Hematol, F-75877 Paris 18, France; [Godon, A.] Angers Hosp, Dept Hematol, Angers, France; [Bruhat, C.] Angers Hosp, Dept Geriatr, Angers, France; [Chauveheid, M-P] Hop Bichat Claude Bernard, AP HP, Dept Internal Med, F-75877 Paris 18, France; [Berrut, G.] Nantes Hosp, Dept Clin Gerontol, Nantes, France; [Verstuyft, C.] Hop Bicetre, AP HP, Serv Genet Mol Pharmacol & Hormonol, Le Kremlin Bicetre, France; [Verstuyft, C.] Univ Paris Sud, EA4123, F-94275 Le Kremlin Bicetre, France; [Aumont, M-C] Hop Bichat Claude Bernard, Dept Cardiol, F-75877 Paris 18, France"	"Comets, E (corresponding author), Univ Paris Diderot, INSERM, UMR738, Paris, France."	"emmanuelle.comets@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"Groupement d'Interet Scientifique (GIS) Longevite; Comite d'Orientation Strategique et de Suivi des Essais Cliniques (COSSEC, INSERM, Paris, France)"	"This study was supported by a grant from the Groupement d'Interet Scientifique (GIS) Longevite, and the genotyping analyses were financed by a grant from the Comite d'Orientation Strategique et de Suivi des Essais Cliniques (COSSEC, INSERM, Paris, France). The promoter of the study was the Institut de la Sante et de la Recherche Medicale (INSERM, Paris, France). Estelle Mottez (INSERM) was instrumental in promoting the study. The Centre d'Investigation Clinique (CIC) of the Bichat hospital (Paris, France) kindly ensured the monitoring of the study. We thank, in particular, Hayk Papayan and Valerie Vignali for their involvement in the study follow-up. We also thank the Centre de Ressources Biologiques (CRB Bichat), especially Joelle Benessiano, for help with the DNA samples. Finally, we thank the nursing staff who ensured daily sample collection and the staff of the various analytical departments involved in the study."	50	7	7	1	5	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"MAY"	2012	91	5	777	786	"NA"	"10.1038/clpt.2011.309"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"929FT"	"WOS:000303047400010"	22472992	"Green Accepted, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Isla, A; Troconiz, IF; de Tejada, IL; Vazquez, S; Canut, A; Lopez, JM; Solinis, M; Gascon, AR"	"Isla, Arantxazu; Troconiz, Inaki F.; Lopez de Tejada, Ignacio; Vazquez, Silvia; Canut, Andres; Muriel Lopez, Jesus; Angeles Solinis, Maria; Rodriguez Gascon, Alicia"	"NA"	"A"	"Population pharmacokinetics of prophylactic cefoxitin in patients undergoing colorectal surgery"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Cefoxitin; Prophylaxis; Surgery; Population pharmacokinetics"	"ANTIMICROBIAL ACTIVITY; CLINICAL PHARMACOLOGY; HEALTHY-VOLUNTEERS; CEPHALOTHIN; INFECTION; MODELS; CEPHALOSPORINS; ANTIBIOTICS; PREVENTION; BINDING"	"To elucidate whether a dose of 2 g cefoxitin as a prophylactic agent in patients undergoing elective colorectal surgery is able to maintain free drug concentrations above the minimum inhibitory concentration of the microorganisms involved in surgical site infection. This was a prospective study involving 56 patients electively undergoing rectal or colon surgery. All plasma concentration-time data were analyzed simultaneously using the population approach to estimate population pharmacokinetic parameters and study the influence of the subjects' demographic characteristics, disease status, surgical procedure, and clinical laboratory values on the pharmacokinetic properties of cefoxitin. A one-compartment open model was chosen to describe plasma concentrations of cefoxitin. Since cefoxitin is eliminated almost entirely via the kidney, creatinine clearance was identified as a covariate of cefoxitin clearance. The relationship between total cefoxitin clearance (CL) and creatinine clearance (CLCR) was best described using a nonlinear model [CL = 11.5 x (CLCR/77)(0.52)]. The population apparent volume of distribution was 12 L. Computer simulations carried out to determine the probability to maintain free plasma concentrations above 8 mg/L (the concentration threshold for susceptible bacteria) 2 h after drug administration revealed that this probability decreased from 84% in patients with a CLCR of 40 mL/min to 28% in patients with a CLCR of 100 mL/min. To ensure cefoxitin target concentrations during surgery, we recommend that cefoxitin be administered every 1.5 h in patients with a CLCR a parts per thousand yen60 mL/min and every hour if the CLCR is a parts per thousand yen100 mL/min. Administration by continuous infusion preceded by a bolus injection should also be considered."	"[Isla, Arantxazu; Angeles Solinis, Maria; Rodriguez Gascon, Alicia] Univ Basque Country, Lab Pharm & Pharmaceut Technol, Fac Pharm, Vitoria 01006, Spain; [Troconiz, Inaki F.] Univ Navarra, Dept Pharm & Pharmaceut Technol, Fac Pharm, E-31080 Pamplona, Spain; [Lopez de Tejada, Ignacio; Muriel Lopez, Jesus] Santiago Hosp, Gen & Digest Surg Unit, Vitoria, Spain; [Vazquez, Silvia; Canut, Andres] Santiago Hosp, Microbiol Unit, Vitoria, Spain"	"Gascon, AR (corresponding author), Univ Basque Country, Lab Pharm & Pharmaceut Technol, Fac Pharm, Paseo Univ 7, Vitoria 01006, Spain."	"alicia.rodriguez@ehu.es"	"Troconiz, Inaki F/I-1740-2017"	"Troconiz, Inaki F/0000-0003-3700-8658; Isla, Arantxazu/0000-0001-7575-2715; Rodriguez-Gascon, Alicia/0000-0002-3195-6385"	"Caja Vital Kutxa; Departamento de Educacion, Universidades e Investigacion, Gobierno Vasco, Spain [IT341-10]; Departamento de Sanidad, Gobierno Vasco, Spain"	"This work was supported by Caja Vital Kutxa and by the Departamento de Educacion, Universidades e Investigacion (IT341-10), Gobierno Vasco, Spain. Silvia Vazquez acknowledges the grant from the Departamento de Sanidad, Gobierno Vasco, Spain."	43	17	19	1	8	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"NA"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"MAY"	2012	68	5	735	745	"NA"	"10.1007/s00228-011-1206-1"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"934OD"	"WOS:000303452800030"	22246211	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Benz-de Bretagne, I; Le Guellec, C; Halimi, JM; Gatault, P; Barbet, C; Alnajjar, A; Buchler, M; Lebranchu, Y; Andres, CR; Vourc'h, P; Blasco, H"	"Benz-de Bretagne, I.; Le Guellec, C.; Halimi, J. M.; Gatault, P.; Barbet, C.; Alnajjar, A.; Buechler, M.; Lebranchu, Y.; Andres, Christian Robert; Vourc'h, P.; Blasco, H."	"NA"	"A"	"New Sampling Strategy Using a Bayesian Approach to Assess Iohexol Clearance in Kidney Transplant Recipients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"glomerular filtration rate; kidney transplantation; iohexol; population pharmacokinetics; Bayesian estimation"	"GLOMERULAR-FILTRATION-RATE; RENAL-FUNCTION EQUATIONS; PREDICTIVE PERFORMANCE; SERUM CREATININE; GFR-DETERMINATION; PLASMA-CLEARANCE; SINGLE; DISEASE; INJECTION; BIAS"	"Background: Glomerular filtration rate (GFR) measurement is a major issue in kidney transplant recipients for clinicians. GFR can be determined by estimating the plasma clearance of iohexol, a nonradiolabeled compound. For practical and convenient application for patients and caregivers, it is important that a minimal number of samples are drawn. The aim of this study was to develop and validate a Bayesian model with fewer samples for reliable prediction of GFR in kidney transplant recipients. Methods: Iohexol plasma concentration-time curves from 95 patients were divided into an index (n = 63) and a validation set (n = 32). Samples (n = 4-6 per patient) were obtained during the elimination phase, that is, between 120 and 270 minutes. Individual reference values of iohexol clearance (CLiohexol) were calculated from k (elimination slope) and V (volume of distribution from intercept). Individual CLiohexol values were then introduced into the Brochner-Mortensen equation to obtain the GFR (reference value). A population pharmacokinetic model was developed from the index set and validated using standard methods. For the validation set, we tested various combinations of 1, 2, or 3 sampling time to estimate CLiohexol. According to the different combinations tested, a maximum a posteriori Bayesian estimation of CLiohexol was obtained from population parameters. Individual estimates of GFR were compared with individual reference values through analysis of bias and precision. A capability analysis allowed us to determine the best sampling strategy for Bayesian estimation. Results: A 1-compartment model best described our data. Covariate analysis showed that uremia, serum creatinine, and age were significantly associated with k(e), and weight with V. The strategy, including samples drawn at 120 and 270 minutes, allowed accurate prediction of GFR (mean bias: -3.71%, mean imprecision: 7.77%). With this strategy, about 20% of individual predictions were outside the bounds of acceptance set at � 10%, and about 6% if the bounds of acceptance were set at � 15%. Conclusions: This Bayesian approach can help to reduce the number of samples required to calculate GFR using Brochner-Mortensen formula with good accuracy."	"[Benz-de Bretagne, I.; Le Guellec, C.; Andres, Christian Robert; Vourc'h, P.; Blasco, H.] Univ Hosp Tours, Biochem & Mol Biol Lab, F-37044 Tours 9, France; [Benz-de Bretagne, I.; Le Guellec, C.; Halimi, J. M.; Gatault, P.; Barbet, C.; Alnajjar, A.; Buechler, M.; Lebranchu, Y.] Univ Tours, EA 4245, Tours, France; [Halimi, J. M.; Gatault, P.; Barbet, C.; Alnajjar, A.; Buechler, M.; Lebranchu, Y.] Univ Hosp Tours, Dept Nephrol & Clin Immunol, F-37044 Tours 9, France; [Andres, Christian Robert; Vourc'h, P.; Blasco, H.] Univ Tours, CNRS FRE 2448, UMR INSERM U930, Tours, France"	"Benz-de Bretagne, I (corresponding author), Univ Hosp Tours, Biochem & Mol Biol Lab, 2 Blvd Tonnelle, F-37044 Tours 9, France."	"isabpsm@free.fr"	"Halimi, jean-michel/AAO-5268-2020; LE GUELLEC, Chantal/P-8704-2014"	"LE GUELLEC, Chantal/0000-0001-5846-8616; Andres, Christian/0000-0002-5062-3156; Gatault, Philippe/0000-0003-1664-2879; blasco, helene/0000-0001-6107-0035"	"NA"	"NA"	27	4	4	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA"	"0163-4356"	"NA"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"JUN"	2012	34	3	289	297	"NA"	"10.1097/FTD.0b013e31824a6534"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"942LU"	"WOS:000304046300009"	22585184	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Troconiz, IF; Boland, K; Staab, A"	"Troconiz, Inaki F.; Boland, Katja; Staab, Alexander"	"NA"	"A"	"Population Pharmacokinetic/Pharmacodynamic Model for the Sedative Effects of Flibanserin in Healthy Volunteers"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"flibanserin; NONMEM; PKPD modeling; sedation"	"DRUG; BIOAVAILABILITY; DYSFUNCTION; ABSORPTION; RECEPTORS; DOPAMINE; DISORDER; AGONIST; WOMEN; RATS"	"Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model. The population model was developed with NONMEM based on data from 24 healthy volunteers. Drowsiness was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100 mg flibanserin together with PK sampling. PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS drowsiness baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal E-MAX model using predicted effect site concentrations (C-e). The VAS . C-e relationship was very steep and effect site and plasma concentration-time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness. At effect site concentrations lower than similar to 200 ng/mL that are reached approximately 4 h after administration, flibanserin shows hardly any effect on the VAS drowsiness scale."	"[Troconiz, Inaki F.] Univ Navarra, Sch Pharm, Dept Pharm & Pharmaceut Technol, E-31080 Pamplona, Navarra, Spain; [Boland, Katja; Staab, Alexander] Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med, Biberach, Germany"	"Troconiz, IF (corresponding author), Univ Navarra, Sch Pharm, Dept Pharm & Pharmaceut Technol, E-31080 Pamplona, Navarra, Spain."	"itroconiz@unav.es"	"Troconiz, Inaki F/I-1740-2017"	"Troconiz, Inaki F/0000-0003-3700-8658"	"Boehringer Ingelheim Pharma GmbH Co KGBoehringer Ingelheim"	"Inaki F. Troconiz has received financial research support from Boehringer Ingelheim Pharma GmbH & Co KG. Katja Boland and Alexander Staab are employees of Boehringer Ingelheim Pharma GmbH & Co KG."	27	10	11	1	6	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"NA"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"JUN"	2012	29	6	1518	1529	"NA"	"10.1007/s11095-011-0648-6"	12	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"943JQ"	"WOS:000304117700009"	22219166	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, DD"	"Wang, Diane D."	"NA"	"M"	"Why Should Prediction Discrepancies Be Renamed Standardized Visual Predictive Check? Response"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Letter"	"NA"	"MODELS"	"NA"	"Pfizer Inc, San Diego, CA 92121 USA"	"Wang, DD (corresponding author), Pfizer Inc, 10555 Sci Ctr Dr, San Diego, CA 92121 USA."	"diane.wang@pfizer.com"	"NA"	"NA"	"NA"	"NA"	6	0	0	0	2	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"0091-2700"	"NA"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"AUG"	2012	52	8	1286	1287	"NA"	"10.1177/0091270011427555"	2	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"979UD"	"WOS:000306844400017"	"NA"	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Cella, M; Knibbe, C; de Wildt, SN; Van Gerven, J; Danhof, M; Della Pasqua, O"	"Cella, Massimo; Knibbe, Catherijne; de Wildt, Saskia N.; Van Gerven, Joop; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Scaling of pharmacokinetics across paediatric populations: the lack of interpolative power of allometric models"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"allometric scaling; dose adjustment; dose interpolation; model-based drug development; paediatric drug development; pharmacokinetic bridging"	"EXTRACORPOREAL MEMBRANE-OXYGENATION; INTENSIVE-CARE PATIENTS; HEALTHY MALE-SUBJECTS; INTEGRATED PHARMACOKINETICS; CRANIOFACIAL SURGERY; DRUG DEVELOPMENT; DOSE SELECTION; MIDAZOLAM; CHILDREN; PHARMACODYNAMICS"	"AIM The objective of this investigation was to assess the performance of an allometric model as the basis for interpolating drug exposure in the context of pharmacokinetic bridging across paediatric subpopulations. METHODS Midazolam was selected as a paradigm compound. Two nonlinear mixed effects models were developed to describe midazolam pharmacokinetics in infants, toddlers and adults (model 1) and in children and adolescents (model 2). Subsequently, systemic drug exposure, expressed in terms of the area under the concentration vs. time curve (AUC), in children and adolescents was interpolated based on pharmacokinetic parameter distributions obtained from the model describing infants, toddlers and adults (model 1). Results were compared with the values obtained from modelling of the data in the corresponding population (model 2). RESULTS The two pharmacokinetic models accurately described midazolam exposure in the population on which they were built. However, the model based on data from infants, toddlers and adults failed to predict the exposure observed in children and adolescents: the mean difference between the predicted and estimated AUC0180 was of -17.8%, with a range of -6.8 to -38.4%.The discrepancy between estimated and interpolated exposure increased proportionally with body weight. CONCLUSIONS The current results indicate that irrespective of whether extrapolation or interpolation methods are to be applied during paediatric drug development, model predictions beyond the range of the data used for parameter estimation may be biased. For accurate inter- or extrapolation to different populations, the assumption of identical parameter-covariate correlations across age groups may not be taken for granted."	"[Cella, Massimo; Knibbe, Catherijne; Danhof, Meindert; Della Pasqua, Oscar] Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, NL-2300 RA Leiden, Netherlands; [de Wildt, Saskia N.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [Van Gerven, Joop] Ctr Human Drug Res, Leiden, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol & Discovery Med, Res Triangle Pk, NC USA"	"Della Pasqua, O (corresponding author), Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, POB 9502, NL-2300 RA Leiden, Netherlands."	"odp72514@gsk.com"	"Cella, Massimo/K-8375-2019; de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647"	"NA"	"NA"	54	13	13	0	6	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"NA"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2012	74	3	525	535	"NA"	"10.1111/j.1365-2125.2012.04206.x"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"984UO"	"WOS:000307218100014"	22300419	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Vialet, R; Boulamery, A; Bruguerolle, B; Simon, N"	"Marsot, Amelie; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas"	"NA"	"A"	"Vancomycin: Predictive Performance of a Population Pharmacokinetic Model and Optimal Dose in Neonates and Young Infants"	"CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT"	"English"	"Article"	"vancomycin; pharmacokinetic; neonates; young infants; optimal dose"	"NA"	"Introduction: Model evaluation is an important issue in population pharmacokinetic analyses. The objectives were to evaluate the predictive performance of previously published pediatric population pharmacokinetic models for vancomycin in a new data set and to propose an optimal dose to obtain a vancomycin concentration target. Methods: External evaluation was conducted for all the published models of vancomycin in neonates and young infants with a new data set of 70 patients. Bias and accuracy were calculated. Advanced analyses were performed to evaluate the predictive performance of the best model. This population pharmacokinetic analysis was performed to simulate doses of vancomycin according to the appropriate target concentration. Results: All models gave almost the same results, except 2 that were not acceptable. Nevertheless, the model described by Oudin et al presented the best results with a bias and accuracy of 4.0% and 27.8%, respectively. Simulations showed that the maintenance dose should be adjusted more precisely to each neonate based on his or her weight and serum creatinine value. Conclusion: Simulations have allowed the authors to describe new dosage schedules, and a chart was created to help clinicians to adapt dosage of vancomycin. Because of pharmacokinetic variability, vancomycin still requires therapeutic drug monitoring."	"[Marsot, Amelie; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas] Aix Marseille Univ, Fac Med Timone, Marseille, France; [Vialet, Renaud] APHM Hop Nord, Serv Reanimat Pediat & Neonatale, Marseille, France"	"Marsot, A (corresponding author), Serv Pharmacol Med & Clin, Fac Med Timone, 27 Blvd Jean Moulin, F-13385 Marseille 5, France."	"Amelie.MARSOT@ap-hm.fr"	"Marsot, Amelie/P-7004-2016; Simon, Nicolas/B-1235-2016"	"Marsot, Amelie/0000-0002-9303-8862; Simon, Nicolas/0000-0003-4393-2257"	"NA"	"NA"	28	4	5	0	2	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2160-7648"	"NA"	"NA"	"CLIN PHARM DRUG DEV"	"Clin. Pharmacol. Drug Dev."	"OCT"	2012	1	4	144	151	"NA"	"10.1177/2160763X12456843"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"V41CB"	"WOS:000209523200004"	27121456	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bartelink, IH; van Kesteren, C; Boelens, JJ; Egberts, TCG; Bierings, MB; Cuvelier, GDE; Wynn, RF; Slatter, MA; Chiesa, R; Danhof, M; Knibbe, CAJ"	"Bartelink, Imke H.; van Kesteren, Charlotte; Boelens, Jaap J.; Egberts, Toine C. G.; Bierings, Marc B.; Cuvelier, Geoff D. E.; Wynn, Robert F.; Slatter, Mary A.; Chiesa, Robert; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Predictive Performance of a Busulfan Pharmacokinetic Model in Children and Young Adults"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"population pharmacokinetics; children; hematopoeitic stem cell transplantation; external validation; under/overweight"	"STEM-CELL TRANSPLANTATION; BMI Z-SCORE; INTRAVENOUS BUSULFAN; MARROW TRANSPLANTATION; DRUG DISPOSITION; ADIPOSITY CHANGE; INFANTS; DISEASE; OBESITY"	"Background: Recently a pediatric pharmacokinetic (PK) model was developed for busulfan to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation in terms of toxicity and event free survival. This study assesses the predictive performance of this busulfan PK model in a new, more diverse pediatric population, including data from patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices, from 5 international pediatric transplant centers. Patients and Methods: The previously published (original) busulfan PK model was developed from data of 245 patients (0.1-26 years of age). To externally validate this model, data were collected from another 158 patients (0.1-35 years) who underwent hematopoietic stem cell transplantation in 5 international transplant centers. Observed versus predicted plots, normalized prediction distribution error analysis, refit of the model on the external (n = 158) and combined datasets (n = 403), and subpopulation analyses were evaluated. Results: The original busulfan PK model was found to be stable and parameter estimates precise. Concentrations predicted by this model were in good agreement with the observed concentrations from the 5 external datasets. Plasma concentrations in patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices were adequately predicted. Conclusions: Our pediatric busulfan PK model has been externally validated. This model predicts busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight age, or body mass index. This busulfan PK model forms the basis for individualized busulfan dosing."	"[Bartelink, Imke H.; Egberts, Toine C. G.] Univ Med Ctr, Dept Clin Pharm, Utrecht, Netherlands; [Bartelink, Imke H.; van Kesteren, Charlotte; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, Dept Pharmacol, Leiden Amsterdam Ctr Drug Res, NL-2300 RA Leiden, Netherlands; [Boelens, Jaap J.; Bierings, Marc B.] Univ Med Ctr Utrecht, Pediat Blood & Marrow Transplantat Program, Utrecht, Netherlands; [Egberts, Toine C. G.] Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharamacoedpidemiol & Clin Pharmacol, NL-3508 TC Utrecht, Netherlands; [Cuvelier, Geoff D. E.] Univ Manitoba, Dept Pediat Hematoloncol CancerCare, Winnipeg, MB R3T 2N2, Canada; [Wynn, Robert F.] Royal Manchester Childrens Hosp, Blood & Marrow Transplant Unit, Manchester M27 1HA, Lancs, England; [Slatter, Mary A.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England; [Chiesa, Robert] Great Ormond St Hos, Bone Marrow Transplantat Dept, London, England; [Chiesa, Robert] San Raffaele Telethon Inst Gene Therapy HSR TIGET, Milan, Italy; [Knibbe, Catherijne A. J.] Clin Pharm St Antonius Hosp, Nieuwegein, Netherlands"	"Bartelink, IH (corresponding author), Univ Med Ctr, Dept Clin Pharm, Utrecht, Netherlands."	"i.h.bartelink@gmail.com"	"Egberts, Toine/K-4579-2019; Egberts, Toine/A-6625-2012"	"Egberts, Toine/0000-0003-1758-7779; Egberts, Toine/0000-0003-1758-7779; Wynn, robert/0000-0002-6046-8428; Boelens, Jaap Jan/0000-0003-2232-6952"	"Dutch Top Institute Pharma [D2-104]; Fondazione TelethonFondazione Telethon Funding Source: Custom"	"The authors wish to thank Liz Rogerson and Mary Coussons for their valuable input. This PK meta-analysis was performed within the framework of the Dutch Top Institute Pharma project number D2-104."	28	28	27	0	1	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA"	"0163-4356"	"NA"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"OCT"	2012	34	5	574	583	"NA"	"10.1097/FTD.0b013e31826051bb"	10	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"007SF"	"WOS:000308907700014"	22972539	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Li, LJ; Shang, DW; Li, WB; Guo, W; Wang, XP; Ren, YP; Li, AN; Fu, PX; Ji, SM; Lu, W; Wang, CY"	"Li, Li-jun; Shang, De-wei; Li, Wen-biao; Guo, Wei; Wang, Xi-pei; Ren, Yu-peng; Li, An-ning; Fu, Pei-xin; Ji, Shuang-min; Lu, Wei; Wang, Chuan-yue"	"NA"	"A"	"Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia"	"ACTA PHARMACOLOGICA SINICA"	"English"	"Article"	"schizophrenia; clozapine; norclozapine; population pharmacokinetics; NONMEM; smoking; male; individualized drug dosing; therapeutic drug monitoring"	"PLASMA CLOZAPINE; CYP1A2 ACTIVITY; CAFFEINE TEST; LONG-TERM; SMOKING; MODEL; SEX; AGE; POLYMORPHISM; DISPOSITION"	"Aim: To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters. Methods: Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors. Results: A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/ h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients. Conclusion: Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring."	"[Shang, De-wei; Wang, Xi-pei; Ren, Yu-peng; Ji, Shuang-min; Lu, Wei] Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China; [Li, Li-jun; Shang, De-wei; Li, Wen-biao; Guo, Wei; Li, An-ning; Wang, Chuan-yue] Capital Med Univ, Beijing An Ding Hosp, Lab Clin Psychopharmacol, Beijing 100088, Peoples R China; [Fu, Pei-xin] Beijing An Kang Hosp, Judicial Expertise Ctr, Beijing 102406, Peoples R China; [Lu, Wei] Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China"	"Lu, W (corresponding author), Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China."	"luwei_pk@bjmu.edu.cn; wang.cy@163.net"	"Wang, Chuan-Yue/C-9369-2015; Guo, Wei/E-5035-2011; Wang, Xipei/AAK-7214-2020; Shang, Dewei/AAI-8415-2020"	"Wang, Chuan-Yue/0000-0001-6549-3713; Guo, Wei/0000-0003-0757-9660; Wang, Xipei/0000-0002-2017-7247; Shang, Dewei/0000-0001-5546-3393"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30770776]; National High Technology Research and Development Program of China (863 Program)National High Technology Research and Development Program of China [2009AA022702]; Beijing Municipal Education Commission Science and Technology Development Program [KM201110025025]; Beijing Municipal Science and Technology CommissionBeijing Municipal Science & Technology Commission [D101107047810001]; Beijing Postdoctoral Research FoundationChina Postdoctoral Science Foundation [2011ZZ-11]"	"This study was supported by the National Natural Science Foundation of China (Grant No 30770776), the National High Technology Research and Development Program of China (863 Program) (Grant No 2009AA022702), the Beijing Municipal Education Commission Science and Technology Development Program (Grant No KM201110025025), the Beijing Municipal Science and Technology Commission (Grant No D101107047810001) and the Beijing Postdoctoral Research Foundation (Grant No 2011ZZ-11)."	40	17	20	0	19	"ACTA PHARMACOLOGICA SINICA"	"SHANGHAI"	"294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA"	"1671-4083"	"NA"	"NA"	"ACTA PHARMACOL SIN"	"Acta Pharmacol. Sin."	"NOV"	2012	33	11	1409	1416	"NA"	"10.1038/aps.2012.71"	8	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"033FA"	"WOS:000310778400011"	22820910	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Bouazza, N; Pestre, V; Jullien, V; Curis, E; Urien, S; Salmon, D; Treluyer, JM"	"Bouazza, Naim; Pestre, Vincent; Jullien, Vincent; Curis, Emmanuel; Urien, Saik; Salmon, Dominique; Treluyer, Jean-Marc"	"NA"	"A"	"Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"clindamycin; osteomyelitis; population pharmacokinetics"	"STAPHYLOCOCCUS-AUREUS; PARAMETERS; ADHERENCE; BONE"	"AIMS This study was performed to describe clindamycin, administered either orally or intravenously, concentration-time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme. METHODS Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software. RESULTS A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h(-1) (0.39), 70.2 l and 0.92 h(-1), respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C-min of 2mg l(-1) were then calculated. CONCLUSIONS The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed."	"[Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Hop Tarnier, AP HP, Unite Rech Clin, F-75006 Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Univ Paris 05, EA 3620, Paris, France; [Pestre, Vincent; Salmon, Dominique] Hop Cochin, F-75674 Paris, France; [Jullien, Vincent; Treluyer, Jean-Marc] Hop Cochin St Vincent de Paul, AP HP, Serv Pharmacol Clin, Paris, France; [Curis, Emmanuel] Univ Paris 05, Fac Pharm, Lab Biomath, Paris, France; [Urien, Saik; Treluyer, Jean-Marc] INSERM, CIC 0901, Paris, France"	"Bouazza, N (corresponding author), Hop Tarnier, AP HP, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"naim.bouazza@cch.aphp.fr"	"Urien, Saik/G-3240-2013; treluyer, Jean-Marc/F-8036-2010; Curis, Emmanuel/A-4185-2012"	"Curis, Emmanuel/0000-0001-8382-1493"	"NA"	"NA"	22	33	34	1	17	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2012	74	6	971	977	"NA"	"10.1111/j.1365-2125.2012.04292.x"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"037MG"	"WOS:000311108800009"	22486719	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, RFW; Knibbe, CAJ; Kulo, A; de Hoon, J; Verbesselt, R; Danhof, M; Allegaert, K"	"De Cock, Roosmarijn F. W.; Knibbe, Catherijne A. J.; Kulo, Aida; de Hoon, Jan; Verbesselt, Rene; Danhof, Meindert; Allegaert, Karel"	"NA"	"A"	"Developmental pharmacokinetics of propylene glycol in preterm and term neonates"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"neonates; population pharmacokinetics; propylene glycol; toxicity"	"TOXICITY; HYPEROSMOLALITY; EXCIPIENTS; LORAZEPAM; INFUSION; INFANTS; HUMANS; PLASMA"	"WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Propylene glycol is commonly used as an excipient in dose forms and is ingested by neonates when administering different drugs. While propylene glycol is generally considered to be safe, toxic effects like bradycardia, lactic acidosis and convulsions have been reported. Information on the pharmacokinetics of propylene glycol in neonates is lacking to provide insight into the possible risk of toxicity. WHAT THIS STUDY ADDS This study describes the pharmacokinetics of propylene glycol in preterm and term neonates co-administered with paracetamol and phenobarbital. A pharmacokinetic model was developed which identified birth weight and postnatal age as important covariates for clearance. The model was used to simulate exposure to propylene glycol co-administered with both drugs. AIM Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 6303980 g, postnatal age (PNA) 130 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 2440 weeks). RESULTS In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CLi= 0.0849 x {(bBW/2720)1.69x (PNA/3)0.201}). Volume of distribution scaled allometrically with current bodyweight (Vi= 0.967 x {(BW/2720)1.45}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33144 and 28218 mg l-1 (peak) and 19109 and 6112 mg l-1 (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA."	"[Allegaert, Karel] Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, B-3000 Louvain, Belgium; [De Cock, Roosmarijn F. W.; Knibbe, Catherijne A. J.; Danhof, Meindert] Leiden Univ, LACDR, Div Pharmacol, Leiden, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands; [Kulo, Aida; de Hoon, Jan; Verbesselt, Rene] Katholieke Univ Leuven Hosp, Ctr Clin Pharmacol, B-3000 Louvain, Belgium; [Kulo, Aida] Univ Sarajevo, Fac Med, Inst Pharmacol Clin Pharmacol & Toxicol, Sarajevo 71000, Bosnia & Herceg"	"Allegaert, K (corresponding author), Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, Herestr 49, B-3000 Louvain, Belgium."	"karel.allegaert@uz.kuleuven.ac.be"	"Kulo, Aida/AAC-3341-2020; de Hoon, Jan/E-3256-2018; allegaert, karel/C-3611-2016"	"de Hoon, Jan/0000-0002-5215-9836; allegaert, karel/0000-0001-9921-5105; kulo cesic, Aida/0000-0002-5891-3780"	"Top Institute Pharma [D2-104]; Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen) by a Fundamental Clinical InvestigatorshipFWO [1800209 N]; JoinEU-SEE scholarship"	"This study was performed within the framework of Top Institute Pharma project number D2-104.; The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen) by a Fundamental Clinical Investigatorship (1800209 N). The clinical research of A. Kulo is supported by a JoinEU-SEE scholarship (2009-2010). The authors also would like to thank LAP&P Consultants for their technical support with NONMEM."	28	23	23	0	9	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"NA"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JAN"	2013	75	1	162	171	"NA"	"10.1111/j.1365-2125.2012.04312.x"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"056YM"	"WOS:000312528100015"	22536830	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Fakhoury, M; Baudouin, V; Storme, T; Maisin, A; Deschenes, G; Jacqz-Aigrain, E"	"Zhao, Wei; Fakhoury, May; Baudouin, Veronique; Storme, Thomas; Maisin, Anne; Deschenes, Georges; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Tacrolimus; Once daily; Prolonged-release formulation; Pediatrics; Pediatric pharmacology; Population pharmacokinetics; Pharmacogenetics; CYP3A5; Kidney transplantation"	"SINGLE NUCLEOTIDE POLYMORPHISMS; TWICE-DAILY TACROLIMUS; PHARMACODYNAMICS; MODEL; MYCOPHENOLATE; ABSORPTION; ESTIMATOR; ADHERENCE; NONMEM; CYP3A"	"Tacrolimus(PR) is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus(PR) in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus(PR) pharmacokinetics, including CYP3A5 polymorphism. Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene. The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)(0.75)] was lower in patients with CYP3A5*3/*3 as compared to patients with the CYP3A5*1/*3 (32.2 � 10.1 vs. 53.5 � 20.2 L/h, p = 0.01). The population pharmacokinetic model of tacrolimus(PR) was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus (PR) dosing regimen in routine clinical practice."	"[Zhao, Wei; Fakhoury, May; Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Baudouin, Veronique; Maisin, Anne; Deschenes, Georges] Univ Paris Diderot, Hop Robert Debre, AP HP, Dept Pediat Nephrol, Paris, France; [Storme, Thomas] Univ Paris Diderot, Hop Robert Debre, AP HP, Dept Pharm, Paris, France; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, INSERM, Clin Invest Ctr CIC9202, Dept Pediat Pharmacol & Pharmacogenet, F-75935 Paris 19, France"	"Jacqz-Aigrain, E (corresponding author), Hop Robert Debre, INSERM, Clin Invest Ctr CIC9202, Dept Pediat Pharmacol & Pharmacogenet, 48 Blvd Serurier, F-75935 Paris 19, France."	"evelyne.jacqz-aigrain@rdb.aphp.fr"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; deschenes, georges/0000-0002-5158-2915; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"Global Research in Paediatrics - Network of Excellence (GRIP, EU) [261060]"	"We thank all the children and their families participating in this study. We also acknowledge the local clinical investigators (Marc Fila, Sonia Azib, Theresa Kwon, Anne Laure Leclerc, Marie-Alice Macher, Ferielle Louillet and Daolun Zhang) for conducting the study and technicians (Christel Grondin, Michel Popon, Samira Benakouche and Yves Medard) for technical support. This work was supported by Global Research in Paediatrics - Network of Excellence (GRIP, EU-funded FP7 project, Grant Agreement number 261060)."	29	41	42	0	12	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"NA"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"FEB"	2013	69	2	189	195	"NA"	"10.1007/s00228-012-1330-6"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"074DB"	"WOS:000313791600007"	22706623	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wen, YG; Shang, DW; Xie, HZ; Wang, XP; Ni, XJ; Zhang, M; Lu, W; Qiu, C; Liu, X; Li, FF; Li, X; Luo, FT"	"Wen, Yu-Guan; Shang, De-Wei; Xie, He-Zhi; Wang, Xi-Pei; Ni, Xiao-Jia; Zhang, Ming; Lu, Wei; Qiu, Chang; Liu, Xia; Li, Fang-Fang; Li, Xuan; Luo, Fu-Tian"	"NA"	"A"	"Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake"	"HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL"	"English"	"Article"	"blonanserin; population pharmacokinetics; food effect; NONMEM; clinical trial"	"TANDEM MASS-SPECTROMETRY; ANTIPSYCHOTIC AGENT; HUMAN PLASMA; DOUBLE-BLIND; SCHIZOPHRENIA; EFFICACY; NONMEM; DRUG"	"Objective The aim of the study was to better understand blonanserin population pharmacokinetic (PK) characteristics in Chinese healthy subjects. Methods Data from two studies with 50 subjects were analyzed to investigate the population PK characteristics of blonanserin at single dose (4, 8, and 12mg) under fasting, multidose (4mg bid or 8mg qd for 7days) and under food intake condition (single dose, 8mg). Blonanserin plasma concentrations were detected using the high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). A nonlinear mixed-effects model was developed to describe the blonanserin concentrationtime profiles. Results A two compartment model with first-order absorption was built to describe the time-course of blonanserin. The population-predicted system apparent clearance (CL/F), volume of apparent distribution in center (V1/F), and the first-order absorption rate constant (Ka) of blonanserin under fasting was 1230L/h, 9500L, and 3.02h1, respectively. Food intake decreased Ka of blonanserin to 0.78h1. The relative bioavailability between fasting and food intake estimated by the final model was 55%. No clinically significant safety issues were identified. Conclusion This is the first study assessing the PK profile of blonanserin with population PKs method. The results can be used for simulation in further clinical trial and optimize individual dosage regimens using a Bayesian methodology in patients. Copyright (c) 2013 John Wiley & Sons, Ltd."	"[Wen, Yu-Guan; Shang, De-Wei; Ni, Xiao-Jia; Zhang, Ming; Qiu, Chang; Liu, Xia; Li, Xuan] Guangzhou Med Univ, Dept Pharm, Guangzhou Brain Hosp, Guangzhou 510370, Guangdong, Peoples R China; [Xie, He-Zhi] Livzon Pharmaceut Grp Co Ltd, Clin Res Ctr, Zhuhai, Peoples R China; [Wang, Xi-Pei] Guangdong Gen Hosp, Dept Cardiol, Guangdong Cardiovasc Inst, Guangdong Acad Med Sci, Guangzhou, Guangdong, Peoples R China; [Lu, Wei] Peking Univ, Dept Pharmaceut, Sch Pharmaceut Sci, Beijing 100871, Peoples R China; [Li, Fang-Fang] Guangdong Pharmaceut Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China; [Luo, Fu-Tian] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China"	"Wen, YG (corresponding author), Guangzhou Med Univ, Dept Pharm, Guangzhou Brain Hosp, 36 MingXin Rd, Guangzhou 510370, Guangdong, Peoples R China."	"wenyuguande@163.com"	"Shang, Dewei/AAI-8415-2020; Wang, Xipei/AAK-7214-2020"	"Shang, Dewei/0000-0001-5546-3393; Wang, Xipei/0000-0002-2017-7247"	"Guangdong Province Department of Science and Technology [00498500130062027]; Guangdong Pharmaceutical Association [2012A02]; National Science and Technology Major Project for investigational new drug [2008ZX09312-002]; Guangdong Science and Technology Major Project [2011A080300003, 2012A080204017]"	"This work was supported by a grant from Guangdong Province Department of Science and Technology (Grant No. 00498500130062027), Guangdong Pharmaceutical Association (Grant No. 2012A02), National Science and Technology Major Project for investigational new drug (Grant No. 2008ZX09312-002), and Guangdong Science and Technology Major Project (Grant No. 2011A080300003; 2012A080204017). The authors would like to thank Yupeng Ren, MS for his contributions to the model building."	16	8	8	0	11	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0885-6222"	"NA"	"NA"	"HUM PSYCHOPHARM CLIN"	"Hum. Psychopharmacol.-Clin. Exp."	"MAR"	2013	28	2	134	141	"NA"	"10.1002/hup.2290"	8	"Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology"	"Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology"	"116WK"	"WOS:000316913800005"	23417765	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Yang, SY; Lukey, P; Beerahee, M; Hoke, F"	"Yang, Shuying; Lukey, Pauline; Beerahee, Misba; Hoke, Frank"	"NA"	"A"	"Population Pharmacokinetics of Losmapimod in Healthy Subjects and Patients with Rheumatoid Arthritis and Chronic Obstructive Pulmonary Diseases"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"KINASE; INFLAMMATION"	"Background and Objective Losmapimod is an orally available, potent p38 mitogen-activated protein kinase inhibitor. It is in development as an anti-inflammatory drug in different therapeutic areas. Clinical studies have shown that losmapimod is well tolerated and safe in humans and several studies have shown its pharmacological effect in the target diseases. The aim of this work was to develop a population pharmacokinetic model and to explore the covariates affecting the pharmacokinetics of losmapimod using data collected from healthy volunteers and patients with rheumatoid arthritis (RA) and chronic obstructive pulmonary diseases (COPD). Subjects and methods The plasma concentration data were pooled from four of the losmapimod clinical studies, with 30 healthy subjects, 23 subjects with RA and 24 subjects with COPD. Non-linear mixed-effects modelling was used to build a base model to characterize the structure and describe the variability of the pharmacokinetics of losmapimod. The available demographic covariates were explored to further explain the inter-subject variability. New data generated from another RA study with 34 subjects were used to validate the final model. All modelling was conducted using NONMEM (R) VI. Results A two-compartment model with first-order elimination and time-dependent first-order absorption was found to best fit the concentration-time profiles of losmapimod following oral administration. The first phase of the absorption was more variable than the second phase for most of the subjects in the dataset. There was no apparent difference in the structure of the pharmacokinetic model among healthy subjects and patients with RA and COPD. A slightly higher residual error was associated with COPD patients compared with the healthy and RA subjects. Three demographic covariates, namely sex, age and bodyweight, were retained in the final model to explain the inter-individual variability on pharmacokinetic parameters apparent total oral clearance (CL/F), apparent volume of distribution of the central compartment (V-1) and the first-order absorption rate constant (k(a)). Most of the fixed effect parameters (theta(pop,j) and theta for covariate) of the final model were estimated with good precision (% relative standard error [RSE] <= 30 %). The inter-individual variability was precisely estimated (% RSE <= 30 %) for clearance and ka, but less precise for inter-compartmental clearance and volumes of distribution. The mean clearance following oral administration of losmapimod was approximately 31.2 L/h (95 % CI 27.7-35.2) for males and 24.6 L/h ( 95 % CI 22.1-27.3) in females. Conclusion The population pharmacokinetic model described in this work well characterized the pharmacokinetic profile of losmapimod following administration of a single oral dose and repeated oral doses in healthy subjects and patients with RA and COPD. Although sex, bodyweight and age were significant factors influencing some pharmacokinetic parameters of losmapimod, the relatively small magnitude of the effect did not result in concerns for dose adjustment."	"[Yang, Shuying] GlaxoSmithKline, Middlesex, England; [Lukey, Pauline] GlaxoSmithKline, Fibrosis Discovery Performance Unit, Stevenage, Herts, England; [Beerahee, Misba] GlaxoSmithKline, Stevenage, Herts, England; [Hoke, Frank] GlaxoSmithKline, Res Triangle Pk, NC USA"	"Yang, SY (corresponding author), GlaxoSmithKline, Bldg 11,1-2 Iron Bridge Rd,Stockley Pk West, Middlesex, England."	"shuying.y.yang@gsk.com"	"NA"	"NA"	"NA"	"NA"	22	8	8	0	3	"ADIS INT LTD"	"AUCKLAND"	"41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND"	"0312-5963"	"NA"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAR"	2013	52	3	187	198	"NA"	"10.1007/s40262-012-0025-6"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"138QS"	"WOS:000318524100003"	23254770	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Benaboud, S; Urien, S; Thervet, E; Prie, D; Legendre, C; Souberbielle, JC; Hirt, D; Friedlander, G; Treluyer, JM; Courbebaisse, M"	"Benaboud, Sihem; Urien, Saik; Thervet, Eric; Prie, Dominique; Legendre, Christophe; Souberbielle, Jean-Claude; Hirt, Deborah; Friedlander, Gerard; Treluyer, Jean Marc; Courbebaisse, Marie"	"NA"	"A"	"Determination of optimal cholecalciferol treatment in renal transplant recipients using a population pharmacokinetic approach"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"25-Hydroxy vitamin D; Vitamin D insufficiency; Pharmacokinetic modeling; Optimal dosing; Kidney transplant patients; Cholecalciferol"	"VITAMIN-D SUPPLEMENTATION; EXPRESSION; CLEARANCE; CANCER"	"Purpose No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. Methods Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. Results The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V-C/F), 237 L; basal concentration (C-0), 12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. Conclusions We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients."	"[Benaboud, Sihem; Urien, Saik; Hirt, Deborah; Treluyer, Jean Marc] Univ Paris 05, EA3620, Sorbonne Paris Cite, Paris, France; [Benaboud, Sihem; Urien, Saik; Hirt, Deborah; Treluyer, Jean Marc] Hop Tarnier, AP HP, Unite Rech Clin, F-75006 Paris, France; [Thervet, Eric] Univ Paris 05, Hop Europeen Georges Pompidou, AP HP, Serv Nephrol, Paris, France; [Prie, Dominique; Souberbielle, Jean-Claude; Friedlander, Gerard; Courbebaisse, Marie] Univ Paris 05, Hop Necker Enfants Malad, AP HP, Serv Explorat Fonct, Paris, France; [Legendre, Christophe] Univ Paris 05, Hop Necker Enfants Malad, AP HP, Serv Transplantat Renale, Paris, France; [Hirt, Deborah; Treluyer, Jean Marc] Grp Hosp Cochin Broca Hotel Dieu, AP HP, Serv Pharmacol Clin, Paris, France"	"Benaboud, S (corresponding author), Hop Tarnier, AP HP, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"benaboud.sihem@gmail.com"	"NA"	"Friedlander, Gerard/0000-0002-6854-4261"	"NA"	"NA"	20	7	8	0	3	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"MAR"	2013	69	3	499	506	"NA"	"10.1007/s00228-012-1378-3"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"122RJ"	"WOS:000317335200024"	22936122	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Grassin-Delyle, S; Couturier, R; Abe, E; Alvarez, JC; Devillier, P; Urien, S"	"Grassin-Delyle, Stanislas; Couturier, Roland; Abe, Emuri; Alvarez, Jean Claude; Devillier, Philippe; Urien, Saik"	"NA"	"A"	"A Practical Tranexamic Acid Dosing Scheme Based on Population Pharmacokinetics in Children Undergoing Cardiac Surgery"	"ANESTHESIOLOGY"	"English"	"Article"	"NA"	"EPSILON-AMINOCAPROIC ACID; CARDIOPULMONARY BYPASS; BLOOD-LOSS; PEDIATRIC-PATIENTS; OPERATIONS; MODELS; APROTININ; EFFICACY; SOFTWARE; DEFECTS"	"Background: Pediatric cardiac surgery patients are at high risk for bleeding, and the antifibrinolytic drug tranexamic acid (TA) is often used to reduce blood loss. However, dosing schemes remain empirical as a consequence of the absence of pharmacokinetic study in this population. The authors' objectives were thus to investigate the population pharmacokinetics of TA in pediatric cardiac surgery patients during cardiopulmonary bypass (CPB). Methods: Twenty-one patients were randomized to receive TA either continuously (10 mg/kg followed by an infusion of 1 mg.kg(-1.)h(-1) throughout the operation, and 10 mg/kg into the CPB) or discontinuously (10 mg/kg, then 10 mg/kg into the CPB and 10 mg.kg(-1.)h(-1) at the end of CPB). Serum concentrations were measured at eight time points with chromatography-mass spectrometry and the data were modeled using Monolix (Lixoft, Orsay, France). Results: Tranexamic acid pharmacokinetics was ascribed to a two-compartment open model. The main covariate effects were body weight and CPB. Representative pharmacokinetic parameters adjusted to a 70-kg body weight were as follows: systemic clearance, 2.45 l/h; volume of distribution in the central compartment, 14.1 l; intercompartmental clearance, 5.74 l/h; and peripheral volume, 32.8 l. In accordance with this model, the authors proposed a weight-adjusted dosing scheme to maintain effective TA concentrations in children during surgery, consisting of one loading dose followed by a continuous infusion. Conclusions: The authors report for the first time the pharmacokinetics of TA in children undergoing cardiac surgery with CPB, and propose a dosing scheme for optimized TA administration in those children."	"[Grassin-Delyle, Stanislas; Devillier, Philippe] Hop Foch, Pharmacol Lab, UPRES EA220, Suresnes, France"	"Grassin-Delyle, S (corresponding author), UPRES EA220, Pharmacol Lab, 11 Rue Guillaume Lenoir, F-92150 Suresnes, France."	"s.grassindelyle@hopital-foch.org"	"Urien, Saik/G-3240-2013"	"ALVAREZ, jean claude/0000-0001-5344-9475"	"Sanofi-Aventis (Paris, France)Sanofi-Aventis"	"Received from the Laboratoire de Pharmacologie, UPRES EA220, Hopital Foch, Suresnes, France. Submitted for publication July 6, 2012. Accepted for publication November 30, 2012. Support was provided solely from institutional and/or departmental sources. Monolix is a shareware software sponsored by governmental organizations and pharmaceutical companies including Sanofi-Aventis (Paris, France), the company selling the drug for this study. This company was never involved at any time in the drug assays, data interpretation, pharmacokinetic analysis, or in writing the article, and was kept blind about the study's results until their publication. The authors declare no competing conflict of interest."	30	36	38	0	5	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA"	"0003-3022"	"NA"	"NA"	"ANESTHESIOLOGY"	"Anesthesiology"	"APR"	2013	118	4	853	862	"NA"	"10.1097/ALN.0b013e318283c83a"	10	"Anesthesiology"	"Anesthesiology"	"109GR"	"WOS:000316355000014"	23343649	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Kaguelidou, F; Biran, V; Zhang, DL; Allegaert, K; Capparelli, EV; Holford, N; Kimura, T; Lo, YL; Peris, JE; Thomson, A; van den Anker, JN; Fakhoury, M; Jacqz-Aigrain, E"	"Zhao, Wei; Kaguelidou, Florentia; Biran, Valerie; Zhang, Daolun; Allegaert, Karel; Capparelli, Edmund V.; Holford, Nick; Kimura, Toshimi; Lo, Yoke-Lin; Peris, Jose-Esteban; Thomson, Alison; van den Anker, John N.; Fakhoury, May; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"dosing regimen; external evaluation; neonates; population pharmacokinetics; serum creatinine; vancomycin"	"RENAL-FUNCTION; PRETERM; QUANTIFICATION; CREATININE; PREDICTION; CHILDREN; REGIMENS; INFANTS"	"Aims Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. Method Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)]. Results Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, 0.22, 0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffe) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. Conclusion The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin."	"[Zhao, Wei; Kaguelidou, Florentia; Zhang, Daolun; Fakhoury, May; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, F-75019 Paris, France; [Zhao, Wei; Kaguelidou, Florentia; Jacqz-Aigrain, Evelyne] INSERM, AP HP, Clin Invest Ctr CIC9202, Paris, France; [Kaguelidou, Florentia; Biran, Valerie; Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France; [Biran, Valerie] Hop Robert Debre, AP HP, Dept Neonatol, F-75935 Paris 19, France; [Allegaert, Karel] Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, Louvain, Belgium; [Capparelli, Edmund V.] Univ Calif San Diego, San Diego, CA 92103 USA; [Holford, Nick] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland 1, New Zealand; [Kimura, Toshimi] Tokyo Womens Med Univ Hosp, Dept Pharm, Tokyo, Japan; [Lo, Yoke-Lin] Univ Malaya, Fac Med, Dept Pharm, Kuala Lumpur, Malaysia; [Peris, Jose-Esteban] Univ Valencia, Dept Pharm & Pharmaceut Technol, Valencia, Spain; [Thomson, Alison] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark, Scotland; [Thomson, Alison] Univ Glasgow, Western Infirm, Dept Pharm, Glasgow G11 6NT, Lanark, Scotland; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20052 USA"	"Jacqz-Aigrain, E (corresponding author), Hop Robert Debre, INSERM, Clin Invest Ctr CIC9202, Dept Pediat Pharmacol & Pharmacogenet, 48 Blvd Serurier, F-75935 Paris 19, France."	"evelyne.jacqz-aigrain@rdb.aphp.fr"	"Holford, Nick/B-9774-2008; LO, YOKE LIN/B-8879-2010; Lo, Lin/B-1477-2010; Thomson, Alison H H/H-9743-2016; Zhao, Wei/D-3322-2011; allegaert, karel/C-3611-2016"	"Holford, Nick/0000-0002-4031-2514; LO, YOKE LIN/0000-0001-5521-2543; Lo, Lin/0000-0001-5521-2543; Thomson, Alison H H/0000-0002-2354-6116; Zhao, Wei/0000-0002-1830-338X; allegaert, karel/0000-0001-9921-5105; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"la Foundation PremUp; Global Research in Paediatrics Network of Excellence (GRIP); EUEuropean Union (EU) [261060]; Fund for Scientific Research, Flanders (Belgium) (F.W.O. Vlaanderen)FWO [1800209 N]; IRPA from the Ministry of Science, Technology and Innovation of Malaysia [06-02-03-0246-EA246]"	"All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: Dr Wei Zhao and Professor Evelyne Jacqz-Aigrain had support from 'la Foundation PremUp' (Professor Daniele Evain Brion, France) and Global Research in Paediatrics Network of Excellence (GRIP, EU-funded FP7 project, Grant Agreement number 261060) for the submitted work. The clinical research of Dr Karel Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) (F.W.O. Vlaanderen) by a Fundamental Clinical Investigatorship (1800209 N). The clinical research of Dr Yoke-Lin Lo is supported by IRPA grant 06-02-03-0246-EA246 from the Ministry of Science, Technology and Innovation of Malaysia. There were no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work."	48	64	66	2	17	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"APR"	2013	75	4	1068	1080	"NA"	"10.1111/j.1365-2125.2012.04406.x"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"108WF"	"WOS:000316326200020"	23148919	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Foissac, F; Treluyer, JM; Souberbielle, JC; Rostane, H; Urien, S; Viard, JP"	"Foissac, Frantz; Treluyer, Jean-Marc; Souberbielle, Jean-Claude; Rostane, Hafeda; Urien, Saik; Viard, Jean-Paul"	"NA"	"A"	"Vitamin D3 supplementation scheme in HIV-infected patients based upon pharmacokinetic modelling of 25-hydroxycholecalciferol"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"25-hydroxycholecalciferol; HIV-infected adults patients; population pharmacokinetics"	"REVERSE-TRANSCRIPTASE INHIBITOR; D DEFICIENCY; HIGH-FREQUENCY; PREVALENCE; DISEASE; COHORT; ADULTS"	"Aims Vitamin D deficiency is prevalent in HIV-infected patients and has been associated with osteopenia and HIV disease progression. Our aims were to investigate the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D], the effect of antiretroviral treatment (ARV) and others factors that may influence the pharmacokinetics, and to determine a vitamin D3 dosing scheme to reach the 30ngml1 threshold (defined as 25(OH)D sufficiency). Methods This monocentric retrospective study included 422 HIV-infected patients aged 16 to 85 years. A total of 723 25(OH)D concentrations were available for pharmacokinetic evaluation and a population pharmacokinetic model was developed with MONOLIX 3.2. Results Median 25(OH)D at baseline was 16ngml1 (interquartile range 1123ngml1) for the total population, 17% of patient had concentrations below 10ngml1, 68% between 10 and 30ngml1 and 15% above 30ngml1. 25(OH)D pharmacokinetics were best described by a one compartment model with an additional endogenous production. The effects of season and skin phototype were significant on production rate. The endogenous production was 20% lower in non-white skin phototype patients and was decreased by 16% during autumn, winter and spring. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs (ARV). To obtain concentrations between 30 and 80ngml1, the dosing recommendation was 100000IU every month. Conclusions Season and skin phototype had an influence on the endogenous production of 25(OH)D. However no effect of ARV was found. A dosing scheme to reach sufficient 25(OH)D concentrations is proposed."	"[Foissac, Frantz; Treluyer, Jean-Marc; Urien, Saik; Viard, Jean-Paul] Univ Paris 05, EA 3620, Paris, France; [Foissac, Frantz; Treluyer, Jean-Marc; Urien, Saik] AP HP, Unite Rech Clin Paris Ctr, Paris, France; [Treluyer, Jean-Marc; Urien, Saik] INSERM, CIC 0901, Paris, France; [Treluyer, Jean-Marc; Urien, Saik] AP HP, Paris, France; [Treluyer, Jean-Marc] Hop Cochin, Lab Pharmacol, F-75674 Paris, France; [Souberbielle, Jean-Claude] CHU Necker, Lab Physiol, Paris, France; [Rostane, Hafeda; Viard, Jean-Paul] Hop Hotel Dieu, AP HP, Ctr Diagnost & Therapeut, Paris, France"	"Foissac, F (corresponding author), Hop Tarnier, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"frantz.foissac@cch.aphp.fr"	"Urien, Saik/G-3240-2013; treluyer, Jean-Marc/F-8036-2010"	"NA"	"Paediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET)"	"The authors thank the clinical research team of the immunoinfectiology unit of the Hotel-Dieu hospital (Agnes Cros, Aline Maignan) for patients' file management and data quality control. We acknowledge the Paediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET) for their financial support."	46	7	7	0	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAY"	2013	75	5	1312	1320	"NA"	"10.1111/bcp.12006"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"122ZD"	"WOS:000317356600014"	23072545	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ni, SQ; Zhao, W; Wang, J; Zeng, S; Chen, SQ; Jacqz-Aigrain, E; Zhao, ZY"	"Ni, Shao-qing; Zhao, Wei; Wang, Jue; Zeng, Su; Chen, Shu-qing; Jacqz-Aigrain, Evelyne; Zhao, Zheng-yan"	"NA"	"A"	"Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration"	"ACTA PHARMACOLOGICA SINICA"	"English"	"Article"	"ciclosporin; immunosuppressant; aplastic anemia; population pharmacokinetics; stanozolol; serum creatinine; pediatrics"	"STEM-CELL TRANSPLANTATION; DRUG-METABOLISM; PHARMACOGENETICS; TACROLIMUS; RECIPIENTS; EXPOSURE; NONMEM"	"Aim: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics. Methods: A total of 102 children with either acquired or congenital aplastic anemia aged 8.8 � 3.6 years (range 0.9-17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors. Results: A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9-29.3). The weight normalized CL/F was 0.45 (range: 0.27-0.70) L.h(-1).kg(-1). The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin. Conclusion: Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia."	"[Ni, Shao-qing; Wang, Jue] Zhejiang Univ, Sch Med, Childrens Hosp, Dept Clin Pharmacol, Hangzhou 310003, Zhejiang, Peoples R China; [Ni, Shao-qing; Wang, Jue; Zhao, Zheng-yan] Zhejiang Key Lab Diag & Therapy Neonatal Dis, Hangzhou 310003, Zhejiang, Peoples R China; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Hop Robert Debre, Assistance Publ Hop Paris, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC9202, Paris, France; [Zeng, Su; Chen, Shu-qing] Zhejiang Univ, Coll Pharmaceut Sci, Dept Pharmaceut Anal & Drug Metab, Hangzhou 310058, Zhejiang, Peoples R China; [Zhao, Zheng-yan] Zhejiang Univ, Sch Med, Childrens Hosp, Dept Pediat, Hangzhou 310003, Zhejiang, Peoples R China"	"Zeng, S (corresponding author), Zhejiang Univ, Coll Pharmaceut Sci, Dept Pharmaceut Anal & Drug Metab, Hangzhou 310058, Zhejiang, Peoples R China."	"nsqshc@gmail.com; zhaozy@zju.edu.cn"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067; Chen, Shuqing/0000-0002-0792-3735"	"Natural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province [Y2080183]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81273607]; Science and Technologies Foundation of China [2009ZX09304]; National Science and Technology Major Projects for Major New Drugs Innovation and Development [2013ZX09303003]; European commissionEuropean Commission Joint Research Centre [261060]"	"This work was supported by grants from the Natural Science Foundation of Zhejiang Province (Y2080183), the National Natural Science Foundation of China (81273607), the Science and Technologies Foundation of China (2009ZX09304) and the National Science and Technology Major Projects for Major New Drugs Innovation and Development (2013ZX09303003). Doctor Wei ZHAO and Professor Evelyne JACQZ-AIGRAIN received support from the European commission for their pediatric pharmacology collaborative work in China (FP7 Global research in pediatrics GRIP, grant agreement No 261060)."	26	7	10	0	16	"ACTA PHARMACOLOGICA SINICA"	"SHANGHAI"	"294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA"	"1671-4083"	"NA"	"NA"	"ACTA PHARMACOL SIN"	"Acta Pharmacol. Sin."	"JUL"	2013	34	7	969	975	"NA"	"10.1038/aps.2013.9"	7	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"176UZ"	"WOS:000321332700013"	23624757	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ince, I; de Wildt, SN; Wang, CG; Peeters, MYM; Burggraaf, J; Jacqz-Aigrain, E; van den Anker, JN; Tibboel, D; Danhof, M; Knibbe, CAJ"	"Ince, Ibrahim; de Wildt, Saskia N.; Wang, Chengueng; Peeters, Mariska Y. M.; Burggraaf, Jacobus; Jacqz-Aigrain, Evelyne; van den Anker, John N.; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"A Novel Maturation Function for Clearance of the Cytochrome P450 3A Substrate Midazolam from Preterm Neonates to Adults"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; HUMAN LIVER; CHILDREN; MODEL; CYP3A; EXPRESSION; INFANTS; DRUG; METABOLISM; PHARMACODYNAMICS"	"Major changes in cytochrome P450 (CYP) 3A activity may be expected in the first few months of life with, later, relatively limited changes. In this analysis we studied the maturation of in vivo CYP3A-mediated clearance of midazolam, as model drug, from preterm neonates of 26 weeks gestational age (GA) to adults. Pharmacokinetic data after intravenous administration of midazolam were obtained from six previously reported studies. Subjects were premature neonates (n = 24; GA 26-33.5 weeks, postnatal age (PNA) 3-11 days, and n = 24; GA 26-37 weeks, PNA 0-1 days), 23 children after elective major craniofacial surgery (age 3-23 months), 18 pediatric intensive-care patients (age 2 days-17 years), 18 pediatric oncology patients (age 3-16 years), and 20 healthy male adults (age 20-31 years). Population pharmacokinetic modeling with systematic covariate analysis was performed by use of NONMEM v6.2. Across the entire lifespan from premature neonates to adults, bodyweight was a significant covariate for midazolam clearance. The effect of bodyweight was best described by use of an allometric equation with an exponent changing with bodyweight in an exponential manner from 0.84 for preterm neonates (0.77 kg) to 0.44 for adults (89 kg), showing that the most rapid maturation occurs during the youngest age range. An in-vivo maturation function for midazolam clearance from premature neonates to adults has been developed. This function can be used to derive evidence-based doses for children, and to simulate exposure to midazolam and possibly other CYP3A substrates across the pediatric age range in population pharmacokinetic models or physiologically based pharmacokinetic models."	"[Ince, Ibrahim; de Wildt, Saskia N.; Wang, Chengueng; Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg & Intens Care, Rotterdam, Netherlands; [Ince, Ibrahim; Wang, Chengueng; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Amsterdam Ctr Drug Res, Dept Pharmacol, Leiden, Netherlands; [Peeters, Mariska Y. M.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands; [Burggraaf, Jacobus] Leiden Univ, Ctr Human Drug Res, Leiden, Netherlands; [Jacqz-Aigrain, Evelyne] Univ Diderot, Sorbonne Press Paris Cite, Dept Pediat Pharmacol & Pharmacogenet, Hop Robert Debre, Paris, France; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Washington, DC 20052 USA"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"Dutch Top Institute Pharma project [D2-104]; Dutch Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); Erasmus MC fellowship; ZonMW clinical fellowship"	"The authors would like to thank Associate Professor Daryl J. Murry, PharmD, PhD, University of Iowa College of Pharmacy, Iowa City, Iowa, USA, for his valuable comments on the manuscript, and for his willingness to share his original data. This work was performed within the framework of Dutch Top Institute Pharma project number D2-104. The work of C. A. J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organization for Scientific Research (NWO). Dr de Wildt's research is supported by Erasmus MC and ZonMW clinical fellowships. All other authors have no conflicts of interest that are directly relevant to the contents of this study."	49	29	29	0	8	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUL"	2013	52	7	555	565	"NA"	"10.1007/s40262-013-0050-0"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"171UW"	"WOS:000320956200004"	23512668	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Foissac, F; Bouazza, N; Frange, P; Blanche, S; Faye, A; Lachassinne, E; Dollfus, C; Hirt, D; Benaboud, S; Treluyer, JM; Urien, S"	"Foissac, Frantz; Bouazza, Naim; Frange, Pierre; Blanche, Stephane; Faye, Albert; Lachassinne, Eric; Dollfus, Catherine; Hirt, Deborah; Benaboud, Sihem; Treluyer, Jean-Marc; Urien, Saik"	"NA"	"A"	"Evaluation of nevirapine dosing recommendations in HIV-infected children"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"children; nevirapine; population pharmacokinetics"	"FIXED-DOSE COMBINATION; POPULATION PHARMACOKINETICS; HIV-1-INFECTED INDIVIDUALS; PLASMA-CONCENTRATIONS; LAMIVUDINE; STAVUDINE; TABLETS; SAFETY; FORMULATIONS; INFANTS"	"Aims Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations. Methods Concentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolix4.0. Results Nevirapine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9lh-1 (70kg)-1 and 140l (70kg)-1, respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3mgl-1 is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3-6 and 6-10kg weight ranges following the WHO recommendations. Conclusions It is suggested to increase doses to 75 and 100mg twice daily for the 3-6 and 6-10kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3mgl-1."	"[Foissac, Frantz; Bouazza, Naim; Frange, Pierre; Blanche, Stephane; Hirt, Deborah; Benaboud, Sihem; Treluyer, Jean-Marc; Urien, Saik] Univ Paris 05, Sorbonne Paris Cite, EA 3620, Paris, France; [Foissac, Frantz; Bouazza, Naim; Hirt, Deborah; Benaboud, Sihem; Treluyer, Jean-Marc; Urien, Saik] AP HP, Unite Rech Clin, Paris Ctr, Paris, France; [Frange, Pierre; Blanche, Stephane] Hopital Necker, AP HP, Unite Immunol Hematol & Rhumatol Pediat, Paris, France; [Faye, Albert] Hop Robert Debre, AP HP, Serv Pediat Gen, F-75019 Paris, France; [Faye, Albert] Univ Paris 05, Sorbonne Paris Cite, Paris, France; [Lachassinne, Eric] Hop Jean Verdier, AP HP, Serv Pediat, Paris, France; [Dollfus, Catherine] Hop Trousseau, AP HP, Serv Hematol & Oncol Pediat, F-75571 Paris, France; [Hirt, Deborah; Treluyer, Jean-Marc; Urien, Saik] INSERM, CIC 0901, Paris, France; [Hirt, Deborah; Treluyer, Jean-Marc; Urien, Saik] AP HP, Paris, France; [Treluyer, Jean-Marc] Hop Cochin, Pharmacol Lab, F-75674 Paris, France"	"Foissac, F (corresponding author), Hop Tarnier, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"frantz.foissac@cch.aphp.fr"	"treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013"	"NA"	"Paediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET)"	"We acknowledge the Paediatric European Network Treatment AIDS Laboratory Network (PENTA LABNET) for their financial support."	34	8	8	0	5	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"NA"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUL"	2013	76	1	137	144	"NA"	"10.1111/bcp.12069"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"167ZU"	"WOS:000320674900014"	23278548	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Thai, HT; Veyrat-Follet, C; Mentre, F; Comets, E"	"Hoai-Thu Thai; Veyrat-Follet, Christine; Mentre, France; Comets, Emmanuelle"	"NA"	"A"	"Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Population pharmacokinetics; Target-mediated drug disposition; Aflibercept; VEGF; Covariate effect; Dosing schedule"	"MEDIATED DRUG DISPOSITION; ENDOTHELIAL GROWTH-FACTOR; PHASE-III TRIAL; VEGF DISTRIBUTION; CANCER; MODEL; ANGIOGENESIS; BEVACIZUMAB; DOCETAXEL; BLOOD"	"Aflibercept (Zaltrap(A (R))) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL (f) ) and bound aflibercept (CL (b) ) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V (p) ) and bound (V (b) ) aflibercept were similar (4 L). CL (f) and V (p) increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL (f) compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept."	"[Hoai-Thu Thai; Veyrat-Follet, Christine] Sanofi R&D, Disposit Safety & Anim Res, F-91380 Chilly Mazarin, France; [Hoai-Thu Thai; Mentre, France; Comets, Emmanuelle] Univ Paris 07, INSERM, UMR 738, F-75018 Paris, France; [Hoai-Thu Thai; Mentre, France; Comets, Emmanuelle] Univ Paris Diderot, Sorbonne Paris Cite, UMR 738, F-75018 Paris, France"	"Thai, HT (corresponding author), Sanofi R&D, Disposit Safety & Anim Res, 1 Ave Pierre Brossolette, F-91380 Chilly Mazarin, France."	"hoai-thu.thai@sanofi.com"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"SanofiSanofi-Aventis; UMR 738 INSERM-University Paris Diderot (Head Professor France Mentre); Sanofi. Christine Veyrat-Follet is employee of Sanofi"	"During this work, Hoai-Thu Thai was a PhD student with a research grant funded by Sanofi and UMR 738 INSERM-University Paris Diderot (Head Professor France Mentre) had a research grant from Sanofi. Christine Veyrat-Follet is employee of Sanofi."	41	10	10	0	10	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"JUL"	2013	72	1	167	180	"NA"	"10.1007/s00280-013-2182-1"	14	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"170XU"	"WOS:000320889300017"	23673444	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Guy-Viterbo, V; Scohy, A; Verbeeck, RK; Reding, R; Wallemacq, P; Musuamba, FT"	"Guy-Viterbo, V.; Scohy, A.; Verbeeck, R. K.; Reding, R.; Wallemacq, P.; Musuamba, Flora Tshinanu"	"NA"	"A"	"Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Tacrolimus; Pediatrics; Liver transplantation; Population pharmacokinetics; Therapeutic drug monitoring"	"SOLID-ORGAN TRANSPLANTATION; APPARENT CLEARANCE; RECIPIENTS; PREDICTION; PHARMACODYNAMICS; POLYMORPHISMS; THERAPY; KIDNEY; MODEL; PHARMACOGENETICS"	"Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation. Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients' demographics, biochemical test results and physiological characteristics. The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h(-1) and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution. We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM."	"[Guy-Viterbo, V.; Scohy, A.; Wallemacq, P.; Musuamba, Flora Tshinanu] Catholic Univ Louvain, Louvain Ctr Toxicol & Appl Pharmacol, B-1200 Brussels, Belgium; [Verbeeck, R. K.; Musuamba, Flora Tshinanu] Catholic Univ Louvain, Louvain Drug Res Inst, B-1200 Brussels, Belgium; [Reding, R.] Catholic Univ Louvain, St Luc Univ Hosp, Transplantat Unit, B-1200 Brussels, Belgium"	"Musuamba, FT (corresponding author), Catholic Univ Louvain, Louvain Drug Res Inst, Ave Mounier 73,B 7313, B-1200 Brussels, Belgium."	"flora.musuamba@uclouvain.be"	"MUSUAMBA TSHINANU, FLORA/P-1917-2016"	"MUSUAMBA TSHINANU, FLORA/0000-0001-8276-8870"	"NA"	"NA"	36	23	25	0	3	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"NA"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"AUG"	2013	69	8	1533	1542	"NA"	"10.1007/s00228-013-1501-0"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"182XI"	"WOS:000321777700004"	23588560	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Urien, S; Bardin, C; Bader-Meunier, B; Mouy, R; Compeyrot-Lacassagne, S; Foissac, F; Florkin, B; Wouters, C; Neven, B; Treluyer, JM; Quartier, P"	"Urien, Saik; Bardin, Christophe; Bader-Meunier, Brigitte; Mouy, Richard; Compeyrot-Lacassagne, Sandrine; Foissac, Franz; Florkin, Benoit; Wouters, Carine; Neven, Benedicte; Treluyer, Jean-Marc; Quartier, Pierre"	"NA"	"A"	"Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes"	"BMC PHARMACOLOGY & TOXICOLOGY"	"English"	"Article"	"NA"	"RECEPTOR ANTAGONIST ANAKINRA"	"Background: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes. Methods: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix. Results: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days. Conclusions: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below."	"[Urien, Saik; Foissac, Franz; Treluyer, Jean-Marc] AP HP, CIC Inserm Necker Cochin 0901, Paris EA 3620, Paris, France; [Urien, Saik; Bader-Meunier, Brigitte; Foissac, Franz; Neven, Benedicte; Treluyer, Jean-Marc; Quartier, Pierre] Univ Paris 05, Sorbonne Paris Cite, Paris, France; [Urien, Saik; Bader-Meunier, Brigitte; Foissac, Franz; Neven, Benedicte; Treluyer, Jean-Marc; Quartier, Pierre] Inst IMAGINE, Paris, France; [Bardin, Christophe; Treluyer, Jean-Marc] Hop Cochin, AP HP, F-75674 Paris, France; [Bader-Meunier, Brigitte; Mouy, Richard; Compeyrot-Lacassagne, Sandrine; Florkin, Benoit; Wouters, Carine; Neven, Benedicte; Quartier, Pierre] Hop Necker Enfants Malad, AP HP, Unite Immunohematol & Rhumatol Pediat, Paris, France"	"Urien, S (corresponding author), AP HP, CIC Inserm Necker Cochin 0901, Paris EA 3620, Paris, France."	"saik.urien@cch.aphp.fr"	"Urien, Saik/G-3240-2013; treluyer, Jean-Marc/F-8036-2010"	"Wouters, Carine/0000-0002-6426-8845; bader-meunier, brigitte/0000-0001-8476-8196; Quartier, Pierre/0000-0002-1769-549X"	"NA"	"NA"	10	24	24	0	7	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"NA"	"2050-6511"	"NA"	"BMC PHARMACOL TOXICO"	"BMC Pharmacol. Toxicol."	"AUG 5"	2013	14	"NA"	"NA"	"NA"	40	"10.1186/2050-6511-14-40"	6	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"198ID"	"WOS:000322915000001"	23915458	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Baey, C; Didier, A; Lemaire, S; Maupas, F; Cournede, PH"	"Baey, Charlotte; Didier, Anne; Lemaire, Sebastien; Maupas, Fabienne; Cournede, Paul-Henry"	"NA"	"A"	"Modelling the interindividual variability of organogenesis in sugar beet populations using a hierarchical segmented model"	"ECOLOGICAL MODELLING"	"English"	"Article"	"Nonlinear mixed model; Hierarchical model; Segmented regression; Sugar beet; Interindividual variability; Plant growth modelling"	"MIXED-EFFECTS MODELS; LEAF APPEARANCE; SCOTS PINE; GROWTH; PHYLLOCHRON; ARCHITECTURE; POLYMORPHISM; PREDICTION; CANOPY; HEIGHT"	"Modelling the interindividual variability in plant populations is a key issue to enhance the predictive capacity of plant growth models at the field scale. In the case of sugar beet, this variability is well illustrated by rate of leaf appearance, or by its inverse the phyllochron. Indeed, if the mean phyllochron remains stable among seasons, there is a strong variability between individuals, which is not taken into account when using models based only on mean population values. In this paper, we proposed a nonlinear mixed model to assess the variability of the dynamics of leaf appearance in sugar beet crops. As two linear phases can be observed in the development of new leaves, we used a piecewise-linear mixed model. Four parameters were considered: thermal time of initiation, rate of leaf appearance in the first phase, rupture thermal time, and difference in leaf appearance rates between the two phases. The mean population values as well as the interindividual variabilities (IIV) of the parameters were estimated by the model for a standard population of sugar beet, and we showed that the IIV of the four parameters were significant. Also, the rupture thermal time was found to be non significantly correlated to the other three parameters. We compared our piecewise-linear formulation with other formulations such as sigmoid or Gompertz models, but they provided higher AIC and BIC. A method to assess the effects of environmental factors on model parameters was also studied and applied to the comparison of three levels of Nitrogen (control, standard and high dose). Taking into account the IIV, our model showed that plants receiving Nitrogen tended to have a later time of initiation, a higher rate of leaf appearance, and an earlier rupture time, but these differences were not dose-dependent (no differences between standard and high dose of Nitrogen). No differences were found on the leaf appearance rate of the second phase between the three treatments. (C) 2013 Elsevier B.V. All rights reserved."	"[Baey, Charlotte; Cournede, Paul-Henry] Ecole Cent Paris, Lab Math Appl Syst, F-92290 Chatenay Malabry, France; [Didier, Anne; Lemaire, Sebastien; Maupas, Fabienne] Inst Tech Betterave, F-75008 Paris, France"	"Baey, C (corresponding author), Ecole Cent Paris, Lab Math Appl Syst, Grande Voie Vignes, F-92290 Chatenay Malabry, France."	"charlotte.baey@ecp.fr; didier@itbfr.org; lemaire@itbfr.org; maupas@itbfr.org; paul-heruy.cournede@ecp.fr"	"Cournede, Paul-Henry/AAS-8340-2020"	"Baey, Charlotte/0000-0002-1413-1058"	"NA"	"NA"	57	9	9	0	22	"ELSEVIER"	"AMSTERDAM"	"RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS"	"0304-3800"	"1872-7026"	"NA"	"ECOL MODEL"	"Ecol. Model."	"AUG 10"	2013	263	"NA"	56	63	"NA"	"10.1016/j.ecolmodel.2013.04.013"	8	"Ecology"	"Environmental Sciences & Ecology"	"197NJ"	"WOS:000322857600006"	"NA"	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Grassin-Delyle, S; Tremey, B; Abe, E; Fischler, M; Alvarez, JC; Devillier, P; Urien, S"	"Grassin-Delyle, S.; Tremey, B.; Abe, E.; Fischler, M.; Alvarez, J. C.; Devillier, P.; Urien, S."	"NA"	"A"	"Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass"	"BRITISH JOURNAL OF ANAESTHESIA"	"English"	"Article"	"cardiopulmonary bypass; cardiovascular surgical procedures; pharmacokinetics; tranexamic acid"	"CORONARY SURGERY; DOUBLE-BLIND; MODELS; DRUGS"	"Interest in antifibrinolytic tranexamic acid (TA) has grown since the widespread removal of aprotinin, but its dosing during cardiac surgery is still debated. The objectives of this study were to investigate the population pharmacokinetics (PK) of TA given with either low- or high-dose continuous infusion schemesin adult cardiac surgery patients during cardiopulmonary bypass (CPB). Patients were randomized to receive either low-dose (10 mg kg(1) followed by an infusion of 1 mg kg(1) h(1) throughout the operation, and 1 mg kg(1) into the CPB) or high-dose (30 mg kg(1), then 16 mg kg(1) h(1), and 2 mg kg(1) into the CPB) TA. Serum TA concentrations were measured in 61 patients and the data were modelled using Monolix. TA concentrations were 2855 g ml(1) in the low-dose group and 114209 g ml(1) in the high-dose group throughout surgery. TA PK was best described by a two-compartment open model. The main covariate effect was bodyweight, whereas the CPB did not influence the PK. Assuming a bodyweight of 70 kg, the population estimates were 4.8 litre h(1) for clearance, 6.6 litre for the volume of the central compartment, 32.2 litre h(1) for the diffusional clearance, and the peripheral volume of distribution was 10.8 litre. The PK of TA was satisfactorily described by an open two-compartmental model, which was used to propose a dosing scheme suitable for obtaining and maintaining the desired plasma concentration in a stable and narrow range in cardiac surgery patients. ClinicalTrials.gov, NCT00809393."	"[Grassin-Delyle, S.; Devillier, P.] Hop Foch, Pharmacol Lab, UPRES EA220, F-92150 Suresnes, France; [Tremey, B.; Fischler, M.] Hop Foch, Serv Anesthesie, F-92150 Suresnes, France; [Grassin-Delyle, S.; Abe, E.; Alvarez, J. C.] Hop Raymond Poincare, AP HP, Lab Pharmacol Toxicol, Garches, France; [Fischler, M.; Alvarez, J. C.; Devillier, P.] Univ Versailles St Quentin Yvelines, UFR Sci Sante, Montigny Le Bretonneux, France; [Urien, S.] AP HP, URC Paris Ctr, CIC Inserm Necker Cochin 0901, Paris, France; [Urien, S.] Univ Paris 05, EA 3620, Sorbonne Paris Cite, Paris, France"	"Grassin-Delyle, S (corresponding author), UPRES EA220, Pharmacol Lab, 11 Rue Guillaume Lenoir, F-92150 Suresnes, France."	"s.grassindelyle@hopital-foch.org"	"Urien, Saik/G-3240-2013"	"ALVAREZ, jean claude/0000-0001-5344-9475"	"Hopital Foch, Suresnes, France"	"Financial support was provided only by Hopital Foch, Suresnes, France."	28	33	35	0	5	"ELSEVIER SCI LTD"	"OXFORD"	"THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND"	"0007-0912"	"1471-6771"	"NA"	"BRIT J ANAESTH"	"Br. J. Anaesth."	"DEC"	2013	111	6	916	924	"NA"	"10.1093/bja/aet255"	9	"Anesthesiology"	"Anesthesiology"	"258CM"	"WOS:000327436600009"	23880099	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Biran, V; Jacqz-Aigrain, E"	"Zhao, Wei; Biran, Valerie; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Amikacin Maturation Model as a Marker of Renal Maturation to Predict Glomerular Filtration Rate and Vancomycin Clearance in Neonates"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; SINGLE-INJECTION; INULIN-CLEARANCE; PRETERM INFANTS; CHILDREN; VARIABILITY; PARAMETERS; INFUSION; KIDNEY"	"Amikacin clearance has recently been proposed as a marker of renal maturation in neonates. However, the predictive value of this marker is still unknown. The objective of the present exploratory study was to evaluate the predictive performance of renal maturation model derived from amikacin to predict the glomerular filtration rate (GFR) and vancomycin clearance in neonates. The GFR and vancomycin clearance in neonates were predicted using a maturation model derived from amikacin via estimation and simulation in a cohort of 116 neonates using non-linear mixed-effects modeling NONMEMA (R) software. Our results demonstrate good correlations between predicted and observed GFR and vancomycin clearance in neonates. The square of the correlation coefficient, and means of the prediction error (2.5th-97.5th percentiles) and absolute prediction error (2.5th-97.5th percentiles) are 0.96, 1.2 % (-39.7 to 30.0 %) and 12.3 % (0.4-39.7 %), respectively, for GFR, and 0.97, -11.3 % (-38.2 to 15.4 %) and 14.0 % (0.5-38.2 %), respectively, for vancomycin. The prediction error is not significantly correlated with age. An amikacin maturation model can precisely reflect maturation of glomerular filtration and thus predict the dosage regimens of other renally excreted drugs by glomerular filtration in neonates."	"[Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC9202, Hop Robert Debre, AP HP,Dept Pediat Pharmacol & Pharmacogenet, F-75935 Paris 19, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC9202, F-75935 Paris 19, France; [Biran, Valerie] Hop Robert Debre, NICU, F-75019 Paris, France; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France"	"Zhao, W (corresponding author), INSERM, Clin Invest Ctr CIC9202, Hop Robert Debre, AP HP,Dept Pediat Pharmacol & Pharmacogenet, 48 Blvd Serurier, F-75935 Paris 19, France."	"wei.zhao@rdb.aphp.fr; evelyne.jacqz-aigrain@rdb.aphp.fr"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"la Foundation PremUp; Global Research in Paediatrics-Network of Excellence (GRIP); EUEuropean Union (EU) [261060]"	"This work was supported by la Foundation PremUp (Professor Daniele Evain Brion, France) and Global Research in Paediatrics-Network of Excellence (GRIP, EU-funded FP7 project, Grant Agreement number 261060)."	43	24	24	0	6	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2013	52	12	1127	1134	"NA"	"10.1007/s40262-013-0101-6"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"257RK"	"WOS:000327403400007"	24027065	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Deng, C; Liu, T; Wu, K; Wang, S; Li, L; Lu, H; Zhou, T; Cheng, D; Zhong, X; Lu, W"	"Deng, C.; Liu, T.; Wu, K.; Wang, S.; Li, L.; Lu, H.; Zhou, T.; Cheng, D.; Zhong, X.; Lu, W."	"NA"	"A"	"Predictive performance of reported population pharmacokinetic models of vancomycin in Chinese adult patients"	"JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS"	"English"	"Article"	"Bayesian method; external evaluation; NONMEM; population pharmacokinetics; target concentration intervention; vancomycin"	"TARGET CONCENTRATION INTERVENTION; CRITICALLY-ILL PATIENTS; CARE-UNIT PATIENTS; SERUM CREATININE; RENAL-FUNCTION; GENTAMICIN; PARAMETERS"	"What is known and objectiveThere are numerous studies on population pharmacokinetics of vancomycin in adult patients. However, there is no such research for Chinese adult patients. This study was conducted to evaluate the predictive performance of reported population pharmacokinetic models of vancomycin in Chinese adult patients and to identify some models appropriate for our population. MethodsA literature search was conducted in PubMed to obtain the population pharmacokinetic models of vancomycin published between December 2010 and September 2012. The models were assessed using concentration data collected from Chinese patients for external validation. Models with relatively poor predictability were excluded from further analysis. The performance of the remaining models was evaluated in patients with different levels of creatinine clearance, age, body weight and sex by Bayesian method. This method was also used to compare the predictive performance based on peak concentration and trough concentration and the predictability based on different number of observed concentrations. ResultsOne hundred and sixty-five blood concentrations from 72 Chinese adult patients were collected retrospectively to serve as the test data set. The evaluated models included all those reported in the seven publications reviewed by Marsot etal. and three other studies published after December 2010. Three models with poor performance on external validation were excluded from the next Bayesian analysis. The distribution of covariates in the model building data set had an important effect on prediction. The predictability based on peak/trough concentration was similar among the evaluated models, and no significant difference was found using our data set except for Roberts' model. As expected, an increased number of samples improved the performance of the Bayesian prediction. What is new and conclusionWith our data set, the performance of the evaluated models varied. The characteristics of the patient population and distribution of covariates should be given more consideration when choosing a model to predict blood concentrations. The model developed by Purwonugroho etal. using a data set from patients similar to ours is appropriate for Bayesian dose predictions for vancomycin concentrations in our population of Chinese adult patients."	"[Deng, C.; Wu, K.; Wang, S.; Li, L.; Zhou, T.; Lu, W.] Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100871, Peoples R China; [Liu, T.; Lu, H.; Cheng, D.; Zhong, X.] Guangxi Med Univ, Affiliated Hosp 1, Guangxi, Peoples R China; [Wu, K.] Univ Chicago, Dept Med, Chicago, IL 60637 USA"	"Lu, W (corresponding author), Peking Univ, Dept Pharmaceut, Sch Pharmaceut Sci, Hlth Sci Ctr, 38 Xueyuan Rd, Beijing 100871, Peoples R China."	"luwei_pk@hsc.pku.edu.cn"	"NA"	"NA"	"NA"	"NA"	36	10	15	0	6	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0269-4727"	"1365-2710"	"NA"	"J CLIN PHARM THER"	"J. Clin. Pharm. Ther."	"DEC"	2013	38	6	480	489	"NA"	"10.1111/jcpt.12092"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"242JY"	"WOS:000326237800009"	24033587	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Simon, N; Marsot, A; Villard, E; Choquet, S; Khe, HX; Zahr, N; Lechat, P; Leblond, V; Hulot, JS"	"Simon, N.; Marsot, A.; Villard, E.; Choquet, S.; Khe, H-X; Zahr, N.; Lechat, P.; Leblond, V.; Hulot, J-S"	"NA"	"A"	"Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy"	"PHARMACOGENOMICS JOURNAL"	"English"	"Article"	"multidrug-resistance-associated proteins; methotrexate; polymorphisms; lymphoid malignancy; pharmacokinetics"	"ACUTE LYMPHOBLASTIC-LEUKEMIA; METABOLITE 7-HYDROXYMETHOTREXATE; BAYESIAN-ESTIMATION; CHILDREN; EXPRESSION; MRP2; ELIMINATION; PROTEIN; YOUNG; OSTEOSARCOMA"	"Human multidrug resistance-related protein 2 (MRP2, encoded by ABCC2) is involved in the transport of anionic drugs such as methotrexate (MTX). We prospectively investigated the influence of four common ABCC2 genetic variants (rs717620, rs2273697, rs8187694 and rs8187710) on MTX pharmacokinetics parameters. MTX concentrations were monitored in 50 patients with lymphoid malignancy (27 males; mean age: 53 � 17 years) receiving high-dose MTX (5.13 � 1.88 g m(-2) in a 4-h perfusion). The population pharmacokinetics modelling showed that ABCC2 - 24T allele (rs717620) had a combined influence on both MTX elimination and distribution. The MTX clearance and distribution volume were significantly higher in carriers of at least one copy of the - 24T allele as compared with noncarriers: 8.6 � 2.2 vs 6.7 � 2.5 l h(-1), P<0.01 and 30.7 � 7.7 vs 22.1 � 8.8 l, P<0.001, respectively. Consequently, - 24T allele carriers were more prone to reach MTX nontoxic levels, 48 h after administration."	"[Simon, N.; Marsot, A.] Aix Marseille Univ, Serv Pharmacol Med & Clin, AP HM, Hop Timone, Marseille, France; [Villard, E.; Hulot, J-S] Univ Paris 06, UMR S 956, Paris, France; [Choquet, S.; Leblond, V.] Pitie Salpetriere Univ Hosp, Dept Haematol, AP HP, Paris, France; [Khe, H-X] Pitie Salpetriere Univ Hosp, Dept Neurol, AP HP, Paris, France; [Zahr, N.; Lechat, P.; Hulot, J-S] Pitie Salpetriere Univ Hosp, AP HP, Dept Pharmacol, Paris, France"	"Hulot, JS (corresponding author), Hop La Pitie Salpetriere, Serv Pharmacol, 47-83 Bld Hop, F-75013 Paris, France."	"jean-sebastien.hulot@psl.aphp.fr"	"Hulot, Jean-Sebastien/A-2278-2016; Marsot, Amelie/P-7004-2016; Simon, Nicolas/B-1235-2016; ZAHR, Noel/AAJ-2267-2020; choquet, sylvain/O-7952-2017; Hulot, Jean-Sebastien/AAM-6490-2020"	"Hulot, Jean-Sebastien/0000-0001-5463-6117; Marsot, Amelie/0000-0002-9303-8862; Simon, Nicolas/0000-0003-4393-2257; Hulot, Jean-Sebastien/0000-0001-5463-6117; villard, eric/0000-0001-9801-7297; ZAHR, Noel/0000-0002-7858-2325"	"Assistance-Publique Hopitaux de Paris"	"The study was sponsored by Assistance-Publique Hopitaux de Paris."	32	20	21	0	3	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1470-269X"	"1473-1150"	"NA"	"PHARMACOGENOMICS J"	"Pharmacogenomics J."	"DEC"	2013	13	6	507	513	"NA"	"10.1038/tpj.2012.37"	7	"Genetics & Heredity; Pharmacology & Pharmacy"	"Genetics & Heredity; Pharmacology & Pharmacy"	"258HJ"	"WOS:000327449700005"	23069858	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Pai, MP"	"Pai, Manjunath P."	"NA"	"A"	"Serum and urine pharmacokinetics of tigecycline in obese class III and normal weight adults"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"obesity; pharmacodynamics; minocycline; pharmacology; glycylcyclines"	"POPULATION PHARMACOKINETICS; EFFICACY; PREDICTION; SAFETY"	"Objectives: To compare the serum and urine pharmacokinetics (PK) of intravenous tigecycline in obese class III (obese-C-3) adults with those in normal weight (NW) adults. Patients and methods: Obese-C-3 (n = 8) and NW (n = 4) healthy adult volunteers received a single intravenous dose of 100 mg of tigecycline for 30 min. Serum (0-96 h) and urine (0-48 h) tigecycline concentrations were assayed by liquid chromatography with tandem mass spectrometry. Parametric population PK systems analyses were used to model the data and assess the effects of total body weight (TBW) on PK parameters. The area under the concentration-time curve extrapolated to infinity (AUC(0-infinity)) was simulated to estimate the probability of AUC(0-infinity): MIC target attainment and cumulative fraction of response (CFR) based on wild-type MIC distributions of select pathogens. Clinicaltrials.gov: NCT01560143. Results: The median (range) age, TBW and initial body mass index were 42 (20-50) years, 121 (61-160) kg and 43.8 (20.8-53.8) kg/m(2), respectively. The serum concentration-time profiles and exposures were similar in the obese-C-3 and NW adults, with a mean urine recovery of 15.8% and 13.4%, respectively. The median (range) AUC(0-infinity) was 8.19 (6.12, 11.2) and 7.50 (6.78, 9.13) mg.h/L in the obese-C-3 and NW groups, respectively. The clearance of tigecycline was not related to TBW. The CFR was calculated to be <90% against Acinetobacter baumannii, Enterobacter cloacae and Klebsiella pneumoniae for an AUC(0-infinity): MIC target >= 6.96. Conclusions: The serum and urine PK of tigecycline is similar in obese-C-3 and NW healthy adults. A lower CFR is predicted against certain Gram-negative pathogens with the current standard tigecycline dosing regimen, irrespective of TBW."	"Albany Coll Pharm & Hlth Sci, Albany, NY 12208 USA"	"Pai, MP (corresponding author), Albany Coll Pharm & Hlth Sci, Albany, NY 12208 USA."	"amit.pai@acphs.edu"	"NA"	"Pai, Manjunath/0000-0001-7119-5034"	"Pfizer Pharmaceuticals, New York, NY, USA [WS2001231]"	"This study was supported through an investigator-initiated grant (WS2001231) from Pfizer Pharmaceuticals, New York, NY, USA."	27	19	22	0	4	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JAN"	2014	69	1	190	199	"NA"	"10.1093/jac/dkt299"	10	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"271XR"	"WOS:000328425400029"	23883872	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Ternant, D; Buchler, M; Thibault, G; Ohresser, M; Watier, H; Lebranchu, Y; Paintaud, G"	"Ternant, David; Buechler, Matthias; Thibault, Gilles; Ohresser, Marc; Watier, Herve; Lebranchu, Yvon; Paintaud, Gilles"	"NA"	"A"	"Influence of Fc gamma RIIIA genetic polymorphism on T-lymphocyte depletion induced by rabbit antithymocyte globulins in kidney transplant patients"	"PHARMACOGENETICS AND GENOMICS"	"English"	"Article"	"antithymocyte globulins; dose-response relationship; immunoglobulin G receptors; kidney transplantation; pharmacogenetics"	"C-RECEPTOR POLYMORPHISMS; ANTI-THYMOCYTE GLOBULIN; INDUCTION; THERAPY; IGG; PHARMACOKINETICS; THYMOGLOBULIN; RECIPIENTS; CLEARANCE; RITUXIMAB"	"IntroductionPolyclonal antithymocyte globulins (ATG) have been used in transplantation for several decades, but the sources of the interindividual variability of their effect are poorly understood. An influence of the FCGR3A-158V/F genetic polymorphism on the horse ATG concentration-effect relationship was reported in kidney transplant patients. The objective of the present study was to confirm the influence of the FCGR3A polymorphism on the extent of lymphocyte depletion in kidney transplant patients treated with rabbit antithymocyte globulin (r-ATG).Materials and methodsOf the 194 transplant patients treated with r-ATG between 1998 and 2002 in our institution, 69 patients were eligible and included in this retrospective study. Biomarkers of response were CD3 and CD4 counts. Dose-effect data were analyzed using a population approach, and a two-compartment turnover model with stimulation of lymphocyte output'. Since r-ATG concentrations were not available, a K-PD model was used. The influence of FCGR3A genotype on estimated parameters was investigated.ResultsThe r-ATG infusion rate leading to a 50% stimulation of CD3 output (EDK50), which is inversely related to patient sensitivity to r-ATG treatment, decreased with the number of V alleles (P=0.0016).ConclusionThe genetic polymorphism of FCGR3A influences r-ATG effect on CD3 count in kidney transplant patients, those with the V allele being more sensitive to antilymphocyte serum. These results also suggest that r-ATG act, at least in part, by antibody-dependent cellular cytotoxicity."	"[Ternant, David; Thibault, Gilles; Watier, Herve; Paintaud, Gilles] Univ Tours, Tours, France; [Ternant, David; Thibault, Gilles; Ohresser, Marc; Watier, Herve; Paintaud, Gilles] Univ Tours, CNRS, UMR GICC 7292, Tours, France; [Ternant, David; Paintaud, Gilles] Univ Hosp Tours, Lab Pharmacol Toxicol, F-37044 Tours 9, France; [Thibault, Gilles; Watier, Herve] Fac Med Tours, Immunol Lab, F-37032 Tours, France; [Buechler, Matthias; Lebranchu, Yvon] Dept Nephrol & Clin Immunol, Tours, France"	"Ternant, D (corresponding author), Univ Hosp Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours 9, France."	"david.ternant@univ-tours.fr"	"NA"	"PAINTAUD, Gilles/0000-0003-0158-1356"	"Societe Francaise de Transplantation"	"This work was supported by the Societe Francaise de Transplantation. The authors thank Prof. Michel Tod and Dr Melanie Wilbaux for statistical modeling advice."	35	7	7	0	3	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"1744-6872"	"1744-6880"	"NA"	"PHARMACOGENET GENOM"	"Pharmacogenet. Genomics"	"JAN"	2014	24	1	26	34	"NA"	"10.1097/FPC.0000000000000017"	9	"Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy"	"Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy"	"274TT"	"WOS:000328629800004"	24322002	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Aspiroz, EL; Buelga, DS; Figueroa, SEC; Merino, MDV; Sanchez, MC; Hurle, ADG; Carracedo, A; Sanchez, MJG"	"Lopez Aspiroz, Elena; Santos Buelga, Dolores; Cabrera Figueroa, Salvador Enrique; Valverde Merino, Maria de la Paz; Cordero Sanchez, Miguel; Dominguez-Gil Hurle, Alfonso; Carracedo, Angel; Garcia Sanchez, Maria Jose"	"Tormes Team"	"A"	"Population pharmacokinetic/pharmacogenetic model of lopinavir/ritonavir in HIV-infected patients"	"PERSONALIZED MEDICINE"	"English"	"Article"	"HIV-infected patients; lopinavir; ritonavir; pharmacogenetics; population pharmacokinetics; therapeutic drug monitoring"	"LOPINAVIR PLASMA-CONCENTRATIONS; STEADY-STATE PHARMACOKINETICS; TROUGH CONCENTRATIONS; PROTEASE INHIBITORS; CYP3A5 GENOTYPE; ORAL CLEARANCE; P-GLYCOPROTEIN; RITONAVIR; VARIABILITY; RESISTANCE"	"Aim: This study aims to develop a population pharmacokinetic/pharmacogenetic model for lopinavir/ritonavir (LPV/r) in European HIV-infected patients. Materials & methods: A total of 693 LPV/r plasma concentrations were assessed and 15 single-nucleotide polymorphisms were genotyped. The population pharmacokinetic/pharmacogenetic model was created using a nonlinear mixed-effect approach (NONMEM (R) v.7.2.0., ICON Development Solutions, Dublin, Ireland). Results: Covariates significantly related to LPV/r apparent clearance (CL/F) were ritonavir trough concentration (RTC), BMI, high-density lipoprotein cholesterol (HDL-C) and certain single-nucleotide polymorphisms in genes encoding for metabolizing enzymes, which are representable as follows: CL/F = (0.216BMI  0.0125HDL-C) x 0.713(RTC) x 1.26(rs28371764[C/T]) x 0.528(rs6945984[C/C]) x 0.302(CYP3A4[1461insA/del]) Conclusion: The LPV/r standard dose appears to be appropriate for the rs28371764[C/T] genotype. However, lower doses should be recommended for the rs6945984[C/C] and CYP3A4[1461insA/del] genotypes and even for those patients without any of these variants, as the standard dose seems to be higher than that which is required in order to achieve therapeutic levels."	"[Lopez Aspiroz, Elena; Cabrera Figueroa, Salvador Enrique; Valverde Merino, Maria de la Paz; Dominguez-Gil Hurle, Alfonso] Univ Hosp Salamanca, Pharm Serv, Salamanca 37007, Spain; [Santos Buelga, Dolores; Dominguez-Gil Hurle, Alfonso; Garcia Sanchez, Maria Jose] Univ Salamanca, Fac Pharm, Dept Pharm & Pharmaceut Technol, E-37008 Salamanca, Spain; [Cabrera Figueroa, Salvador Enrique] Univ Austral Chile, Inst Farm, Fac Ciencias, Valdivia, Chile; [Cordero Sanchez, Miguel] Univ Hosp Salamanca, Infect Dis Serv, Salamanca 37007, Spain; [Carracedo, Angel] Univ Santiago de Compostela, Grp Med Xen, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Santiago De Compostela, Spain; [Carracedo, Angel] Fdn Publ Galega Med Xen, Inst Invest Sanitaria Santiago de Compostela IDIS, SERGAS Serv Galega Saude, Santiago De Compostela, Spain; [Carracedo, Angel] King Abdulaziz Univ, Ctr Excellence Genom Med Res, Jeddah 21413, Saudi Arabia"	"Figueroa, SEC (corresponding author), Univ Hosp Salamanca, Pharm Serv, Paseo San Vicente 58, Salamanca 37007, Spain."	"scabrera@uach.cl"	"Carracedo, Angel/D-4257-2012"	"Carracedo, Angel/0000-0003-1085-8986"	"Europharma Foundation"	"The authors acknoweledge the financial support of the Europharma Foundation under a collaboration agreement between the University of Salamanca and the University Austral of Chile and the genotyping services that were provided by the Spanish 'Centro Nacional de Genotipado' CEGEN-USC in the Fundacion Galega de Medicina Xenomica (www.cegen.org). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed."	52	2	2	0	6	"FUTURE MEDICINE LTD"	"LONDON"	"UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND"	"1741-0541"	"1744-828X"	"NA"	"PERS MED"	"Pers. Med."	"NA"	2014	11	7	693	704	"NA"	"10.2217/pme.14.58"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AT4SG"	"WOS:000344931400011"	29764054	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Chaturvedula, A; Sale, ME; Lee, H"	"Chaturvedula, Ayyappa; Sale, Mark E.; Lee, Howard"	"NA"	"A"	"Genetic Algorithm Guided Population Pharmacokinetic Model Development for Simvastatin, Concurrently or Non-Concurrently Co-Administered With Amlodipine"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"population pharmacokinetics; genetic algorithm; simvastatin; simvastatin acid; amlodipine; drug interaction"	"REDUCTASE INHIBITORS; BIOEQUIVALENCE; ACID"	"An automated model development was performed for simvastatin, co-administered with amlodipine concurrently or non-concurrently (i.e., 4hours later) in 17 patients with coexisting hyperlipidemia and hypertension. The single objective hybrid genetic algorithm (SOHGA) was implemented in the NONMEM software by defining the search space for structural, statistical and covariate models. Candidate models obtained from the SOHGA runs were further assessed for biological plausibility and the precision of parameter estimates, followed by traditional backward elimination process for model refinement. The final population pharmacokinetic model shows that the elimination rate constant for simvastatin acid, the active form by hydrolysis of its lactone prodrug (i.e., simvastatin), is only 44% in the concurrent amlodipine administration group compared with the non-concurrent group. The application of SOHGA for automated model selection, combined with traditional model selection strategies, appears to save time for model development, which also can generate new hypotheses that are biologically more plausible."	"[Chaturvedula, Ayyappa] Univ Calif San Francisco, Sch Pharm, Ctr Drug Dev Sci, Dept Bioengn, San Francisco, CA 94143 USA; [Sale, Mark E.] Next Level Solut Inc, Raleigh, NC USA; [Lee, Howard] Univ Calif San Francisco, Sch Pharm, Ctr Drug Dev Sci, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA; [Chaturvedula, Ayyappa] Mercer Univ, Coll Pharm, Dept Pharm Practice, Atlanta, GA USA; [Chaturvedula, Ayyappa] Mercer Univ, Coll Pharm, Dept Pharmaceut Sci, Atlanta, GA USA; [Lee, Howard] Seoul Natl Univ Hosp, Clin Trials Ctr, Dept Clin Pharmacol & Therapeut, Seoul 110744, South Korea"	"Lee, H (corresponding author), Seoul Natl Univ Hosp, Clin Trials Ctr, Dept Clin Pharmacol & Therapeut, 101 Daehak Ro, Seoul 110744, South Korea."	"howardlee@snu.ac.kr"	"NA"	"NA"	"NA"	"NA"	17	1	1	0	2	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1552-4604"	"NA"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"FEB"	2014	54	2	141	149	"NA"	"10.1002/jcph.176"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"290YU"	"WOS:000329795400003"	24114976	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Imbert, B; Alvarez, JC; Grassin-Delyle, S; Jaquet, I; Lancon, C; Simon, N"	"Marsot, Amelie; Imbert, Bruce; Alvarez, Jean-Claude; Grassin-Delyle, Stanislas; Jaquet, Isabelle; Lancon, Christophe; Simon, Nicolas"	"NA"	"A"	"High Variability in the Exposure of Baclofen in Alcohol-Dependent Patients"	"ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH"	"English"	"Article"	"Baclofen; Population Pharmacokinetics; Alcohol-Dependent Patients; High Variability"	"HIGH-DOSE BACLOFEN; PHARMACOKINETICS; ABSTINENCE; DRINKERS; SAFETY"	"BackgroundBaclofen is a GABA-B receptor agonist used in the treatment of spasticity. Recently, baclofen is used out of its label to decrease craving of alcoholic patients. Its optimal use in these patients requires further pharmacokinetic information. The objective of this study was to characterize the pharmacokinetics of baclofen in alcohol-dependent patients. Randomized clinical trials are ongoing to evaluate the efficacy for this new indication. MethodsThirty-seven outpatients (weight: 74.0kg [42.0 to 104.0]; age: 49years [31 to 68]) followed in the addictology unit were studied. Total mean dose of 77.9mg (30 to 240) per day was administered by oral route. Therapeutic drug monitoring allowed the measurement of 139 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, sex), biological data (creatinine, urea, AST, ALT, albumin, PR, VGM, PAL, CDT, GGT), and tobacco consumption (number of cigarettes and Fagerstrom test). Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model (NONMEM 7.2 software). ResultsData were modeled with a 1-compartment pharmacokinetic model. The population typical mean (95% confidence interval [95% CI]) values for clearance (CL), apparent volume of distribution (V), and rate constant of absorption (Ka) were 9.9l/h (9.0 to 11.1), 80.7l (63.6 to 96.9), and 4.6/h (1.5 to 19.9), respectively. The interindividual variability of CL (95% CI) and V (95% CI), and residual variability (95% CI) were 56.0% (47.9 to 60.7), 68.3% (48.7 to 80.1), and 0.096mg/l (0.079 to 0.107), respectively. ConclusionsBaclofen exhibited a linear pharmacokinetics with a proportional relationship from 30 to 240mg per day, the dose range currently used in alcoholic patients. A wide interpatient variability was observed which could not be explained by the covariates. This high variation of baclofen exposure may explain the lack of response observed for some patients."	"[Marsot, Amelie; Simon, Nicolas] Aix Marseille Univ, Hop Timone, APHM, Serv Pharmacol Clin, Marseille, France; [Marsot, Amelie; Lancon, Christophe; Simon, Nicolas] Aix Marseille Univ, Equipe Accueil Sante Publ & Malad Chron 3279, Marseille, France; [Imbert, Bruce; Jaquet, Isabelle; Lancon, Christophe; Simon, Nicolas] Aix Marseille Univ, Hop St Marguerite, APHM, Serv Addictol, Marseille, France; [Alvarez, Jean-Claude; Grassin-Delyle, Stanislas] CHU Raymond Poincare, Lab Pharmacol Toxicol, Garches, France"	"Marsot, A (corresponding author), Fac Med Timone, Serv Pharmacol Clin, 27 Blvd Jean Moulin, F-13385 Marseille 5, France."	"Amelie.MARSOT@ap-hm.fr"	"Imbert, Bruce/L-3145-2016; Simon, Nicolas/B-1235-2016; Marsot, Amelie/P-7004-2016"	"Imbert, Bruce/0000-0002-0359-6255; Simon, Nicolas/0000-0003-4393-2257; Marsot, Amelie/0000-0002-9303-8862; ALVAREZ, jean claude/0000-0001-5344-9475"	"NA"	"NA"	16	28	28	0	2	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0145-6008"	"1530-0277"	"NA"	"ALCOHOL CLIN EXP RES"	"Alcoholism (NY)"	"FEB"	2014	38	2	316	321	"NA"	"10.1111/acer.12235"	6	"Substance Abuse"	"Substance Abuse"	"297PC"	"WOS:000330266400004"	24033763	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Musuamba, FT; Guy-Viterbo, V; Reding, R; Verbeeck, RK; Wallemacq, P"	"Musuamba, Flora T.; Guy-Viterbo, Vanessa; Reding, Raymond; Verbeeck, Roger K.; Wallemacq, Pierre"	"NA"	"A"	"Population Pharmacokinetic Analysis of Tacrolimus Early After Pediatric Liver Transplantation"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"tacrolimus; population pharmacokinetics; pediatric liver transplantation; modeling; dose individualization"	"SOLID-ORGAN TRANSPLANTATION; APPARENT CLEARANCE; RECIPIENTS; PREDICTION; PHARMACODYNAMICS; POLYMORPHISMS; THERAPY; MODEL; PARAMETERS; CHILDREN"	"Background: Tacrolimus (TAC) pharmacokinetics (PKs) show considerable unexplained variability, particularly in the early period after transplantation. Therefore, TAC is a good candidate for therapeutic drug monitoring. The main objective of the present work was to propose a robust PK model for TAC in the early period after transplantation, with the final goal to provide practitioners with a tool for dose individualization in pediatric patients. Methods: TAC concentration data were obtained from 82 pediatric liver allograft recipients during the first 2 weeks after transplantation. Previously published models, and a model recently developed by our group for pediatrics early after pediatric liver transplantation, were fitted to the data and their predictive performance compared with the performances of a model developed using the data from 82 pediatric patients. Results: During the data-driven analysis, the PKs of TAC were best described by a 1-compartment model with time-varying first order elimination. Apparent volume of distribution and blood clearance estimates were 283 L and 10 L/h, respectively. The absorption was also considered to be a first order process, with a first order rate fixed to 4.45 hours. Parameters were estimated with good precision and accuracy. Although hematocrit levels, time after transplantation, liver weight, and body weight influenced the clearance, body weight was the only covariate retained on volume of central and peripheral compartments. Two of the 5 previous models showed acceptable predictive performances using the observed data. Conclusions: Time after transplantation, body weight, and hematocrit levels were shown to influence TAC PK in the early pediatric post-liver transplantation period and should be considered, besides therapeutic drug monitoring, by clinicians for the TAC posology prescription and adaptation."	"[Musuamba, Flora T.; Guy-Viterbo, Vanessa; Wallemacq, Pierre] Catholic Univ Louvain, Louvain Ctr Toxicol & Appl Pharmacol, B-1200 Brussels, Belgium; [Musuamba, Flora T.; Verbeeck, Roger K.] Catholic Univ Louvain, Louvain Drug Res Inst, B-1200 Brussels, Belgium; [Reding, Raymond] Catholic Univ Louvain, St Luc Univ Hosp, Transplantat Unit, B-1200 Brussels, Belgium"	"Musuamba, FT (corresponding author), Catholic Univ Louvain, Louvain Drug Res Inst, Ave Mounier 73,B 7313, B-1200 Brussels, Belgium."	"flora.musuamba@uclouvain.be"	"MUSUAMBA TSHINANU, FLORA/P-1917-2016"	"MUSUAMBA TSHINANU, FLORA/0000-0001-8276-8870"	"NA"	"NA"	32	23	24	0	0	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"FEB"	2014	36	1	54	61	"NA"	"NA"	8	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AI9WK"	"WOS:000337294400007"	24081207	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Admiraal, R; van Kesteren, C; Boelens, JJ; Bredius, RGM; Tibboel, D; Knibbe, CAJ"	"Admiraal, Rick; van Kesteren, Charlotte; Boelens, Jaap Jan; Bredius, Robbert G. M.; Tibboel, Dick; Knibbe, Catherijne A. J."	"NA"	"A"	"Towards evidence-based dosing regimens in children on the basis of population pharmacokinetic pharmacodynamic modelling"	"ARCHIVES OF DISEASE IN CHILDHOOD"	"English"	"Article"	"NA"	"GLOMERULAR-FILTRATION-RATE; PEDIATRIC COVARIATE MODEL; PREDICTIVE PERFORMANCE; AMIKACIN; INFANTS; MATURATION; MORPHINE; BUSULFAN; CLEARANCE; DRUGS"	"When growing up, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of drugs change, which may alter the effect of drugs. To ensure optimal drug efficacy and safety in paediatric care, PK and PD relationships of drugs need to be explored in children. This article presents an outline on performing a population PK/PD study and translating these results into rational dosing regimens, with the development and prospective evaluation of PK/PD derived evidence-based dosing regimen being discussed. Examples on amikacin, morphine and busulfan are provided, showing how PK (/PD) modelling not only led to optimization and individualization in paediatric clinical care for the specific drugs but also to insight in maturation of organ systems involved. It is shown that the latter results can subsequently be used as a basis for dosing of other drugs eliminated through the same pathway. Ultimately, these efforts should lead to predictable drug efficacy and safety across all age groups."	"[Admiraal, Rick; van Kesteren, Charlotte; Boelens, Jaap Jan] Univ Med Ctr Utrecht, Dept Paediat Immunol, Utrecht, Netherlands; [Admiraal, Rick; van Kesteren, Charlotte; Boelens, Jaap Jan; Knibbe, Catherijne A. J.] Univ Med Ctr Utrecht, Lab Appl Immunol, U DANCE, Utrecht, Netherlands; [Admiraal, Rick; van Kesteren, Charlotte; Bredius, Robbert G. M.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Admiraal, Rick; Tibboel, Dick; Knibbe, Catherijne A. J.] Leiden Univ, Med Ctr, Dept Paediat, Leiden, Netherlands; [Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Ctr, Rotterdam, Netherlands; [Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Ctr, Dept Paediat Surg, Rotterdam, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Bredius, Robbert/AAF-2592-2019"	"Boelens, Jaap Jan/0000-0003-2232-6952"	"Dutch Organisation for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); ZonMWNetherlands Organization for Health Research and Development [40-41500-98-11044]"	"The work of CAJK is supported by the Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Dutch Organisation for Scientific Research (NWO). The work of RA and CvK was supported by ZonMW grant number 40-41500-98-11044."	37	34	34	0	3	"BMJ PUBLISHING GROUP"	"LONDON"	"BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND"	"0003-9888"	"1468-2044"	"NA"	"ARCH DIS CHILD"	"Arch. Dis. Child."	"MAR"	2014	99	3	267	272	"NA"	"10.1136/archdischild-2013-303721"	6	"Pediatrics"	"Pediatrics"	"AD7YO"	"WOS:000333483600023"	24356807	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, RFW; Allegaert, K; Sherwin, CMT; Nielsen, EI; de Hoog, M; van den Anker, JN; Danhof, M; Knibbe, CAJ"	"De Cock, Roosmarijn F. W.; Allegaert, Karel; Sherwin, Catherine M. T.; Nielsen, Elisabet I.; de Hoog, Matthijs; van den Anker, Johannes N.; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"A Neonatal Amikacin Covariate Model Can Be Used to Predict Ontogeny of Other Drugs Eliminated Through Glomerular Filtration in Neonates"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"developmental changes; extrapolation; glomerular filtration rate; neonates; pharmacokinetics"	"POPULATION PHARMACOKINETICS; OFF-LABEL; CHILDREN; VANCOMYCIN; CLEARANCE; RECOGNITION; GENTAMICIN; MATURATION; PHYSIOLOGY; NEWBORNS"	"Recently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs. Five different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin. The extensively validated covariate model for amikacin clearance was used to predict clearance of these drugs. In addition, independent reference models were developed based on a systematic covariate analysis. The descriptive and predictive properties of the models developed using the amikacin covariate model were good, and fairly similar to the independent reference models (goodness-of-fit plots, NPDE). Moreover, similar clearance values were obtained for both approaches. Finally, the same covariates as in the covariate model of amikacin, i.e. birth bodyweight and postnatal age, were identified on clearance in the independent reference models. This study shows that pediatric covariate models may contain physiological information since information derived from one drug can be used to describe other drugs. This semi-physiological approach may be used to optimize sparse data analysis and to derive individualized dosing algorithms for drugs in children."	"[De Cock, Roosmarijn F. W.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, LACDR, Div Pharmacol, Leiden, Netherlands; [Allegaert, Karel] Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, Louvain, Belgium; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Div Clin Pharmacol, Salt Lake City, UT USA; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Clin Trials Off, Salt Lake City, UT USA; [Nielsen, Elisabet I.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [de Hoog, Matthijs; van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Rotterdam, Netherlands; [de Hoog, Matthijs; van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Nielsen, Elisabet/X-3368-2019; allegaert, karel/C-3611-2016; Sherwin, Catherine Mary Turner/B-2888-2012"	"allegaert, karel/0000-0001-9921-5105; Sherwin, Catherine Mary Turner/0000-0002-0844-3207"	"Top Institute Pharma [D2-104]; Fund for Scientific Research, FlandersFWO [1800214N]; IWT-SBO projectInstitute for the Promotion of Innovation by Science and Technology in Flanders (IWT) [130033]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01HD060543, K24DA027992, R01HD048689, U54HD071601]; FP7 grant TINN [223614]; FP7 grant TINN2 [260908]; FP7 grant NEUROSIS [223060]; FP7 grant GRIP [261060]"	"This study was performed within the framework of Top Institute Pharma project number D2-104. The clinical research of Karel Allegaert is supported by the Fund for Scientific Research, Flanders (Clinical Fellowship 1800214N) and has been supported by an IWT-SBO project (130033). The clinical research of J. van den Anker is supported by NIH grants (R01HD060543, K24DA027992, R01HD048689, U54HD071601) and FP7 grants TINN (223614), TINN2 (260908), NEUROSIS (223060), and GRIP (261060). The authors also would like to thank LAP&P Consultants for their technical support with NONMEM."	35	52	53	0	13	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"MAR"	2014	31	3	754	767	"NA"	"10.1007/s11095-013-1197-y"	14	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"AB7ZB"	"WOS:000332008800018"	24065592	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Sostelly, A; Payen, L; Guitton, J; Di Pietro, A; Falson, P; Honorat, M; Boumendjel, A; Geze, A; Freyer, G; Tod, M"	"Sostelly, Alexandre; Payen, Lea; Guitton, Jerome; Di Pietro, Attilio; Falson, Pierre; Honorat, Mylene; Boumendjel, Ahcene; Geze, Annabelle; Freyer, Gilles; Tod, Michel"	"NA"	"A"	"Quantitative evaluation of the combination between cytotoxic drug and efflux transporter inhibitors based on a tumour growth inhibition model"	"FUNDAMENTAL & CLINICAL PHARMACOLOGY"	"English"	"Article"	"NONMEM; Tumor growth modelling; ABC transporters; Anticancer drug resistance"	"PHASE-I TRIAL; P-GLYCOPROTEIN INHIBITOR; MULTIDRUG-RESISTANCE; TRIHYDROCHLORIDE LY335979; CANCER; DOXORUBICIN; IRINOTECAN; ZOSUQUIDAR"	"ATP-Binding Cassette transporters such as ABCG2 confer resistance to various anticancer drugs including irinotecan and its active metabolite, SN38. Early quantitative evaluation of efflux transporter inhibitors-cytotoxic combination requires quantitative drug-disease models. A proof-of-concept study has been carried out for studying the effect of a new ABCG2 transporter inhibitor, MBLI87 combined to irinotecan in mice xenografted with cells overexpressing ABCG2. Mice were treated with irinotecan alone or combined to MBLI87, and tumour size was periodically measured. To model those data, a tumour growth inhibition model was developed. Unperturbed tumour growth was modelled using Simeoni's model. Drug effect kinetics was accounted for by a Kinetic-Pharmacodynamic approach. Effect of inhibitor was described with a pharmacodynamic interaction model where inhibitor enhances activity of cytotoxic. This model correctly predicted tumour growth dynamics from our study. MBLI87 increased irinotecan potency by 20% per mu mol of MBLI87. This model retains enough complexity to simultaneously describe tumour growth and effect of this type of drug combination. It can thus be used as a template to early evaluate efflux transporter inhibitors in-vivo."	"[Sostelly, Alexandre; Guitton, Jerome; Freyer, Gilles; Tod, Michel] Fac Med & Maieut Lyon Sud Charles, Ciblage Therapeut Oncol, EMR3738, Oullins, France; [Sostelly, Alexandre; Honorat, Mylene] Univ Lyon, Lyon, France; [Payen, Lea; Guitton, Jerome; Tod, Michel] Univ Lyon 1, F-69365 Lyon, France; [Payen, Lea; Honorat, Mylene] Leon Berard FNCLCC, Ctr Cancerol Lyon CRCL, INSERM U1052, Lyon, France; [Payen, Lea; Guitton, Jerome] Hos Civils Lyon, Biochem Lab Lyon Sud CBS, Oullins, France; [Di Pietro, Attilio; Falson, Pierre] Univ Lyon, CNRS, UMR 5086,IFR 128 BioSci Gerland Lyon, Inst Biol & Chim Prot,Equipe Labellise Ligue 2009, Lyon, France; [Geze, Annabelle; Tod, Michel] Univ Grenoble, CNRS, UMR5063, Dept Pharmacochim Mol, Grenoble, France; [Freyer, Gilles] Hos Civils Lyon, Lyon, France"	"Sostelly, A (corresponding author), Fac Med & Maieut Lyon Sud Charles, Ciblage Therapeut Oncol, EMR3738, Oullins, France."	"alexandre.sostelly@gmail.com"	"NA"	"Falson, Pierre/0000-0002-9760-4577; Guitton, Jerome/0000-0001-6180-5708"	"NA"	"NA"	31	7	8	1	14	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0767-3981"	"1472-8206"	"NA"	"FUND CLIN PHARMACOL"	"Fundam. Clin. Pharmacol."	"APR"	2014	28	2	161	169	"NA"	"10.1111/fcp.12005"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AC0XV"	"WOS:000332219700005"	23384250	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Valade, E; Treluyer, JM; Bouazza, N; Ghosn, J; Foissac, F; Benaboud, S; Fauchet, F; Viard, JP; Urien, S; Hirt, D"	"Valade, Elodie; Treluyer, Jean-Marc; Bouazza, Naim; Ghosn, Jade; Foissac, Frantz; Benaboud, Sihem; Fauchet, Floris; Viard, Jean-Paul; Urien, Saik; Hirt, Deborah"	"NA"	"A"	"Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"DISOPROXIL FUMARATE; HEALTHY-VOLUNTEERS; STEADY-STATE; COMBINATION; QUANTIFICATION; PREDICTION; INFECTION; TENOFOVIR; TRIAL"	"The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CLCR), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC(0-24)) was 12.5 mg.h/liter for patients with normal renal function (CLCR, >80 ml/min), 14.7 mg.h/liter for patients with mild renal impairment (CLCR, 79 to 50 ml/min), and 17.9 mg.h/liter for patients with moderate renal impairment (CLCR, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC(0-48), 17.2 mg.h/liter) than for patients with normal renal function (median AUC(0-48), 25.6 mg.h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function."	"[Valade, Elodie; Treluyer, Jean-Marc; Ghosn, Jade; Fauchet, Floris; Viard, Jean-Paul; Urien, Saik; Hirt, Deborah] Univ Paris 05, EA 3620, Sorbonne Paris Cite, Paris, France; [Valade, Elodie; Treluyer, Jean-Marc; Bouazza, Naim; Foissac, Frantz; Benaboud, Sihem; Fauchet, Floris; Urien, Saik; Hirt, Deborah] AP HP, Unite Rech Clin Paris Ctr, Paris, France; [Treluyer, Jean-Marc; Bouazza, Naim; Foissac, Frantz; Benaboud, Sihem; Urien, Saik] CIC 0901 INSERM, Paris, France; [Treluyer, Jean-Marc; Benaboud, Sihem; Hirt, Deborah] Grp Hosp Paris Ctr, AP HP, Hop Cochin, Serv Pharmacol Clin, Paris, France; [Ghosn, Jade; Viard, Jean-Paul] Grp Hosp Paris Ctr, AP HP, Hotel Dieu, Ctr Diagnost & Therapeut, Paris, France"	"Valade, E (corresponding author), Univ Paris 05, EA 3620, Sorbonne Paris Cite, Paris, France."	"elodie.valade@free.fr"	"treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013; Viard, Jean-Paul/O-6467-2017"	"Viard, Jean-Paul/0000-0001-5946-8896"	"NA"	"NA"	20	28	28	0	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2014	58	4	2256	2261	"NA"	"10.1128/AAC.02058-13"	6	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"AD9SU"	"WOS:000333605600051"	24492366	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, RFW; Smits, A; Allegaert, K; de Hoon, J; Saegeman, V; Danhof, M; Knibbe, CAJ"	"De Cock, R. F. W.; Smits, A.; Allegaert, K.; de Hoon, J.; Saegeman, V.; Danhof, M.; Knibbe, C. A. J."	"NA"	"A"	"Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"developmental pharmacology; antibiotics; protein binding"	"PROTEIN-BINDING; DRUG DISPOSITION; INFANTS; AMOXICILLIN; FLUCLOXACILLIN; CEPHALOSPORINS; ANTIBACTERIAL; PHARMACOLOGY; PREGNANCY; THERAPY"	"Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing. Thirty-six neonates [median birth body weight 2720 (range 5404200) g, current body weight (cBW) 2755 (8304200) g and postnatal age (PNA) 9 (130) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (60 of the time) in all patients. A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (B-max) of 136 mg/L and a dissociation constant (K-D) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for B-max, explaining 50, 58 and 41 of inter-individual variability in V, clearance and B-max, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed. A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates."	"[De Cock, R. F. W.; Danhof, M.; Knibbe, C. A. J.] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Smits, A.; Allegaert, K.] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Smits, A.; Allegaert, K.] Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, Louvain, Belgium; [de Hoon, J.] Katholieke Univ Leuven Hosp, Ctr Clin Pharmacol, Louvain, Belgium; [Saegeman, V.] Katholieke Univ Leuven Hosp, Dept Lab Med, Louvain, Belgium; [Knibbe, C. A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3435 CM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Smits, Anne/AAG-4433-2019; allegaert, karel/C-3611-2016; de Hoon, Jan/E-3256-2018"	"Smits, Anne/0000-0002-0710-6698; allegaert, karel/0000-0001-9921-5105; de Hoon, Jan/0000-0002-5215-9836"	"Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen)FWO [1800214N]"	"The work was partly supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen), with a Fundamental Clinical Investigatorship (grant number 1800214N) to K. A."	44	14	14	0	12	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"MAY"	2014	69	5	1330	1338	"NA"	"10.1093/jac/dkt527"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"AF4MY"	"WOS:000334688400024"	24492261	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Zhang, DL; Fakhoury, M; Fahd, M; Duquesne, F; Storme, T; Baruchel, A; Jacqz-Aigrain, E"	"Zhao, Wei; Zhang, Daolun; Fakhoury, May; Fahd, Mony; Duquesne, Frederique; Storme, Thomas; Baruchel, Andre; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Population Pharmacokinetics and Dosing Optimization of Vancomycin in Children with Malignant Hematological Disease"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"TRANSPLANT PATIENTS; PEDIATRIC-PATIENTS; MODEL; PREDICTION; ONCOLOGY; AGENTS"	"An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had sub-therapeutic steady-state trough concentrations (C-ss/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target C-ss/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population."	"[Zhao, Wei; Zhang, Daolun; Fakhoury, May; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, F-75019 Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Investigat Ctr CIC1426, Paris, France; [Fahd, Mony; Duquesne, Frederique; Baruchel, Andre] Hop Robert Debre, AP HP, Dept Pediat Hematooncol, F-75019 Paris, France; [Storme, Thomas] Hop Robert Debre, AP HP, Dept Pharm, F-75019 Paris, France; [Baruchel, Andre; Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France"	"Zhao, W (corresponding author), Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, F-75019 Paris, France."	"wei.zhao@rdb.aphp.fr; evelyne.jacqz-aigrain@rdb.aphp.fr"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"project Global Research in Pediatrics-Network of Excellence (European Union) [261060]"	"This work was supported by the project Global Research in Pediatrics-Network of Excellence (European Union-funded FP7 project, grant agreement number 261060)."	25	40	42	1	5	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JUN"	2014	58	6	3191	3199	"NA"	"10.1128/AAC.02564-13"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"AK9VP"	"WOS:000338776900026"	24663023	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Shang, DW; Li, LJ; Wang, XP; Wen, YG; Ren, YP; Guo, W; Li, WB; Li, L; Zhou, TY; Lu, W; Wang, CY"	"Shang, De-Wei; Li, Li-Jun; Wang, Xi-Pei; Wen, Yu-Guan; Ren, Yu-Peng; Guo, Wei; Li, Wen-Biao; Li, Liang; Zhou, Tian-Yan; Lu, Wei; Wang, Chuan-Yue"	"NA"	"A"	"Population Pharmacokinetic/Pharmacodynamic Model of Clozapine for Characterizing the Relationship Between Accumulated Exposure and PANSS Scores in Patients With Schizophrenia"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"clozapine; schizophrenia; NONMEM; PK; PD model"	"DRUG-MONITORING SERVICE; PLASMA CLOZAPINE; NORCLOZAPINE; PHARMACOKINETICS; ANTIPSYCHOTICS; RESISTANT; VARIABLES; NONMEM; SEX"	"Background:The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling.Methods:Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, E-max, and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens.Results:A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the E-max model. The maximum decrease in PANSS during clozapine treatment (E-max) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E-max was 296 mg center dot L-1 center dot h(-1)center dot d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen.Conclusions:The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients."	"[Shang, De-Wei; Li, Li-Jun; Guo, Wei; Li, Wen-Biao; Wang, Chuan-Yue] Capital Med Univ, Beijing Anding Hosp, Beijing Key Lab Mental Disorders, Beijing, Peoples R China; [Shang, De-Wei; Wen, Yu-Guan] Guangzhou Med Univ, Guangzhou Brain Hosp, Dept Pharm, Guangzhou, Guangdong, Peoples R China; [Wang, Xi-Pei] Guangdong Acad Med Sci, Guangdong Cardiovasc Inst, Guangdong Gen Hosp, Dept Cardiol, Guangzhou, Guangdong, Peoples R China; [Ren, Yu-Peng; Li, Liang; Zhou, Tian-Yan; Lu, Wei] Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China; [Wang, Chuan-Yue] Capital Med Univ, Beijing Neurosci Disciplines, State Key Lab Incubat Base, Beijing Key Lab Brain Major Disorders, Beijing, Peoples R China"	"Lu, W (corresponding author), Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, 38 Xueyuan Rd, Beijing 100191, Peoples R China."	"luwei_pk@bjmu.edu.cn"	"Guo, Wei/M-4228-2019; Guo, Wei/E-5035-2011; Wang, Chuan-Yue/C-9369-2015; Wang, Xipei/AAK-7214-2020; Shang, Dewei/AAI-8415-2020"	"Guo, Wei/0000-0003-0757-9660; Guo, Wei/0000-0003-0757-9660; Wang, Chuan-Yue/0000-0001-6549-3713; Wang, Xipei/0000-0002-2017-7247; Shang, Dewei/0000-0001-5546-3393"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [30770776]; National High Technology Research and Development Program of China (863 Program)National High Technology Research and Development Program of China [2009AA022702]; Beijing Municipal Education Commission Science and Technology Development Program [KM201110025025]; Beijing Postdoctoral Research FoundationChina Postdoctoral Science Foundation [2011ZZ-11]; National Science and Technology Major Project for investigational new drug [2012ZX09303-003]; Medical Scientific Research Foundation of Guangdong Province [B2011276]; Guangzhou Medical Science and Technology Project [20121A011096]; Science and Technology Major Project of Guangdong Province [2011A080300003, 2012A080204017]"	"Supported by the National Natural Science Foundation of China (Grant 30770776), the National High Technology Research and Development Program of China (863 Program) (Grant 2009AA022702), Beijing Municipal Education Commission Science and Technology Development Program (Grant KM201110025025), Beijing Postdoctoral Research Foundation (Grant 2011ZZ-11), National Science and Technology Major Project for investigational new drug (2012ZX09303-003), Medical Scientific Research Foundation of Guangdong Province (B2011276), Guangzhou Medical Science and Technology Project (20121A011096), Science and Technology Major Project of Guangdong Province (Grant 2011A080300003 and 2012A080204017)."	27	8	8	0	7	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"JUN"	2014	36	3	378	386	"NA"	"10.1097/FTD.0000000000000014"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AJ4XE"	"WOS:000337682000015"	24342896	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Djerada, Z; Fournet-Fayard, A; Gozalo, C; Lelarge, C; Lamiable, D; Millart, H; Malinovsky, JM"	"Djerada, Zoubir; Fournet-Fayard, Aurelie; Gozalo, Claire; Lelarge, Chantal; Lamiable, Denis; Millart, Herve; Malinovsky, Jean-Marc"	"NA"	"A"	"Population pharmacokinetics of nefopam in elderly, with or without renal impairment, and its link to treatment response"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"analgesia; elderly; logistic regression; nefopam; population pharmacokinetics; renal impairment"	"POSTOPERATIVE ANALGESIA; ORAL NEFOPAM; EFFICACY; PAIN; TRANSPLANTATION; VOLUNTEERS; MANAGEMENT; SURGERY; MODELS; PLASMA"	"Aims Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use. Methods Elderly patients (n = 48), 65-99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20mg) was administered as a 30min infusion postoperatively. Simultaneously, a 1min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1.3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression. Results A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3lh-1 (53.2%), 114l (121%), 80.7lh-1 (79%) and 208l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration. Conclusions We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20mg), simulations suggest an infusion time of >45min in elderly patients with or without renal impairment."	"[Djerada, Zoubir; Gozalo, Claire; Lamiable, Denis; Millart, Herve] Reims Univ Hosp, Dept Pharmacol, F-51095 Reims, France; [Fournet-Fayard, Aurelie; Lelarge, Chantal; Malinovsky, Jean-Marc] Reims Univ Hosp, Dept Anesthesia & Intens Care Pole URAD, F-51092 Reims, France"	"Djerada, Z (corresponding author), Reims Univ Hosp, SFR CAP Sante, EA 3801, Dept Pharmacol, 51 Rue Cognacq Jay, F-51095 Reims, France."	"zoubir.djerada@univ-reims.fr"	"NA"	"djerada, zoubir/0000-0002-4022-7889"	"Regional Clinical Research Program of Reims University Hospital [PHRC 2004-R11-07]"	"All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: this study was funded by the Regional Clinical Research Program of Reims University Hospital, in 2004 (PHRC 2004-R11-07); no financial relationships with any organizations that might have an interest in the submitted work; no other relationships or activities that could appear to have influenced the submitted work."	36	18	18	0	7	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUN"	2014	77	6	1027	1038	"NA"	"10.1111/bcp.12291"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AJ2UT"	"WOS:000337519900013"	24252055	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, RFW; Allegaert, K; Vanhaesebrouck, S; de Hoon, J; Verbesselt, R; Danhof, M; Knibbe, CAJ"	"De Cock, Roosmarijn F. W.; Allegaert, Karel; Vanhaesebrouck, Sophie; de Hoon, Jan; Verbesselt, Rene; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Low but Inducible Contribution of Renal Elimination to Clearance of Propylene Glycol in Preterm and Term Neonates"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"propylene glycol; renal and hepatic elimination; neonates; population pharmacokinetics"	"PHARMACOKINETICS; EXCIPIENTS; TOXICITY; INFUSION; ALCOHOL; HUMANS"	"Background:Despite limited information being available on the pharmacokinetics of excipients, propylene glycol (PG) is often used as an excipient in both adults and children. The aim of this study is to characterize the renal and hepatic elimination of PG in preterm and term neonates.Methods:The pharmacokinetic analysis of PG was performed in NONMEM 6.2. on the basis of PG concentrations in plasma and/or urine samples for a total of 69 (pre)term neonates (birth weight 630-3980 g, gestational age 24-41 weeks, postnatal age 1-29 days) who received PG coadministered with intravenous paracetamol (5-10 mg/kg per 6 hours), phenobarbital (5 mg center dot kg(-1)center dot d(-1)), or both. To capture the time-dependent trend in the renal excretion of PG, different models based on time after the first dose, urine volume, and creatinine amount in urine were tested.Results:A one-compartment model parameterized in terms of renal clearance, hepatic clearance, and volume of distribution was found to adequately describe the observations in both plasma and urine. After the first dose was administered, the renal elimination of PG was 15% of total clearance, which increased over time to 25% at 24 hours after the first dose of PG. This increase was best described using a hyperbolic function based on time after the first dose.Conclusions:Renal elimination of PG in (pre)term neonates is low, particularly compared with the reported percentage of 45% in adults, but it may increase with time after the first dose of PG. To study whether this increase is caused by an autoinduced increase in the renal secretion or a reduction of tubular reabsorption of PG, further research is needed."	"[De Cock, Roosmarijn F. W.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, LACDR, Div Pharmacol, Leiden, Netherlands; [Allegaert, Karel; Vanhaesebrouck, Sophie] Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium; [de Hoon, Jan; Verbesselt, Rene] Univ Hosp Leuven, Ctr Clin Pharmacol, Leuven, Belgium; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"de Hoon, Jan/E-3256-2018; allegaert, karel/C-3611-2016"	"de Hoon, Jan/0000-0002-5215-9836; allegaert, karel/0000-0001-9921-5105"	"Fund for Scientific Research, Flanders (Belgium; FWO Vlaanderen)FWO; Top Institute Pharma [D2-104]"	"The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium; FWO Vlaanderen) by a Fundamental Clinical Investigatorship (1800209 N).; This study was performed within the framework of Top Institute Pharma project number D2-104."	24	11	11	0	8	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"JUN"	2014	36	3	278	287	"NA"	"10.1097/FTD.0000000000000003"	10	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AJ4XE"	"WOS:000337682000002"	24305628	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Stockmann, C; Sherwin, CMT; Buterbaugh, W; Spigarelli, MG; Gottschlich, MM; Healy, D; Kagan, RJ"	"Stockmann, Chris; Sherwin, Catherine M. T.; Buterbaugh, Whitney; Spigarelli, Michael G.; Gottschlich, Michele M.; Healy, Daniel; Kagan, Richard J."	"NA"	"A"	"Preliminary Assessment of Zolpidem Pharmacokinetics in Pediatric Burn Patients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"zolpidem tartrate; pharmacokinetics; pediatric burns; sleep"	"SLEEP; INSOMNIA; CHILDREN; EFFICACY; MODELS; INJURY; SAFETY; PAIN"	"Purpose:Severely burned patients frequently experience sleep fragmentation and insomnia. This study evaluated the population pharmacokinetics of the sleep-enhancing agent zolpidem among burned children.Methods:Zolpidem was administered according to the following age-based dosing schedule: 2.5 mg per dose for 2-4 year olds, 5.0 mg per dose for 5-10 year olds, and 10 mg per dose for older than 10 years. Serum samples were collected before and 1, 2, 4, 5, 6, and 8 hours after dosing. The population pharmacokinetic analysis modeled zolpidem concentrations using nonlinear mixed effects models.Results:Eleven patients with a mean (SD) age of 8.3 � 4.0 years and a mean total burn surface area of 56% � 22% were recruited. Seventy-three zolpidem concentrations were measured with a mean Cmax of 291 � 140 ng/mL. A 2-compartment model with first-order absorption best described the data. Zolpidem clearance was estimated at 0.03 L center dot h(-1)center dot kg(-1) (relative standard error, 55%) and increased with body weight (P < 0.05). The central compartment volume of distribution was estimated at 0.05 L/kg (relative standard error, 25%), which was inversely related to the proportion of the body surface with third-degree burns (P < 0.001).Conclusions:A population pharmacokinetic model has been developed that reliably characterized the pharmacokinetic parameters of zolpidem when used as a sleep-enhancing agent among pediatric burn patients. Additional studies are needed to link this pharmacokinetic model with pharmacodynamic data, which may include an assessment of the effects of higher zolpidem doses and/or more frequent administration upon sleep architecture."	"[Stockmann, Chris; Sherwin, Catherine M. T.; Spigarelli, Michael G.] Univ Utah, Sch Med, Div Clin Pharmacol, Dept Pediat, Salt Lake City, UT 84108 USA; [Buterbaugh, Whitney; Healy, Daniel] Univ Cincinnati, James L Winkle Coll Pharm, Cincinnati, OH 45221 USA; [Gottschlich, Michele M.; Healy, Daniel; Kagan, Richard J.] Shriners Hosp Children, Cincinnati, OH USA; [Gottschlich, Michele M.; Kagan, Richard J.] Univ Cincinnati, Dept Surg, Cincinnati, OH 45221 USA"	"Stockmann, C (corresponding author), Univ Utah, Hlth Sci Ctr, Div Clin Pharmacol, Dept Pediat, Salt Lake City, UT 84108 USA."	"chris.stockmann@hsc.utah.edu"	"Stockmann, Chris/P-1996-2014; Sherwin, Catherine Mary Turner/B-2888-2012"	"Stockmann, Chris/0000-0002-5779-5567; Sherwin, Catherine Mary Turner/0000-0002-0844-3207"	"Shriners Hospitals for Children [70097, 71005]"	"This work was sponsored by a grant from Shriners Hospitals for Children to M. M. G. (grants 70097 and 71005)."	29	4	4	0	5	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"JUN"	2014	36	3	295	301	"NA"	"10.1097/FTD.0000000000000017"	7	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AJ4XE"	"WOS:000337682000004"	24365985	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"ter Heine, R; van Maarseveen, EM; van der Westerlaken, MML; Braun, KPJ; Koudijs, SM; ten Berg, MJ; Malingre, MM"	"ter Heine, Rob; van Maarseveen, Erik M.; van der Westerlaken, Monique M. L.; Braun, Kees P. J.; Koudijs, Suzanne M.; ten Berg, Maarten J.; Malingre, Mirte M."	"NA"	"A"	"The Quantitative Effect of Serum Albumin, Serum Urea, and Valproic Acid on Unbound Phenytoin Concentrations in Children"	"JOURNAL OF CHILD NEUROLOGY"	"English"	"Article"	"phenytoin; albumin; urea; valproic acid; carbamazepine; bilirubin"	"PLASMA-PROTEIN BINDING; PEDIATRIC-PATIENTS; UREMIA; PREDICTION; DRUGS; PHARMACOKINETICS; CARBAMAZEPINE; HEMODIALYSIS; VARIABILITY; INHIBITOR"	"Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity."	"[ter Heine, Rob; van der Westerlaken, Monique M. L.; Malingre, Mirte M.] Meander Med Ctr, Dept Clin Pharm, NL-3818 ES Amersfoort, Netherlands; [van Maarseveen, Erik M.] Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands; [Braun, Kees P. J.; Koudijs, Suzanne M.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Child Neurol, Utrecht, Netherlands; [ten Berg, Maarten J.] Med Ctr Utrecht, Dept Clin Chem & Hematol, Utrecht, Netherlands"	"ter Heine, R (corresponding author), Meander Med Ctr, Dept Clin Pharm, Utrechtseweg 160, NL-3818 ES Amersfoort, Netherlands."	"rob@terheine.nl"	"Heine, Rob ter/A-1757-2016"	"NA"	"NA"	"NA"	34	1	1	0	1	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"0883-0738"	"1708-8283"	"NA"	"J CHILD NEUROL"	"J. Child Neurol."	"JUN"	2014	29	6	803	810	"NA"	"10.1177/0883073813486294"	8	"Clinical Neurology; Pediatrics"	"Neurosciences & Neurology; Pediatrics"	"AM8ZN"	"WOS:000340168800011"	23670246	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Ternant, D; Ducourau, E; Perdriger, A; Corondan, A; Le Goff, B; Devauchelle-Pensec, V; Solau-Gervais, E; Watier, H; Goupille, P; Paintaud, G; Mulleman, D"	"Ternant, David; Ducourau, Emilie; Perdriger, Aleth; Corondan, Anca; Le Goff, Benoit; Devauchelle-Pensec, Valerie; Solau-Gervais, Elisabeth; Watier, Herve; Goupille, Philippe; Paintaud, Gilles; Mulleman, Denis"	"NA"	"A"	"Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"inflammation; infliximab; monoclonal antibodies; pharmacokinetics; rheumatoid arthritis"	"TNF-ALPHA; POPULATION PHARMACOKINETICS; ANKYLOSING-SPONDYLITIS; CLINICAL-RESPONSE; METHOTREXATE; ANTIBODIES; THERAPY; PHARMACODYNAMICS; IMMUNOGENICITY; EFFICACY"	"Aims Infliximab, an anti-tumour necrosis factor- monoclonal antibody, is indicated in rheumatoid arthritis (RA). Our objective was to evaluate the influence of the sources of infliximab pharmacokinetic variability in RA. Methods Eighty-four patients treated with infliximab for RA were included in a prospective noncomparative study. They were analysed between two consecutive infliximab infusions. Infliximab concentrations were measured before the infusion, 2h, 1 and 4 weeks after the infusion and immediately before the next infusion. Infliximab concentrations were described using a two-compartment population pharmacokinetic model. Results The mean (interindividual standard deviation) estimated central volume of distribution was 2.3l (36%) and systemic clearance was 0.019lh-1 (37%). The central volume of distribution increased with bodyweight; it was doubled between 50 and 90kg. Systemic clearance increased with pre-infusion C-reactive protein concentration by 20%, varying from 3 to 14mgl-1, and was decreased by 30% when methotrexate was coadministered. Conclusions The influence of methotrexate and inflammation on infliximab clearance suggests that individual adjustment of infliximab doses according to disease activity may be useful in RA."	"[Ternant, David; Ducourau, Emilie; Watier, Herve; Goupille, Philippe; Paintaud, Gilles; Mulleman, Denis] Univ Tours, GICC, Tours, France; [Ternant, David; Ducourau, Emilie; Watier, Herve; Goupille, Philippe; Paintaud, Gilles; Mulleman, Denis] CNRS, UMR 7293, Tours, France; [Ternant, David; Ducourau, Emilie; Watier, Herve; Goupille, Philippe; Paintaud, Gilles; Mulleman, Denis] CHRU Tours, F-37044 Tours 9, France; [Perdriger, Aleth] CHRU Rennes, Rennes, France; [Corondan, Anca] CHR Orleans, Orleans, France; [Le Goff, Benoit] CHRU Nantes, Nantes, France; [Devauchelle-Pensec, Valerie] Univ Bretagne Occidentale, CHRU Brest, EA 2216, Brest, France; [Solau-Gervais, Elisabeth] CHRU Poitiers, Poitiers, France; [Goupille, Philippe; Mulleman, Denis] INSERM, CIC 202, Tours, France"	"Ternant, D (corresponding author), CHRU Tours, Lab Pharmacol Toxicol, CNRS, UMR 7292, 2 Blvd Tonnelle, F-37044 Tours 9, France."	"david.ternant@free.fr"	"Le Goff, Benoit/K-8229-2015; Mulleman, Denis/O-3221-2019; Mulleman, Denis/K-5822-2012"	"Le Goff, Benoit/0000-0002-4540-4549; Mulleman, Denis/0000-0003-4089-7513; PAINTAUD, Gilles/0000-0003-0158-1356"	"BMSBristol-Myers Squibb; RocheRoche Holding; AbbottAbbott Laboratories; MSD; AmgenAmgen; Chugai; PfizerPfizer; UCBUCB Pharma SA; JanssenJohnson & Johnson USAJanssen Biotech Inc; LillyEli Lilly; Roche Pharma; NovartisNovartis; French Ministry for Health and Sport; FEDER (Fonds europeen de developpement regional)European Union (EU)"	"ED has received fees for serving as a speaker for BMS; she has been personally invited to attend international congresses by Roche, Chugai, UCB, BMS and Abbott. BLG has received fees for serving as a speaker for Roche and Abbott; he has been personally invited to attend international congresses by Pfizer and Abbott; he received funding for scientific research from MSD and Roche. AC has received fees for serving as a speaker for Amgen; she has been personally invited to attend international congresses by MSD and Roche. VD-P has participated on behalf of her institution in clinical trials sponsored by Abbott, Roche, Chugai, BMS, Pfizer and UCB; she has been personally invited to attend international congresses by UCB, Chugai, Roche and Abbott. ES-G has participated on behalf of her institution in clinical trials sponsored by Roche and BMS, and her hospital received grants for research from Roche in 2010 and 2011; she has acted as a consultant and given lectures on behalf of her institution for Roche, Abbott, BMS and Pfizer; she has been personally invited to attend international congresses by BMS, Roche and Abbott. PG has participated on behalf of his institution in clinical trials sponsored by Abbott, BMS, Janssen, Lilly, MSD, Pfizer, Roche and UCB; he has acted as a consultant and given lectures for Abbott, BMS, Janssen, MSD, Pfizer and UCB; he has been personally invited to attend international congresses by Abbott, MSD and Pfizer. GP is a consultant for Laboratoires Francais du Fractionnement et des Biotechnologies (LFB) and Pierre-Fabre Laboratories; his research team has received finance from Roche Pharma, Chugai, Pfizer, Novartis and Janssen. DM has participated on behalf of his institution in clinical trials sponsored by Abbott, Roche, BMS, Pfizer, UCB and MSD; his hospital received a grant for research from Abbott in 2004; he has acted as a consultant and given lectures on behalf of his institution for MSD and Pfizer; he has been personally invited to attend international congresses by MSD, Roche, BMS and Abbott. The other authors have no competing interests to declare.; The authors thank Dr Nicole Gando-Loembe and Stephanie Gerard for recruiting patients; Dr Bruno Giraudeau for his methodological advice in the study design; Yoann Desvignes for technical support with the study protocol and data management; Helene Bansard, Fanny Teasdale, Francoise Gouais and Fabienne Chapacou for blood sampling; Coraline Gadras and Celine Vignault for blood sample management; Anne-Claire Duveau for technical assistance with infliximab assays; Audrey Farnault for technical assistance for assays of antibody toward infliximab and Laura Heraty for her kind assistance with the manuscript. This work was promoted by the Regional University Hospital Center of Tours and supported by grants from the French Ministry for Health and Sport within the framework of the 'Programme Hospitalier de Recherche Clinique 2007'. The Regional University Hospital of Tours received a FEDER (Fonds europeen de developpement regional - European funding for regional development) for its CePiBAc (Centre pilote de suivi biologique des anticorps therapeutiques - Pilot centre for therapeutic antibodies monitoring). This work was a collaborative venture by HUGO (Hopitaux Universitaires du Grand Ouest - Western France University Hospitals Network)."	24	47	48	0	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUL"	2014	78	1	118	128	"NA"	"10.1111/bcp.12313"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AJ8RS"	"WOS:000337975400012"	24354889	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Colin, P; Eleveld, DJ; Struys, MMRF; T'Jollyn, H; Van Bortel, LM; Ruige, J; De Waele, J; Van Bocxlaer, J; Boussery, K"	"Colin, Pieter; Eleveld, Douglas J.; Struys, Michel M. R. F.; T'Jollyn, Huybrecht; Van Bortel, Luc M.; Ruige, Johannes; De Waele, Jan; Van Bocxlaer, Jan; Boussery, Koen"	"NA"	"A"	"Moxifloxacin dosing in post-bariatric surgery patients"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"bariatric surgery; moxifloxacin; NONMEM; PK-PD; pharmacokinetics"	"GASTRIC BYPASS-SURGERY; RESISTANT STREPTOCOCCUS-PNEUMONIAE; VITRO DYNAMIC-MODEL; ORAL BIOAVAILABILITY; DRUG ABSORPTION; HUMAN PLASMA; PHARMACOKINETICS; FLUOROQUINOLONES; LEVOFLOXACIN; CIPROFLOXACIN"	"Introduction Given the ever increasing number of obese patients and obesity related bypass surgery, dosing recommendations in the post-bypass population are needed. Using a population pharmacokinetic (PK) analysis and PK-pharmacodynamic (PD) simulations, we investigated whether adequate moxifloxacin concentrations are achieved in this population. Methods In this modelling and simulation study we used data from a trial on moxifloxacin PK. In this trial, volunteers who had previously undergone bariatric surgery (at least 6 months prior to inclusion), received two doses (intravenous and oral) of 400mg moxifloxacin administered on two occasions. Results In contrast to other papers, we found that moxifloxacin PK were best described by a three compartmental model using lean body mass (LBM) as a predictor for moxifloxacin clearance. Furthermore, we showed that the probability of target attainment for bacterial eradication against a hypothetical Streptococcus pneumoniae infection is compromised in patients with higher LBM, especially when targeting microorganisms with minimum inhibitory concentrations (MICs) of 0.5mgl-1 or higher (probability of target attainment (PTA) approaching zero). When considering the targets for suppression of bacterial resistance formation, even at MIC values as low as 0.25mgl-1, standard moxifloxacin dosing does not attain adequate levels in this population. Furthermore, for patients with a LBM of 78kg or higher, the probability of hitting this target approaches zero. Conclusions Throughout our PK-PD simulation study, it became apparent that, whenever optimal bacterial resistance suppression is deemed necessary, the standard moxifloxacin dosing will not be sufficient. Furthermore, our study emphasizes the need for a LBM based individualized dosing of moxifloxacin in this patient population."	"[Colin, Pieter; T'Jollyn, Huybrecht; Van Bocxlaer, Jan; Boussery, Koen] Univ Ghent, Fac Pharmaceut Sci, Lab Med Biochem & Clin Anal, B-9000 Ghent, Belgium; [Eleveld, Douglas J.; Struys, Michel M. R. F.] Univ Groningen, Univ Med Ctr Groningen, Dept Anesthesiol, Groningen, Netherlands; [Struys, Michel M. R. F.] Univ Ghent, Dept Anesthesia, B-9000 Ghent, Belgium; [Van Bortel, Luc M.] Univ Ghent, Heymans Inst Pharmacol, B-9000 Ghent, Belgium; [Ruige, Johannes] Ghent Univ Hosp, Dept Endocrinol & Metab Dis, Ghent, Belgium; [De Waele, Jan] Ghent Univ Hosp, Dept Crit Care Med, Ghent, Belgium"	"Colin, P (corresponding author), Harelbekestr 72, B-9000 Ghent, Belgium."	"pieter.colin@ugent.be"	"Colin, Pieter/AAK-3525-2020"	"Colin, Pieter/0000-0003-3616-5539; T'jollyn, Huybrecht/0000-0003-2101-9926"	"Drug Research Unit Ghent of Ghent University Hospital"	"We thank the Drug Research Unit Ghent of Ghent University Hospital for clinical study support."	26	4	4	0	7	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUL"	2014	78	1	84	93	"NA"	"10.1111/bcp.12302"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AJ8RS"	"WOS:000337975400009"	24313873	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Sahota, T; Sanderson, I; Danhof, M; Della Pasqua, O"	"Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Model-based analysis of thromboxane B-2 and prostaglandin E-2 as biomarkers in the safety evaluation of naproxen"	"TOXICOLOGY AND APPLIED PHARMACOLOGY"	"English"	"Article"	"Biomarkers; Safety pharmacology; Naproxen; PKPD modelling; Drug development; Long term safety"	"VS. SEQUENTIAL-ANALYSIS; IN-VITRO; MECHANISM; ROFECOXIB; TOXICITY; PHARMACOLOGY; PERFORMANCE; ATTRITION; PLASMA; COX-2"	"The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C-max and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15,40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B-2 and prostaglandin E-2 were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB2 and PGE(2) was described by direct inhibition models with maximum pharmacological effects achieved at doses >7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. (C) 2014 Elsevier Inc. All rights reserved."	"[Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar] Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Uxbridge, Middx, England"	"Della Pasqua, O (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, NL-2300 RA Leiden, Netherlands."	"NA"	"NA"	"NA"	"NA"	"NA"	40	6	7	0	7	"ACADEMIC PRESS INC ELSEVIER SCIENCE"	"SAN DIEGO"	"525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA"	"0041-008X"	"1096-0333"	"NA"	"TOXICOL APPL PHARM"	"Toxicol. Appl. Pharmacol."	"AUG 1"	2014	278	3	209	219	"NA"	"10.1016/j.taap.2014.03.010"	11	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"AJ6DH"	"WOS:000337779400002"	24667227	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Benz-de Bretagne, I; Zahr, N; Le Gouge, A; Hulot, JS; Houillier, C; Khe, HX; Gyan, E; Lissandre, S; Choquet, S; Le Guellec, C"	"Benz-de Bretagne, Isabelle; Zahr, Noel; Le Gouge, Amelie; Hulot, Jean-Sebastien; Houillier, Caroline; Khe Hoang-Xuan; Gyan, Emmanuel; Lissandre, Severine; Choquet, Sylvain; Le Guellec, Chantal"	"NA"	"A"	"Urinary coproporphyrin I/(I plus III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"benzimidazole; drug transporters; drug-drug interactions; methotrexate; MRP2 (multi-drug resistance protein-2)/ABCC2; population pharmacokinetics"	"ORGANIC ANION-TRANSPORTER; HIGH-DOSE METHOTREXATE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CANCER RESISTANCE PROTEIN; GENETIC POLYMORPHISMS; ABCC2 MRP2; IN-VIVO; POPULATION PHARMACOKINETICS; BILIARY-EXCRETION; HEPATIC-UPTAKE"	"AIMS The urinary coproporphyrin I/(I  III) ratio may be a surrogate for MRP2 activity. We conducted a prospective study in patients receiving methotrexate (MTX) to examine the relationship between this ratio and the pharmacokinetics of a MRP2 substrate. METHODS Three urine samples were collected from 81 patients for UCP I/(I  III) ratio determination: one before (P1), one at the end of MTX infusion (P2), and one on the day of hospital discharge (P3). Three polymorphisms of ABCC2 were analysed and their relationships with basal UCP I/(I  III) ratio values assessed. All associated drugs were recorded and a drug interaction score (DIS) was assigned. Population pharmacokinetic analysis was conducted to assess whether MTX clearance (MTXCL) was associated with the basal UCP I/(I  III) ratio, its variation during MTX infusion, the DIS or other common covariates. RESULTS The basal UCP I/(I  III) ratio was not associated with ABCC2 polymorphisms and did not differ according to the DIS. Significant changes in the ratio were observed over time, with an increase between P1 and P2 and a decrease at P3 (P < 0.001). No association was found between basal UCP I/(I  III) ratio and MTXCL. The final model indicates that MTXCL was dependent on the change in the ratio between P1 and P3, DIS and creatinine clearance. CONCLUSION The basal UCP I/(I  III) ratio is not predictive of MTXCL. However, it is sensitive to the presence of MTX, so it is plausible that it reflects a function modified in response to the drug."	"[Benz-de Bretagne, Isabelle; Le Guellec, Chantal] CHRU Tours, Lab Biochim & Biol Mol, Tours, France; [Benz-de Bretagne, Isabelle; Le Guellec, Chantal] Univ Tours, PRES Ctr Val de Loire Univ, EA4245, Tours, France; [Zahr, Noel; Hulot, Jean-Sebastien] CHU Pitie Salpetriere, AP HP, Serv Pharmacol, Paris, France; [Le Gouge, Amelie] CHRU Tours, Ctr Invest Clin, Tours, France; [Le Gouge, Amelie] Univ Tours, PRES Ctr Val de Loire Univ, Inserm 202, Tours, France; [Hulot, Jean-Sebastien] Univ Paris 06, UMR S 956, Paris, France; [Houillier, Caroline; Khe Hoang-Xuan] CHU Pitie Salpetriere, AP HP, Serv Neurol, Ctr Expert Natl LOC, Paris, France; [Gyan, Emmanuel; Lissandre, Severine] CHRU Tours, Serv Hematol & Therapie Cellulaire, Tours, France; [Choquet, Sylvain] CHU Pitie Salpetriere, AP HP, Serv Hematol, Paris, France"	"Benz-de Bretagne, I (corresponding author), Lab Biochim & Biol Mol, 2 Blvd Tonnelle, F-37044 Tours 9, France."	"isabelle.benz-debretagne@univ-tours.fr"	"LE GUELLEC, Chantal/P-8704-2014; choquet, sylvain/O-7952-2017; Hulot, Jean-Sebastien/AAM-6490-2020; ZAHR, Noel/AAJ-2267-2020; Hulot, Jean-Sebastien/A-2278-2016"	"LE GUELLEC, Chantal/0000-0001-5846-8616; Hulot, Jean-Sebastien/0000-0001-5463-6117; Hulot, Jean-Sebastien/0000-0001-5463-6117; ZAHR, Noel/0000-0002-7858-2325; GYAN, Emmanuel/0000-0002-7651-9189"	"association La Ligue contre le Cancer; Projet Hospitalier de Recherche Clinique (PHRC); Assistance Publique - Hopitaux de Paris (AP-HP)"	"We thank the association La Ligue contre le Cancer, the Projet Hospitalier de Recherche Clinique (PHRC) and the Assistance Publique - Hopitaux de Paris (AP-HP) for their financial support. We would like to thank Dr. Edelman of Alex Edelman & Associates for correcting the English version of the manuscript."	75	9	9	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"AUG"	2014	78	2	329	342	"NA"	"10.1111/bcp.12326"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AN0AY"	"WOS:000340244800011"	24433481	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Brevaut-Malaty, V; Vialet, R; Boulamery, A; Bruguerolle, B; Simon, N"	"Marsot, Amelie; Brevaut-Malaty, Veronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas"	"NA"	"A"	"Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach"	"FUNDAMENTAL & CLINICAL PHARMACOLOGY"	"English"	"Article"	"absolute bioavailability; phenobarbital; paediatrics; pharmacokinetic"	"CLINICAL PHARMACOKINETICS; NEWBORNS; SEIZURES"	"Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [ per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (V-d) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, V-d, F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration."	"[Marsot, Amelie; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas] Hop Enfants La Timone, Serv Pharmacol Med & Clin, F-13385 Marseille 5, France; [Brevaut-Malaty, Veronique] Hop Nord Marseille, Serv Neonatol, Marseille 20, France; [Vialet, Renaud] Hop Nord Marseille, Serv Reanimat Pediat & Neonatale, Marseille 20, France"	"Marsot, A (corresponding author), Hop Enfants La Timone, Serv Pharmacol Med & Clin, Bat F,264 Rue, F-13385 Marseille 5, France."	"amelie.marsot@ap-hm.fr"	"Simon, Nicolas/B-1235-2016; Marsot, Amelie/P-7004-2016"	"Simon, Nicolas/0000-0003-4393-2257; Marsot, Amelie/0000-0002-9303-8862"	"NA"	"NA"	15	11	11	0	15	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0767-3981"	"1472-8206"	"NA"	"FUND CLIN PHARMACOL"	"Fundam. Clin. Pharmacol."	"AUG"	2014	28	4	465	471	"NA"	"10.1111/fcp.12042"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AL9YG"	"WOS:000339498900011"	23855753	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"ter Heine, R; Binkhorst, L; de Graan, AJM; de Bruijn, P; Beijnen, JH; Mathijssen, RHJ; Huitema, ADR"	"ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M.; de Bruijn, Peter; Beijnen, Jos H.; Mathijssen, Ron H. J.; Huitema, Alwin D. R."	"NA"	"A"	"Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"CYP2D6; CYP3A; endoxifen; metabolic phenotype; NONMEM; tamoxifen"	"BREAST-CANCER; POSTMENOPAUSAL WOMEN; LIQUID-CHROMATOGRAPHY; ESTROGEN-RECEPTOR; DUAL-PROBE; IN-VITRO; PHASE-I; DEXTROMETHORPHAN; GENOTYPE; SERUM"	"AIMS Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. METHODS We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. RESULTS Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). CONCLUSIONS We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug-drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice."	"[ter Heine, Rob] Meander Med Ctr, Dept Clin Pharm, NL-3813 TZ Amersfoort, Netherlands; [Binkhorst, Lisette; de Graan, Anne Joy M.; de Bruijn, Peter; Mathijssen, Ron H. J.] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands; [Beijnen, Jos H.; Huitema, Alwin D. R.] Slotervaart Hosp, Dept Pharm & Pharmacol, Amsterdam, Netherlands; [Beijnen, Jos H.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut Sci, Utrecht, Netherlands"	"ter Heine, R (corresponding author), Meander Med Ctr, Dept Clin Pharm, Maatweg 3, NL-3813 TZ Amersfoort, Netherlands."	"rob@terheine.nl"	"Heine, Rob ter/A-1757-2016"	"NA"	"NA"	"NA"	46	16	17	0	13	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2014	78	3	572	586	"NA"	"10.1111/bcp.12388"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AN8ZG"	"WOS:000340894300013"	24697814	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"du Rieu, QC; White-Koning, M; Picaud, L; Lochon, I; Marsili, S; Gladieff, L; Chatelut, E; Ferron, G"	"du Rieu, Quentin Chalret; White-Koning, Melanie; Picaud, Laetitia; Lochon, Isabelle; Marsili, Sabrina; Gladieff, Laurence; Chatelut, Etienne; Ferron, Gwenael"	"NA"	"A"	"Population pharmacokinetics of peritoneal, plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Oxaliplatin; HIPEC; Population pharmacokinetic; Thrombocytopenia; NONMEM"	"TISSUE DISTRIBUTION; OVARIAN-CANCER; CARCINOMATOSIS PATIENTS; COMPLETE RESECTION; CHEMOTHERAPY; CISPLATIN; PERFUSION; ABSORPTION; IRINOTECAN; PLATINUM"	"First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity. IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m(2)) at 360 (n = 58) or 460 mg/m(2) (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma. IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis-Menten equation. The mean (� SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (� 8.5) and 0.49 h (� 0.1), respectively. The mean (� SD) ratio AUC(IP)/AUC(UF) was 5.3 (� 2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC(UF) accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUC(UF), partly dependent on the extent and rate of oxaliplatin absorption. Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients."	"[du Rieu, Quentin Chalret; White-Koning, Melanie; Lochon, Isabelle; Marsili, Sabrina; Chatelut, Etienne; Ferron, Gwenael] Univ Toulouse 3, EA4553, F-31000 Toulouse, France; [du Rieu, Quentin Chalret; White-Koning, Melanie; Lochon, Isabelle; Marsili, Sabrina; Chatelut, Etienne; Ferron, Gwenael] IUCT O, Inst Claudius Regaud, Pharmacol Lab, F-31059 Toulouse, France; [Picaud, Laetitia; Ferron, Gwenael] IUCT O, Inst Claudius Regaud, Dept Chirurg Oncol, F-31059 Toulouse, France; [Gladieff, Laurence] IUCT O, Inst Claudius Regaud, Dept Med Oncol, F-31059 Toulouse, France"	"Chatelut, E (corresponding author), IUCT O, Inst Claudius Regaud, Pharmacol Lab, 1 Ave Irene Joliot Curie, F-31059 Toulouse, France."	"chatelut.etienne@iuct-oncopole.fr"	"Ferron, Gwenael/P-6193-2014; White-Koning, Melanie L/J-5039-2014; GLADIEFF, Laurence/O-5129-2014; , Chatelut/I-7916-2014"	"Ferron, Gwenael/0000-0002-8545-4700; White-Koning, Melanie L/0000-0001-5072-5489; GLADIEFF, Laurence/0000-0002-6980-9719; , Chatelut/0000-0002-7740-9096"	"Institut de Recherches Internationales ServierServier"	"This work was integrated in a Ph.D. project (Quentin Chalret du Rieu), granted by Institut de Recherches Internationales Servier."	38	20	20	0	13	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"SEP"	2014	74	3	571	582	"NA"	"10.1007/s00280-014-2525-6"	12	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"AO2TZ"	"WOS:000341180200016"	25053386	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, RFW; Allegaert, K; Brussee, JM; Sherwin, CMT; Mulla, H; de Hoog, M; van den Anker, JN; Danhof, M; Knibbe, CAJ"	"De Cock, Roosmarijn F. W.; Allegaert, Karel; Brussee, Janneke M.; Sherwin, Catherine M. T.; Mulla, Hussain; de Hoog, Matthijs; van den Anker, Johannes N.; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"antibiotics; developmental changes; glomerular filtration; pediatric age range"	"RENAL-FUNCTION; SERUM CREATININE; POPULATION PHARMACOKINETICS; CHILDREN YOUNGER; ENZYMATIC METHOD; REFERENCE VALUES; INFANTS; PREDICTION; ONTOGENY; ELIMINATION"	"Purpose Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults. Methods In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day-18 years, bodyweight 415 g-85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs. Results Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (Cl-GFR= Cl-drug*(BW/4 kg)(BDE) with BDE = 2.23*BW-0.065). Population clearance values (Cl-drug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively. Discussion Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children."	"[De Cock, Roosmarijn F. W.; Brussee, Janneke M.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Allegaert, Karel] Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Div Clin Pharmacol, Salt Lake City, UT USA; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Clin Trials Off, Salt Lake City, UT USA; [Mulla, Hussain] Univ Hosp Leicester, Dept Pharm, Leicester, Leics, England; [de Hoog, Matthijs; van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Intens Care, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"allegaert, karel/C-3611-2016; Sherwin, Catherine Mary Turner/B-2888-2012"	"allegaert, karel/0000-0001-9921-5105; Sherwin, Catherine Mary Turner/0000-0002-0844-3207; Brussee, Janneke/0000-0002-0813-4463"	"Top Institute Pharma project [D2-104]; Fund for Scientific Research, Flanders (Belgium)FWO [1800214N]; IWT-SBO projectInstitute for the Promotion of Innovation by Science and Technology in Flanders (IWT) [130033]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01HD060543, K24DA027992, R01HD048689, U54HD071601]; FP7 grant TINN [223614]; FP7 grant TINN2 [260908]; FP7 grant NEUROSIS [223060]; FP7 grant GRIP [261060]"	"This study was performed within the framework of Top Institute Pharma project number D2-104. The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) (clinical fellowship 1800214N) and has been supported by an IWT-SBO project (130033). The clinical research of J. van den Anker is supported by NIH grants (R01HD060543, K24DA027992, R01HD048689, U54HD071601) and FP7 grants TINN (223614), TINN2 (260908), NEUROSIS (223060), and GRIP (261060). The authors also would like to thank LAP&P Consultants for their technical support with NONMEM."	44	42	43	3	19	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"OCT"	2014	31	10	2643	2654	"NA"	"10.1007/s11095-014-1361-z"	12	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"AR9JF"	"WOS:000343889300007"	24789450	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Sampson, MR; Frymoyer, A; Rattray, B; Cotten, CM; Smith, PB; Capparelli, E; Bonifacio, SL; Cohen-Wolkowiez, M"	"Sampson, Mario R.; Frymoyer, Adam; Rattray, Benjamin; Cotten, C. Michael; Smith, P. Brian; Capparelli, Edmund; Bonifacio, Sonia L.; Cohen-Wolkowiez, Michael"	"NA"	"A"	"Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"gentamicin; hypothermia; hypoxic ischemic encephalopathy; model validation"	"PRETERM; CREATININE"	"Background: Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated. Methods: A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions. Results: Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05). Conclusions: The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies."	"[Sampson, Mario R.; Smith, P. Brian; Cohen-Wolkowiez, Michael] Duke Clin Res Inst, POB 3499, Durham, NC 27710 USA; [Sampson, Mario R.] Univ N Carolina, Dept Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, Chapel Hill, NC USA; [Frymoyer, Adam] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA; [Rattray, Benjamin; Cotten, C. Michael; Smith, P. Brian; Cohen-Wolkowiez, Michael] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA; [Capparelli, Edmund] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA; [Capparelli, Edmund] Univ Calif San Diego, Sch Pharm, La Jolla, CA 92093 USA; [Bonifacio, Sonia L.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA"	"Cohen-Wolkowiez, M (corresponding author), Duke Clin Res Inst, POB 3499, Durham, NC 27710 USA."	"michael.cohenwolkowiez@duke.edu"	"Smith, Phillip B/I-5565-2014"	"NA"	"US government [1T32GM86330, T32GM07546, 1K23NS082500-01A1, DHHS-1R18AE000028-01, HHSN267200700051C, HHSN275201000003I, UL1TR001117, R01 HL105702, U54 HD071600-01, 1K23HD064814, 1U01FD004858-01, HHSO100201300009C]; GlaxoSmithKlineGlaxoSmithKline; Trius; Cerexa; AbbottAbbott Laboratories; Theravance; Thrasher Research Fund"	"Supported by the US government: 1T32GM86330 (M.R.S.); T32GM07546 (A.F.); 1K23NS082500-01A1 (S.L.B.); DHHS-1R18AE000028-01, HHSN267200700051C, HHSN275201000003I, and UL1TR001117 (P.B.S.); R01 HL105702 (C.M.C.); U54 HD071600-01 (E.C.); and 1K23HD064814, UL1TR001117, 1U01FD004858-01, and HHSO100201300009C (M.C.W.). The following authors also receive non-government support: GlaxoSmithKline (C.M.C.); Trius, Cerexa, Pharmaceuticals, Abbott, and Theravance (E.C.); Thrasher Research Fund (M.C.W.); www.dcri.duke.edu/research/coi.jsp (P.B.S., M.C.W.)."	22	9	9	1	4	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"OCT"	2014	36	5	584	589	"NA"	"10.1097/FTD.0000000000000056"	6	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AQ0SR"	"WOS:000342493500005"	25225917	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"du Rieu, QC; Fouliard, S; White-Koning, M; Kloos, I; Chatelut, E; Chenel, M"	"du Rieu, Quentin Chalret; Fouliard, Sylvain; White-Koning, Melanie; Kloos, Ioana; Chatelut, Etienne; Chenel, Marylore"	"NA"	"A"	"Pharmacokinetic/Pharmacodynamic modeling of abexinostat-induced thrombocytopenia across different patient populations: application for the determination of the maximum tolerated doses in both lymphoma and solid tumour patients"	"INVESTIGATIONAL NEW DRUGS"	"English"	"Article"	"Abexinostat; Thrombocytopenia; PKPD model; Recommended Dose; Simulation; Disease progression"	"HISTONE DEACETYLASE INHIBITOR; CANCER CLINICAL-TRIALS; CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA; PHASE-I; HEMATOLOGICAL TOXICITY; DESIGN; PERFORMANCE; MECHANISMS; HEMORRHAGE; LEUKEMIA"	"Background In the clinical development of oncology drugs, the recommended dose is usually determined using a 3  3 dose-escalation study design. However, this phase I design does not always adequately describe dose-toxicity relationships. Methods 125 patients, with either solid tumours or lymphoma, were included in the study and 1217 platelet counts were available over three treatment cycles. The data was used to build a population pharmacokinetic/pharmacodynamic (PKPD) model using a sequential modeling approach. Model-derived Recommended Doses (MDRD) of abexinostat (a Histone Deacetylase Inhibitor) were determined from simulations of different administration schedules, and the higher bound for the probability of reaching these MDRD with a 3  3 design were obtained. Results The PKPD model developed adequately described platelet kinetics in both patient populations with the inclusion of two platelet baseline counts and a disease progression component for patients with lymphoma. Simulation results demonstrated that abexinostat administration during the first 4 days of each week in a 3-week cycle led to a higher MDRD compared to the other administration schedules tested, with a maximum probability of 40 % of reaching these MDRDs using a 3  3 design. Conclusions The PKPD model was able to predict thrombocytopenia following abexinostat administration in both patient populations. A model-based approach to determine the recommended dose in phase I trials is preferable due to the imprecision of the 3  3 design."	"[du Rieu, Quentin Chalret; Fouliard, Sylvain; Chenel, Marylore] Inst Rech Int Servier, Clin Pharmacokinet Dept, Suresnes, France; [du Rieu, Quentin Chalret; White-Koning, Melanie; Chatelut, Etienne] Univ Toulouse 3, EA4553, F-31062 Toulouse, France; [du Rieu, Quentin Chalret; White-Koning, Melanie; Chatelut, Etienne] Inst Univ Canc Toulouse Oncopole, F-31059 Toulouse 9, France; [Kloos, Ioana] Inst Rech Int Servier, Oncol Business Unit, Suresnes, France"	"Chatelut, E (corresponding author), Inst Univ Canc Toulouse Oncopole, 1 Ave Irene Joliot Curie, F-31059 Toulouse 9, France."	"chatelut.etienne@iuct-oncopole.fr"	"White-Koning, Melanie L/J-5039-2014; , Chatelut/I-7916-2014"	"White-Koning, Melanie L/0000-0001-5072-5489; , Chatelut/0000-0002-7740-9096"	"Institut de Recherches Internationales ServierServier"	"This work was integrated in a Ph. D. project (Quentin Chalret du Rieu), granted by Institut de Recherches Internationales Servier."	40	10	10	0	8	"SPRINGER"	"DORDRECHT"	"VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS"	"0167-6997"	"1573-0646"	"NA"	"INVEST NEW DRUG"	"Invest. New Drugs"	"OCT"	2014	32	5	985	994	"NA"	"10.1007/s10637-014-0118-1"	10	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"AP9PK"	"WOS:000342411500020"	24875134	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Fauchet, F; Treluyer, JM; Preta, LH; Valade, E; Pannier, E; Urien, S; Hirt, D"	"Fauchet, Floris; Treluyer, Jean-Marc; Preta, Laure-Helene; Valade, Elodie; Pannier, Emmanuelle; Urien, Saik; Hirt, Deborah"	"NA"	"A"	"Population Pharmacokinetics of Abacavir in Pregnant Women"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"VIRUS-INFECTED SUBJECTS; QUANTIFICATION LIMIT; ZIDOVUDINE; ADULTS; PHARMACODYNAMICS; LAMIVUDINE; INDINAVIR; EFAVIRENZ; INFANTS; TRIAL"	"For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy."	"[Fauchet, Floris; Treluyer, Jean-Marc; Preta, Laure-Helene; Valade, Elodie; Urien, Saik; Hirt, Deborah] Univ Paris 05, EA 08, Sorbonne Paris Cite, Paris, France; [Fauchet, Floris; Treluyer, Jean-Marc; Valade, Elodie; Urien, Saik; Hirt, Deborah] Hop Tarnier, AP HP, Unite Rech Clin, Paris, France; [Treluyer, Jean-Marc; Hirt, Deborah] Grp Hosp Paris Ctr, AP HP, Serv Pharmacol Clin, Paris, France; [Treluyer, Jean-Marc; Urien, Saik; Hirt, Deborah] INSERM, CIC 0901, Paris, France; [Pannier, Emmanuelle] Grp Hospi, Paris Ctr, Serv Gynecol Obstet, Maternite Port Royal, Paris, France"	"Fauchet, F (corresponding author), Univ Paris 05, EA 08, Sorbonne Paris Cite, Paris, France."	"florisfauchet@gmail.com"	"treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013"	"NA"	"NA"	"NA"	17	5	5	0	9	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"OCT"	2014	58	10	6287	6289	"NA"	"10.1128/AAC.03469-14"	3	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"AS3DT"	"WOS:000344157500081"	25070097	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Hill, H; Le Guellec, C; Neal, T; Mahoney, S; Paulus, S; Castellan, C; Kassai, B; van den Anker, JN; Kearns, GL; Turner, MA; Jacqz-Aigrain, E"	"Zhao, Wei; Hill, Helen; Le Guellec, Chantal; Neal, Tim; Mahoney, Sarah; Paulus, Stephane; Castellan, Charlotte; Kassai, Behrouz; van den Anker, Johannes N.; Kearns, Gregory L.; Turner, Mark A.; Jacqz-Aigrain, Evelyne"	"TINN Consortium"	"A"	"Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"ILL-PATIENTS; SEPSIS; VANCOMYCIN; PEDIATRICS; MANAGEMENT; CHILDREN; MODELS"	"Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA >= 34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation."	"[Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan 250100, Peoples R China; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Paediat Pharmacol & Pharmacogenet, F-75019 Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC1426, Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Univ Paris Descartes, EA7323, Paris, France; [Hill, Helen; Turner, Mark A.] Univ Liverpool, Inst Translat Med, Dept Womens & Childrens Hlth, Liverpool L69 3BX, Merseyside, England; [Hill, Helen; Turner, Mark A.] Liverpool Womens Hosp, Neonatal Unit, Liverpool, Merseyside, England; [Le Guellec, Chantal] Univ Tours, Fac Med, EA4245, Tours, France; [Neal, Tim] Royal Liverpool Univ Hosp, Dept Med Microbiol, Liverpool, Merseyside, England; [Mahoney, Sarah; Paulus, Stephane] Alder Hey Childrens Hosp, Liverpool L12 2AP, Merseyside, England; [Castellan, Charlotte; Kassai, Behrouz] Univ Lyon, EPICIME CIC INSERM Hosp Civils Lyon 1407, Lab Biometrie & Biol Evolut, CNRS UMR5558, Lyon, France; [van den Anker, Johannes N.] Erasmus MC, Sophia Childrens Hosp, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pharmacol, Washington, DC 20052 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Physiol, Washington, DC 20052 USA; [van den Anker, Johannes N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol, Basel, Switzerland; [Kearns, Gregory L.] Childrens Mercy Hosp, Div Clin Pharmacol & Therapeut Innovat, Kansas City, MO 64108 USA; [Kearns, Gregory L.] Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA"	"Jacqz-Aigrain, E (corresponding author), Hop Robert Debre, AP HP, Dept Paediat Pharmacol & Pharmacogenet, F-75019 Paris, France."	"evelyne.jacqz-aigrain@rdb.aphp.fr"	"LE GUELLEC, Chantal/P-8704-2014; Zhao, Wei/D-3322-2011"	"LE GUELLEC, Chantal/0000-0001-5846-8616; Zhao, Wei/0000-0002-1830-338X; Paulus, Stephane/0000-0002-0703-9114; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067; Kassai, Behrouz/0000-0002-1712-120X"	"European CommissionEuropean Commission Joint Research Centre [223614]"	"We thank all the children and their families for participating in this study. This work is part of the TINN network (Collaborative Project) supported by the European Commission under the Health Cooperation Work Program of the 7th Framework Program (grant agreement 223614). We acknowledge the UK National Institute for Health Research for supporting the delivery of the trial and the clinical teams at the Liverpool Women's NHS FT and Alder Hey Children's NHS FT Liverpool UK."	31	25	28	0	7	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"NOV"	2014	58	11	6572	6580	"NA"	"10.1128/AAC.03568-14"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"AS3EF"	"WOS:000344158600029"	25155587	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Foissac, F; Meyzer, C; Frange, P; Chappuy, H; Benaboud, S; Bouazza, N; Friedlander, G; Souberbielle, JC; Urien, S; Blanche, S; Treluyer, JM"	"Foissac, Frantz; Meyzer, Candice; Frange, Pierre; Chappuy, Helene; Benaboud, Sihem; Bouazza, Naim; Friedlander, Gerard; Souberbielle, Jean-Claude; Urien, Saik; Blanche, Stephane; Treluyer, Jean-Marc"	"NA"	"A"	"Determination of optimal vitamin D-3 dosing regimens in HIV-infected paediatric patients using a population pharmacokinetic approach"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"25-hydroxycholecalciferol; children and adolescents; HIV-infected patients; population pharmacokinetics"	"D DEFICIENCY; 25-HYDROXYVITAMIN D; YOUNG-ADULTS; ANTIRETROVIRAL THERAPY; CLINICAL-PRACTICE; D INSUFFICIENCY; RISK-FACTORS; SUPPLEMENTATION; CHILDREN; CHOLECALCIFEROL"	"AimsTo investigate 25-hydroxycholecalciferol [25(OH)D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D-3 dosing schemes to reach sufficient 25(OH)D concentrations (>30ngml(-1)). MethodsThis monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100000 IU vitamin D-3 supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis. ResultsAt baseline 28% of patients had 25(OH)D concentrations below 10ngml(-1), 69% between 10 and 30ngml(-1) and 3% above 30ngml(-1). 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80ngml(-1), patients with baseline concentrations between 10 and 30ngml(-1) should receive 100000 IU per 3 months. However, vitamin D deficient patients (<10ngml(-1)) would need an intensive phase of 100000 IU per 2 weeks (two times) followed 2 weeks later by a maintenance phase of 100000 IU per 3 months. ConclusionsSkin phototype and bodyweight had an influence on the basal production of 25(OH)D. According to 25(OH)D baseline concentrations, dosing schemes to reach sufficient concentrations are proposed."	"[Foissac, Frantz; Meyzer, Candice; Frange, Pierre; Chappuy, Helene; Benaboud, Sihem; Bouazza, Naim; Urien, Saik; Blanche, Stephane; Treluyer, Jean-Marc] Univ Paris 05, EA 3620, Sorbonne Paris Cite, Paris, France; [Foissac, Frantz; Meyzer, Candice; Chappuy, Helene; Benaboud, Sihem; Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] APHP, Unite Rech Clin Paris Ctr, Paris, France; [Meyzer, Candice; Urien, Saik; Treluyer, Jean-Marc] INSERM, CIC 0901, Paris, France; [Meyzer, Candice; Urien, Saik; Treluyer, Jean-Marc] APHP, Paris, France; [Frange, Pierre; Blanche, Stephane] Hop Necker Enfants Malad, APHP, Unite Immunol Hematol & Rhumatol Pediat, Paris, France; [Benaboud, Sihem; Treluyer, Jean-Marc] Hop Cochin, APHP, Lab Pharmacol, F-75674 Paris, France; [Chappuy, Helene] Hop Necker Enfants Malad, APHP, Paris, France; [Chappuy, Helene; Treluyer, Jean-Marc] Univ Paris 05, Sorbonne Paris Cite, Lab Eth Med, Paris, France; [Friedlander, Gerard; Souberbielle, Jean-Claude] Hop Necker Enfants Malad, APHP, Serv Explorat Fonct, Paris, France; [Friedlander, Gerard; Souberbielle, Jean-Claude] Univ Paris 05, Sorbonne Paris Cite, Equipe Homeostasie Phosphate, INSERM,U845, Paris, France"	"Foissac, F (corresponding author), Hop Tarnier, Unite Rech Clin CIC Necker, 89 Rue Assas, F-75006 Paris, France."	"frantz.foissac@cch.aphp.fr"	"treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013"	"Friedlander, Gerard/0000-0002-6854-4261"	"NA"	"NA"	33	1	1	0	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"NOV"	2014	78	5	1113	1121	"NA"	"10.1111/bcp.12433"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AS4CY"	"WOS:000344222100020"	24902982	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Le Guellec, C; Benjamin, DK; Hope, WW; Bourgeois, T; Watt, KM; van den Anker, JN; Matrot, B; Saxen, H; Hoppu, K; Manzoni, P; Jacqz-Aigrain, E"	"Zhao, Wei; Le Guellec, Chantal; Benjamin, Daniel K., Jr.; Hope, William W.; Bourgeois, Thomas; Watt, Kevin M.; van den Anker, Johannes N.; Matrot, Boris; Saxen, Harri; Hoppu, Kalle; Manzoni, Paolo; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"First Dose in Neonates: Are Juvenile Mice, Adults and In Vitro-In Silico Data Predictive of Neonatal Pharmacokinetics of Fluconazole"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"PEDIATRIC DRUG DEVELOPMENT; POPULATION PHARMACOKINETICS; CHILDREN; CLEARANCE; INFANTS; MODEL; ELIMINATION; ALLOMETRY; INFECTION; WEIGHT"	"Background and objectives Selection of the first-dose-in-neonates is challenging. The objective of this proof-of-concept study was to evaluate a pharmacokinetic bridging approach to predict a neonatal dosing regimen. Methods We selected fluconazole as a paradigm compound. We used data from studies in juvenile mice and adults to develop population pharmacokinetic models using NONMEM. We also develop a physiologically-based pharmacokinetic model from in vitro-in silico data using Simcyp. These three models were then used to predict neonatal pharmacokinetics and dosing regimens for fluconazole. Results From juvenile mice to neonates, a correction factor of maximum lifespan potential should be used for extrapolation, while a renal factor'' taking into account renal maturation was required for successful bridging based on adult and in vitro-in silico data. Simulations results demonstrated that the predicted drug exposure based on bridging approach was comparable to the observed value in neonates. The prediction errors were -2.2,  10.1 and -4.6 % for juvenile mice, adults and in vitro-in silico data, respectively."	"[Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan 250012, Peoples R China; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Paediat Pharmacol & Pharmacogenet, F-75019 Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC1426, Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Univ Paris 05, Univ Paris Diderot, EA7323, Paris, France; [Le Guellec, Chantal] Univ Tours, Fac Med, EA4245, Tours, France; [Benjamin, Daniel K., Jr.; Watt, Kevin M.] Duke Clin Res Inst, Durham, NC USA; [Benjamin, Daniel K., Jr.; Watt, Kevin M.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA; [Hope, William W.] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England; [Bourgeois, Thomas; Matrot, Boris] Hop Robert Debre, INSERM, UMR676, F-75019 Paris, France; [van den Anker, Johannes N.] Sophia Childrens Univ Hosp, Erasmus MC, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pharmacol, Washington, DC 20052 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Physiol, Washington, DC 20052 USA; [van den Anker, Johannes N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol, Basel, Switzerland; [Saxen, Harri; Hoppu, Kalle] Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland; [Manzoni, Paolo] St Anna Hosp, Turin, Italy; [Manzoni, Paolo] St Anna Hosp, NICU, Turin, Italy"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan 250012, Peoples R China."	"wei.zhao@rdb.aphp.fr"	"LE GUELLEC, Chantal/P-8704-2014; Hoppu, Kalle/A-2811-2009; Matrot, Boris/Q-6352-2019; Manzoni, Pietro/M-2688-2019; Zhao, Wei/D-3322-2011; Matrot, Boris/I-6240-2017"	"LE GUELLEC, Chantal/0000-0001-5846-8616; Hoppu, Kalle/0000-0001-6775-0453; Matrot, Boris/0000-0002-7845-9618; Manzoni, Pietro/0000-0003-3753-0403; Zhao, Wei/0000-0002-1830-338X; Matrot, Boris/0000-0002-7845-9618; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067; Hope, William/0000-0001-6187-878X"	"European Commission under the Health Cooperation Work Programme of the 7th Framework Programme [223614, 261060]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [CS/08/08/10] Funding Source: Researchfish"	"This work is part of the TINN (Treat Infections in NeoNates) network supported by the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme (Grant agreement no. 223614) and the GRIP network (Global Research in Paediatrics-Network of Excellence) supported by the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme (Grant Agreement number 261060)."	47	7	8	0	14	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NOV"	2014	53	11	1005	1018	"NA"	"10.1007/s40262-014-0169-7"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AU1OJ"	"WOS:000345389700004"	25154507	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Nguyen, THT; Mentre, F; Levi, M; Yu, J; Guedj, J"	"Nguyen, T. H. T.; Mentre, F.; Levi, M.; Yu, J.; Guedj, J."	"NA"	"A"	"A Pharmacokinetic-Viral Kinetic Model Describes the Effect of Alisporivir as Monotherapy or in Combination With Peg-IFN on Hepatitis C Virologic Response"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"INHIBITOR DEBIO 025; INFLAMMATORY CYTOKINES; PEGYLATED INTERFERON; DRUG-INTERACTIONS; HUMAN HEPATOCYTES; VIRUS-INFECTION; P-GLYCOPROTEIN; IN-VITRO; TELAPREVIR; EXPRESSION"	"Alisporivir is a cyclophilin inhibitor with demonstrated in vitro and in vivo activity against hepatitis C virus (HCV). We estimated the antiviral effectiveness of alisporivir alone or in combination with pegylated interferon (peg-IFN) in 88 patients infected with different HCV genotypes treated for 4 weeks. The pharmacokinetics of the two drugs were modeled and used as driving functions for the viral kinetic model. Genotype was found to significantly affect peg-IFN effectiveness (epsilon = 86.3 and 99.1% for genotypes 1/4 and genotypes 2/3, respectively, P < 10(-7)) and the loss rate of infected cells (delta = 0.22 vs. 0.39 per day in genotype 1/4 and genotype 2/3 patients, respectively, P < 10(-6)). Alisporivir effectiveness was not significantly different across genotypes and was high for doses >= 600 mg q.d. We simulated virologic responses with other alisporivir dosing regimens in HCV genotype 2/3 patients using the model. Our predictions consistently matched the observed responses, demonstrating that this model could be a useful tool for anticipating virologic response and optimizing alisporivir-based therapies."	"[Nguyen, T. H. T.; Mentre, F.; Guedj, J.] INSERM, IAME, UMR 1137, Paris, France; [Nguyen, T. H. T.; Mentre, F.; Guedj, J.] Univ Paris Diderot, Sorbonne Paris Cite, IAME, UMR 1137, Paris, France; [Levi, M.] Novartis Pharmaceut, E Hanover, NJ USA; [Yu, J.] Novartis Inst BioMed Res, Cambridge, MA USA"	"Nguyen, THT (corresponding author), INSERM, IAME, UMR 1137, Paris, France."	"thi-huyen.nguyen@inserm.fr"	"Guedj, Jeremie/A-6842-2017"	"Guedj, Jeremie/0000-0002-5534-5482"	"NovartisNovartis"	"T.H.T.N. has a research grant from Novartis. J.G. does consulting for Gilead. J.Y. and M.L. work for Novartis in the Advanced Quantitative Sciences Department. F.M. declared no conflict of interest."	49	8	8	0	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"NOV"	2014	96	5	599	608	"NA"	"10.1038/clpt.2014.173"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AR5OE"	"WOS:000343632900021"	25166216	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Frymoyer, A; Hersh, AL; El-Komy, MH; Gaskari, S; Su, F; Drover, DR; Van Meurs, K"	"Frymoyer, Adam; Hersh, Adam L.; El-Komy, Mohammed H.; Gaskari, Shabnam; Su, Felice; Drover, David R.; Van Meurs, Krisa"	"NA"	"A"	"Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"STAPHYLOCOCCUS-AUREUS INFECTIONS; LATE-ONSET SEPSIS; METHICILLIN-RESISTANT; DISEASES SOCIETY; PHARMACOKINETICS; CHILDREN; INFANTS; PREDICTION; PHARMACODYNAMICS; GUIDELINES"	"National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC(0-24))-to-MIC ratio of > 400. The range of vancomycin trough concentrations that best predicts an AUC(0-24) of > 400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC0-24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC(0-24) achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC(0-24) of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC(0-24) of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of >= 10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of > 20 mg/liter. A vancomycin trough of similar to 10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC(0-24). Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization."	"[Frymoyer, Adam; Su, Felice; Van Meurs, Krisa] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA; [Hersh, Adam L.] Univ Utah, Dept Pediat, Salt Lake City, UT USA; [El-Komy, Mohammed H.] Beni Suef Univ, Dept Pharmaceut & Ind Pharm, Bani Suwayf, Egypt; [Gaskari, Shabnam] Lucile Packard Childrens Hosp Stanford, Dept Pharm, Palo Alto, CA USA; [Drover, David R.] Stanford Univ, Dept Anesthesia, Stanford, CA 94305 USA"	"Frymoyer, A (corresponding author), Stanford Univ, Dept Pediat, Stanford, CA 94305 USA."	"frymoyer@stanford.edu"	"NA"	"Elkomy, Mohammed/0000-0003-4083-6024"	"Stanford Center for Clinical Informatics through NIH CTSA grant [UL1 RR025744]"	"We thank Gomathi Krishnan for her help with data abstraction from the electronic medical records. She is supported by the Stanford Center for Clinical Informatics through NIH CTSA grant UL1 RR025744."	35	49	52	0	2	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"NOV"	2014	58	11	6454	6461	"NA"	"10.1128/AAC.03620-14"	8	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"AS3EF"	"WOS:000344158600014"	25136027	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Valade, E; Treluyer, JM; Dabis, F; Arrive, E; Pannier, E; Benaboud, S; Fauchet, F; Bouazza, N; Foissac, F; Urien, S; Hirt, D"	"Valade, Elodie; Treluyer, Jean-Marc; Dabis, Francois; Arrive, Elise; Pannier, Emmanuelle; Benaboud, Sihem; Fauchet, Floris; Bouazza, Naim; Foissac, Frantz; Urien, Saik; Hirt, Deborah"	"NA"	"A"	"Modified renal function in pregnancy: impact on emtricitabine pharmacokinetics"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"emtricitabine; population pharmacokinetics; pregnancy"	"TENOFOVIR DISOPROXIL FUMARATE; HEALTHY-VOLUNTEERS; STEADY-STATE; WOMEN; COMBINATION; QUANTIFICATION; HEMODYNAMICS; PREDICTION; KIDNEY; SAFETY"	"AimsThe aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy. MethodsFTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3. ResultsFTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5l h(-1), P<0.001), reflecting a modified renal function. FTC daily exposures (AUC) during pregnancy were lower than AUC in non-pregnant women, regardless of the trimester of pregnancy. FTC AUC geometric means were 8.38mg l(-1)h in the second trimester of pregnancy, 8.16mg l(-1)h in the third trimester of pregnancy, 8.30mg l(-1)h on the day of delivery and 9.77mg l(-1)h in non-pregnant women. FTC concentrations 24h after administration were lower in pregnant women compared with non-pregnant women (0.054 vs. 0.079mg l(-1), P<0.001) but still above the inhibitory concentration 50%. ConclusionsFTC CL/F was increased by 18% during pregnancy, reflecting a modified renal function with 50% increase in estimated glomerular filtration rate. However, the impact of this modified renal function on FTC pharmacokinetics was not sufficiently large to consider dose adjustments during pregnancy."	"[Valade, Elodie; Treluyer, Jean-Marc; Fauchet, Floris; Urien, Saik; Hirt, Deborah] Univ Paris 05, EA08, Sorbonne Paris Cite, Paris, France; [Valade, Elodie; Treluyer, Jean-Marc; Benaboud, Sihem; Fauchet, Floris; Bouazza, Naim; Foissac, Frantz; Urien, Saik; Hirt, Deborah] AP HP, Unite Rech Clin Paris Ctr, Paris, France; [Valade, Elodie; Treluyer, Jean-Marc; Pannier, Emmanuelle; Benaboud, Sihem; Fauchet, Floris; Bouazza, Naim; Foissac, Frantz; Urien, Saik; Hirt, Deborah] DHU Risques & Grossesse, Paris, France; [Treluyer, Jean-Marc; Benaboud, Sihem; Bouazza, Naim; Foissac, Frantz; Urien, Saik] CIC 0901 Inserm, Paris, France; [Treluyer, Jean-Marc; Benaboud, Sihem; Hirt, Deborah] Hop Cochin, AP HP, Grp Hosp Paris Ctr, Serv Pharmacol Clin, F-75674 Paris, France; [Dabis, Francois; Arrive, Elise] Univ Bordeaux, Ctr Inserm U897, ISPED, Bordeaux, France; [Pannier, Emmanuelle] Grp Hosp Paris Ctr, AP HP, Serv Gynecol Obstet, Paris, France"	"Valade, E (corresponding author), Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France."	"elodie.valade@free.fr"	"treluyer, Jean-Marc/F-8036-2010; DABIS, FRANCOIS/S-9298-2019; Urien, Saik/G-3240-2013"	"DABIS, FRANCOIS/0000-0002-1614-8857;"	"French Agence Nationale de Recherche contre le VIH/SIDA et les hepatites virales (ANRS)ANRS; European and Developing Countries Clinical Trials Partnership (EDCTP)"	"We acknowledge the French Agence Nationale de Recherche contre le VIH/SIDA et les hepatites virales (ANRS) for sponsoring the TEmAA trial, as well as the European and Developing Countries Clinical Trials Partnership (EDCTP) for their additional financial support. We greatly thank the local investigators and their staff at the Formations Sanitaires Urbaines de Youpougon and Abobo and the Centre Hospitalier Universitaire de Yopougon in Abidjan, Cote d'Ivoire, the Calmette Hospital and Pasteur Institute in Phnom Penh, Cambodia and the Perinatal HIV Research Unit and Lesedi Clinic in Soweto, South Africa. We also thank the women who agreed to participate in the trial and their infants. We acknowledge Gilead Sciences for providing the study drugs. DKE was an EDCTP senior fellow from 2005 to 2007."	27	8	8	0	8	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2014	78	6	1378	1386	"NA"	"10.1111/bcp.12457"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AU1FA"	"WOS:000345365200019"	24995851	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Bellanti, F; Danhof, M; Della Pasqua, O"	"Bellanti, Francesco; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Population pharmacokinetics of deferiprone in healthy subjects"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"deferiprone; dose adjustment; iron overload; population pharmacokinetics; renal impairment; thalassaemia"	"TRANSFUSIONAL IRON OVERLOAD; BETA-THALASSEMIA MAJOR; CHELATION-THERAPY; 1,2-DIMETHYL-3-HYDROXYPYRID-4-ONE; PHARMACODYNAMICS; COMPLICATIONS; EXCRETION; L1"	"AimsTo characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure. MethodsData from 55 adult healthy subjects receiving deferiprone (solution 100mgml(-1)) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries. ResultsA one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4mgl(-1)h, whereas C-max increased from 17.6 to 26.5mgl(-1) after administration of 25 and 75mgkg(-1) doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CLcr. Doses of 60, 40 and 25mgkg(-1) for patients showing mild, moderate and severe renal impairment are proposed based on CLcr values of 60-89, 30-59 and 15-29mlmin(-1), respectively. ConclusionsOur analysis has enabled the assessment of the impact of gender and CLcr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone."	"[Bellanti, Francesco; Danhof, Meindert; Della Pasqua, Oscar] Leiden Acad Ctr Drug Res, Div Pharmacol, NL-2300 RA Leiden, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Stockley Pk, England; [Della Pasqua, Oscar] UCL, Sch Life & Med Sci, London, England"	"Della Pasqua, O (corresponding author), Leiden Acad Ctr Drug Res, Div Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands."	"o.dellapasqua@ucl.ac.uk"	"NA"	"NA"	"DEEP consortium - European Union; FP7 Framework Research Program [HEALTH-2010.4.2-1]"	"All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare FB had financial support from the DEEP consortium (sponsored by the European Union). There are no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.; This contribution is part of the DEferiprone Evaluation in Paediatrics (DEEP) consortium, supported by the FP7 Framework Research Program 'HEALTH-2010.4.2-1: Off-patent medicines for children'."	29	10	10	1	11	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2014	78	6	1397	1406	"NA"	"10.1111/bcp.12473"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AU1FA"	"WOS:000345365200021"	25052529	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Diepstraten, J; Janssen, EJH; Hackeng, CM; van Dongen, EPA; Wiezer, RJ; van Ramshorst, B; Knibbe, CAJ"	"Diepstraten, Jeroen; Janssen, Esther J. H.; Hackeng, Christian M.; van Dongen, Eric P. A.; Wiezer, Rene J.; van Ramshorst, Bert; Knibbe, Catherijne A. J."	"NA"	"A"	"Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Low molecular weight heparins; Pharmacodynamics; Morbid obesity; NONMEM; Anti-Xa"	"DOSING STRATEGY; RECEIVING ENOXAPARIN; RENAL IMPAIRMENT; BODY-WEIGHT; PHARMACOKINETICS; TINZAPARIN; PROPHYLAXIS; OVERWEIGHT; MORTALITY; THERAPY"	"In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI > 40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL = 23.0 mL/min x (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1 = 7.0 L x (LBW/60)). A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively."	"[Diepstraten, Jeroen; Janssen, Esther J. H.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3435 CM Nieuwegein, Netherlands; [Hackeng, Christian M.] St Antonius Hosp, Dept Clin Chem, NL-3435 CM Nieuwegein, Netherlands; [van Dongen, Eric P. A.] St Antonius Hosp, Dept Anesthesiol Intens Care & Pain Management, NL-3435 CM Nieuwegein, Netherlands; [Wiezer, Rene J.; van Ramshorst, Bert] St Antonius Hosp, Dept Surg, NL-3435 CM Nieuwegein, Netherlands; [Knibbe, Catherijne A. J.] Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"NA"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NA"	"NA"	47	11	11	1	4	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JAN"	2015	71	1	25	34	"NA"	"10.1007/s00228-014-1760-4"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AX8JX"	"WOS:000347156900003"	25304008	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Ternant, D; Ducourau, E; Fuzibet, P; Vignault, C; Watier, H; Lequerre, T; Le Loet, X; Vittecoq, O; Goupille, P; Mulleman, D; Paintaud, G"	"Ternant, David; Ducourau, Emilie; Fuzibet, Piera; Vignault, Celine; Watier, Herve; Lequerre, Thierry; Le Loet, Xavier; Vittecoq, Olivier; Goupille, Philippe; Mulleman, Denis; Paintaud, Gilles"	"NA"	"A"	"Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"adalimumab; pharmacokinetic-pharmacodynamic modelling; pharmacodynamics; pharmacokinetics; rheumatoid arthritis"	"C-REACTIVE PROTEIN; MONOCLONAL-ANTIBODY; POPULATION PHARMACOKINETICS; CROHNS-DISEASE; INFLIXIMAB; PHARMACODYNAMICS; METHOTREXATE; ASSOCIATION; CHILDREN; EFFICACY"	"AimsThis study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokinetic-pharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA). MethodsAdalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated. ResultsThirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (V-d/F)=10.8l (92%); apparent clearance (CL/F)=0.32lday(-1) (17%); first-order absorption rate (k(a))=0.28 day(-1); CRP input (k(in))=22.0mgl(-1)day(-1) (65%); adalimumab concentration leading to a 50% decrease in k(in) (C-50)=3.6mgl(-1) (88%); baseline DAS28 (DAS(0))=5.5mgl(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS(0) (IC50)=11.0mgl(-1) (71%). Simulations showed that a 160mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection. ConclusionsThis is the first study to describe adalimumab pharmacokinetics and the concentration-effect relationship in RA. A 160mg loading dose may lead to an increased benefit from treatment in RA patients."	"[Ternant, David; Ducourau, Emilie; Fuzibet, Piera; Vignault, Celine; Watier, Herve; Goupille, Philippe; Mulleman, Denis; Paintaud, Gilles] Univ Tours, UMR 7292, CNRS, Tours, France; [Ternant, David; Vignault, Celine; Paintaud, Gilles] CHRU Tours, Lab Pharmacol Toxicol, F-37044 Tours, France; [Ducourau, Emilie; Fuzibet, Piera; Goupille, Philippe; Mulleman, Denis] CHRU Tours, Serv Rhumatol, F-37044 Tours, France; [Watier, Herve] CHRU Tours, Immunol Lab, F-37044 Tours, France; [Lequerre, Thierry; Le Loet, Xavier; Vittecoq, Olivier] Univ Rouen, INSERM, U905, Rouen, France; [Lequerre, Thierry; Le Loet, Xavier; Vittecoq, Olivier] CIC CRB0204, Rouen, France; [Lequerre, Thierry; Le Loet, Xavier; Vittecoq, Olivier] CHRU Rouen, Serv Rhumatol, Rouen, France"	"Ternant, D (corresponding author), CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"Mulleman, Denis/K-5822-2012; Mulleman, Denis/O-3221-2019"	"Mulleman, Denis/0000-0003-4089-7513; PAINTAUD, Gilles/0000-0003-0158-1356"	"BMSBristol-Myers Squibb; LillyEli Lilly; MSD; NovartisNovartis; NovoNordiskNovo Nordisk; PfizerPfizer; Roche-ChugaiRoche Holding; UCBUCB Pharma SA; Abbvie; AB Science; Schering PloughMerck & CompanySchering Plough Corporation; AmgenAmgen; Roche Schering Plough; AbbottAbbott Laboratories; GenzymeGenzyme Corporation; Abbott Pharma; LFB (Laboratoire Francais des Biotechnologies); Pierre-Fabre Laboratories; WyethWyeth; Merck SeronoMerck SeronoMerck & Company; European UnionEuropean Union (EU); French Higher Education and Research ministry under the program 'Investissements d'avenir'French National Research Agency (ANR) [LabEx MAbImprove ANR-10-LABX-53-01]"	"TL declares no support from any organization of the submitted work; participated on behalf of his institution in clinical trials sponsored by BMS, Lilly, MSD, Novartis, NovoNordisk, Pfizer, Roche-Chugai, UCB; he has been a consultant for BMS, Pfizer, Roche-Chugai, SOBI, UCB; he has been invited to attend international congresses by MSD and Pfizer.; XLL declares no support from any organization of the submitted work; participated on behalf of his institution in clinical trials sponsored by Abbvie, AB Science, BMS, MSD, Novartis, Pfizer, Roche-Chugai, Schering Plough and UCB; he had been a consultant for Abbvie, Amgen, Novartis, Pfizer, Roche-Chugai and Schering Plough; he has been invited to attend international congresses by MSD, Pfizer and Roche Chugai; he has obtained on behalf of his institution grants for research projects from Abbvie, Amgen, MSD, Pfizer, Roche Schering Plough and UCB.; OV declares no support from any organization of the submitted work; participated on behalf of his institution in clinical trials sponsored by BMS, Roche, Roche-Chugai, Pfizer, UCB, AB Science, Schering Plough and Abbott; he is a member of the French advisory boards of BMS, SOBI and UCB; he has given lectures for BMS, Pfizer, MSD and Roche and has obtained on behalf of his institution grants for research projects from Pfizer, Roche and UCB.; GP declares no support from any organization of the submitted work; is involved in clinical studies sponsored by Genzyme, Novartis and Roche Pharma; his research team has received financial support from Abbott Pharma, Chugai, Janssen, LFB (Laboratoire Francais des Biotechnologies), Pierre-Fabre Laboratories, Wyeth and Merck Serono.; The authors thank Anne-Claire Duveau and Caroline Brochon for technical assistance with adalimumab concentration measurements and Soujanya Ratna Edupugantifor critical revision of the manuscript. This work was post hoc analysis of a previous work published elsewhere (clinicaltrials.gov, NCT00234234). Measurements of adalimumab serum concentrations were carried out within the CePiBAc platform. CePiBAc was cofinanced by the European Union. Europe is committed to the region Centre with the European Regional Development Fund. This work was partly supported by the French Higher Education and Research ministry under the program 'Investissements d'avenir' Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01."	33	35	36	0	16	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"FEB"	2015	79	2	286	297	"NA"	"10.1111/bcp.12509"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AZ9HR"	"WOS:000348525100013"	25223394	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Lin, WW; Jiao, Z; Wang, CL; Wang, HY; Ma, CL; Huang, PF; Guo, XZ; Liu, YW"	"Lin, Wei-wei; Jiao, Zheng; Wang, Chang-lian; Wang, Hua-yan; Ma, Chun-lai; Huang, Ping-fang; Guo, Xian-zhong; Liu, Yi-wei"	"NA"	"A"	"Population Pharmacokinetics of Valproic Acid in Adult Chinese Epileptic Patients and its Application in an Individualized Dosage Regimen"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"valproic acid; population pharmacokinetics; nonlinear mixed effects model; Chinese epileptic patient; dose individualization"	"MIXED-EFFECT MODELS; ANTIEPILEPTIC DRUGS; SERUM CONCENTRATIONS; STEADY-STATE; CHILDREN; CARBAMAZEPINE; CLEARANCE; COMEDICATION; PHENYTOIN; NONMEM"	"Background: There are several reports describing population pharmacokinetic (PPK) models of valproic acid (VPA). However, little was known in Chinese adult patients with epilepsy. The present study aimed to establish a PPK model for VPA in Chinese adult epileptic patients and to demonstrate its use for dose individualization. Methods: Data were obtained from a prospective study of 199 adult epileptic patients at 5 hospitals. The trough concentrations at steady state were measured by fluorescence polarization immunoassay. Data were analyzed using the Nonlinear Mixed Effects Model software. The serum trough concentrations at steady state were also measured using samples (n = 20) collected prospectively from a different hospital from those providing the data for deriving the original model. These independent samples served as an evaluation group. Results: The important determinants of apparent VPA clearance were daily dose, body weight, and combination with carbamazepine, phenytoin, or phenobarbital. The final model predicted the individualized doses accurately. A total of 85% of the trough concentrations in the evaluation group were accurately predicted by the final model, whereas the prediction errors of the other patients were all <� 31%. Conclusions: A PPK model was developed to estimate the individual clearance for patients taking VPA and could be applied for individualizing doses in the target population."	"[Lin, Wei-wei; Wang, Chang-lian; Huang, Ping-fang; Guo, Xian-zhong; Liu, Yi-wei] Fujian Med Univ, Affiliated Hosp 1, Dept Pharm, Fuzhou 350005, Peoples R China; [Jiao, Zheng; Ma, Chun-lai] Fudan Univ, Dept Pharm, Huashan Hosp, Shanghai 200433, Peoples R China; [Wang, Hua-yan] Fujian Med Univ, Affiliated Hosp 1, Dept Neurol, Fuzhou, Peoples R China"	"Wang, CL (corresponding author), Fujian Med Univ, Affiliated Hosp 1, Dept Pharm, 20 Cha Zhong M Rd, Fuzhou 350005, Peoples R China."	"WCL@medmail.com.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162"	"Fujian Medical University [JS10012]; Fujian Medical Innovation Fund [2012-CX-22]; Fujian Natural Science Fund [2013J01370]"	"Supported by the Professor Fund of Fujian Medical University (JS10012), the Fujian Medical Innovation Fund (2012-CX-22), and the Fujian Natural Science Fund (2013J01370)."	40	10	16	0	6	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"FEB"	2015	37	1	76	83	"NA"	"10.1097/FTD.0000000000000100"	8	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AZ4IN"	"WOS:000348184900011"	24831653	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Musuamba, FT; Teutonico, D; Maas, HJ; Facius, A; Yang, S; Danhof, M; Della Pasqua, O"	"Musuamba, F. T.; Teutonico, D.; Maas, H. J.; Facius, A.; Yang, S.; Danhof, M.; Della Pasqua, O."	"NA"	"A"	"Prediction of Disease Progression, Treatment Response and Dropout in Chronic Obstructive Pulmonary Disease (COPD)"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"chronic obstructive pulmonary disease; disease modelling; disease progression; dropout; KPD model"	"PHARMACODYNAMIC MODEL; LONGITUDINAL DATA; NONMEM"	"Purpose Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease-and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients. Methods Data from six phase II trials lasting up to 6 months were used. Disease progression (trough FEV1 measurements) was modelled by a time-varying function, whilst the treatment effect was described by an indirect response model. A time-to-event model was used for dropout Results All relevant parameters were characterised with acceptable precision. Two parameters were necessary to model the dropout patterns, which was found to be partly linked to the treatment failure. Disease severity at baseline, previous use of corticosteroids, gender and height were significant covariates on disease baseline whereas disease severity and reversibility to salbutamol/salmeterol were significant covariates on E-max for salmeterol active arm. Conclusion Incorporation of the various interacting factors into a single model will offer the basis for patient enrichment and improved dose rationale in COPD."	"[Musuamba, F. T.; Teutonico, D.; Danhof, M.; Della Pasqua, O.] Gorlaeus Labs, Div Pharmacol, Leiden Acad Ctr Drug Res, NL-2300 RA Leiden, Netherlands; [Maas, H. J.; Yang, S.; Della Pasqua, O.] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Uxbridge, Middx, England; [Facius, A.] Nycomed GmbH, Dept Pharmacometr, Constance, Germany"	"Della Pasqua, O (corresponding author), Gorlaeus Labs, Div Pharmacol, Leiden Acad Ctr Drug Res, POB 9502, NL-2300 RA Leiden, Netherlands."	"odp72514@gsk.com"	"MUSUAMBA TSHINANU, FLORA/P-1917-2016"	"MUSUAMBA TSHINANU, FLORA/0000-0001-8276-8870; Teutonico, Donato/0000-0003-4931-410X"	"TIPharma, a tripartite consortium under the Netherlands Government"	"The authors thank the support from TIPharma, a tripartite consortium created under the auspices of the Netherlands Government for funding the work performed by Flora Musuamba and Donato Teutonico on the evaluation of disease progression in COPD. The authors declare no involvement, financial or otherwise, that might potentially bias the work presented in this manuscript."	33	6	6	0	2	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"FEB"	2015	32	2	617	627	"NA"	"10.1007/s11095-014-1490-4"	11	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"CB1AB"	"WOS:000349357700022"	25231008	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Ding, JJ; Wang, Y; Lin, WW; Wang, CL; Zhao, LM; Li, XG; Zhao, ZG; Miao, LY; Jiao, Z"	"Ding, Junjie; Wang, Yi; Lin, Weiwei; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng"	"NA"	"A"	"A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: A Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"UNBOUND SERUM CONCENTRATIONS; ANTIEPILEPTIC DRUGS; UDP-GLUCURONOSYLTRANSFERASES; CLINICAL PHARMACOKINETICS; CHINESE CHILDREN; CLEARANCE; PREDICTION; ADULTS; GLUCURONIDATION; TRANSPLANTATION"	"Background and Objective Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy. Methods A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEMA (R) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models. Results The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model. Conclusion The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations."	"[Ding, Junjie; Wang, Yi] Fudan Univ, Childrens Hosp, Shanghai 200040, Peoples R China; [Lin, Weiwei; Wang, Changlian] Fujian Med Univ, Dept Pharm, Affiliated Hosp 1, Fuzhou, Peoples R China; [Zhao, Limei] China Med Univ, Shengjing Hosp, Dept Pharm, Shenyang 110001, Peoples R China; [Li, Xingang; Zhao, Zhigang] Capital Med Univ, Beijing Tian Tan Hosp, Dept Pharm, Beijing, Peoples R China; [Miao, Liyan] Soochow Univ, Dept Pharm, Affiliated Hosp 1, Suzhou, Peoples R China; [Jiao, Zheng] Fudan Univ, Huashan Hosp, Dept Pharm, Shanghai 200040, Peoples R China"	"Jiao, Z (corresponding author), Fudan Univ, Huashan Hosp, Dept Pharm, 12 Wu Lu Mu Qi M Rd, Shanghai 200040, Peoples R China."	"zjiao@fudan.edu.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81072702]; Major Research and Development Project of Innovative Drugs, China Ministry of Science and Technology [2012ZX09303004-001]"	"This project was partly supported by the National Natural Science Foundation of China (No. 81072702) and the Major Research and Development Project of Innovative Drugs, China Ministry of Science and Technology (2012ZX09303004-001)."	55	26	32	2	19	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAR"	2015	54	3	305	317	"NA"	"10.1007/s40262-014-0212-8"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CC1MD"	"WOS:000350103900008"	25388986	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Admiraal, R; van Kesteren, C; Jol-van der Zijde, CM; van Tol, MJD; Bartelink, IH; Bredius, RGM; Boelens, JJ; Knibbe, CAJ"	"Admiraal, Rick; van Kesteren, Charlotte; Jol-van der Zijde, Cornelia M.; van Tol, Maarten J. D.; Bartelink, Imke H.; Bredius, Robbert G. M.; Boelens, Jaap Jan; Knibbe, Catherijne A. J."	"NA"	"A"	"Population Pharmacokinetic Modeling of Thymoglobulin (R) in Children Receiving Allogeneic-Hematopoietic Cell Transplantation: Towards Improved Survival Through Individualized Dosing"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"VERSUS-HOST-DISEASE; RABBIT ANTITHYMOCYTE GLOBULIN; PEDIATRIC COVARIATE MODEL; ANTI-THYMOCYTE GLOBULIN; IMMUNE RECONSTITUTION; DRUG DISPOSITION; UNRELATED DONORS; PHARMACODYNAMICS; PROPHYLAXIS; IMPACT"	"Background and Objectives To prevent graft-versus-host disease and rejection in hematopoietic cell transplantation (HCT), children receive Thymoglobulin (R), a polyclonal antibody acting mainly by depleting T cells. The therapeutic window is critical as over-exposure may result in delayed immune reconstitution of donor T cells. In this study, we describe the population pharmacokinetics of Thymoglobulin (R) as a first step towards an evidence-based dosing regimen of Thymoglobulin (R) in pediatric HCT. Methods Serum active Thymoglobulin (R) concentrations were measured in all pediatric HCTs performed between 2004 and 2012 in two pediatric HCT centers in The Netherlands. Population pharmacokinetic analysis was performed using NONMEM (R) version 7.2. Results A total of 3,113 concentration samples from 280 pediatric HCTs were analyzed, with age ranging from 3 months to 23 years old. The cumulative Thymoglobulin (R) dose was 10 mg/kg in 94 % of the patients given in 4 consecutive days. A model incorporating parallel linear and concentration-dependent clearance of Thymoglobulin (R) was identified. Body weight [for linear clearance (CL) and central volume of distribution] as well as lymphocyte count pre-Thymoglobulin (R) infusion (for CL) were important covariates. As such, the current dosing regimen results in higher exposure in children with a higher bodyweight and/ or a lower lymphocyte count pre-Thymoglobulin (R) infusion. Conclusion This model can be used to develop an individual dosing regimen for Thymoglobulin (R), based on both body weight and lymphocyte counts, once the therapeutic window has been determined. This individualized regimen may contribute to a better immune reconstitution and thus outcome of allogeneic HCT."	"[Admiraal, Rick; van Kesteren, Charlotte; Bartelink, Imke H.; Boelens, Jaap Jan] Univ Med Ctr Utrecht, Dept Pediat, Blood & Marrow Transplantat Program, Utrecht, Netherlands; [Admiraal, Rick; van Kesteren, Charlotte; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, NL-2300 RA Leiden, Netherlands; [Admiraal, Rick; Jol-van der Zijde, Cornelia M.; van Tol, Maarten J. D.; Bredius, Robbert G. M.] Leiden Univ, Med Ctr, Dept Pediat, Leiden, Netherlands; [Admiraal, Rick; van Kesteren, Charlotte; Boelens, Jaap Jan] Univ Med Ctr Utrecht, Lab Translat Immunol, U DANCE, Tumor Immunol, Utrecht, Netherlands; [Bartelink, Imke H.] Univ San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94117 USA; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Bredius, Robbert/AAF-2592-2019"	"Boelens, Jaap Jan/0000-0003-2232-6952"	"Netherlands Organisation for Health Research and Development (ZonMW)Netherlands Organization for Health Research and Development [40-41500-98-11044]; Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Dutch Organization for Scientific Research (NWO); ASBMT/CIBMTR (American Society for Blood and Marrow Transplantation/Center for International Blood & Marrow Transplant Research)"	"This study is funded by the Netherlands Organisation for Health Research and Development (ZonMW) grant number 40-41500-98-11044. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Dutch Organization for Scientific Research (NWO). R. Admiraal has received a travel grant to cover part of the costs to present the work at the ASBMT/CIBMTR (American Society for Blood and Marrow Transplantation/Center for International Blood & Marrow Transplant Research) 2014 tandem meeting. The work was performed independently of all funders."	44	38	38	2	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"APR"	2015	54	4	435	446	"NA"	"10.1007/s40262-014-0214-6"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CE0SK"	"WOS:000351515900009"	25466602	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Ternant, D; Berkane, Z; Picon, L; Gouilleux-Gruart, V; Colombel, JF; Allez, M; Louis, E; Paintaud, G"	"Ternant, David; Berkane, Zahir; Picon, Laurence; Gouilleux-Gruart, Valerie; Colombel, Jean-Frederic; Allez, Matthieu; Louis, Edouard; Paintaud, Gilles"	"NA"	"A"	"Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn's Disease"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"FC-GAMMA-RIIIA; C-RECEPTOR POLYMORPHISMS; FUNCTIONAL COMPARISONS; RHEUMATOID-ARTHRITIS; BIOLOGICAL RESPONSE; IGG; MAINTENANCE; THERAPY; IMMUNOGENICITY; ASSOCIATION"	"Background and Objectives Infliximab is a monoclonal anti-tumor necrosis factor-alpha (anti-TNF alpha) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to infliximab in patients with CD. Our aim was to study its influence on infliximab pharmacokinetics and risk of relapse after infliximab discontinuation. Methods In 111 CD patients in remission, infliximab was discontinued and its concentrations were measured for 30 months or until relapse. Infliximab pharmacokinetics were described using monocompartmental population modeling. Results The elimination rate of infliximab increased with C-reactive protein (CRP) [p = 0.00018] and was 16 % higher in FCGR3A-158V/V patients than in F carriers (p = 0.0028). Risk of relapse was higher in patients with baseline CRP >= 5 mg/L than in those with a lower value (p = 0.0000029). In addition, there was a first-order interaction between CRP and the FCGR3A genotype; in patients with high CRP, risk of relapse was higher for V/V patients than for F carriers (hazard ratio 4.80 and 2.84 for V/V and F carriers, respectively; p = 0.013). Conclusion Both increased inflammation and FCGR3A-158V/V genotype are associated with increased infliximab elimination and risk of relapse after infliximab discontinuation in patients with CD."	"[Ternant, David; Berkane, Zahir; Gouilleux-Gruart, Valerie; Paintaud, Gilles] Univ Tours, CNRS, UMR 7292, F-37044 Tours, France; [Ternant, David; Berkane, Zahir; Paintaud, Gilles] CHRU, Lab Pharmacol Toxicol, Tours, France; [Picon, Laurence] CHRU, Dept Gastroenterol, Tours, France; [Gouilleux-Gruart, Valerie] CHRU, Dept Immunol, Tours, France; [Colombel, Jean-Frederic] Icahn Sch Med Mt Sinai, New York, NY 10029 USA; [Allez, Matthieu] Univ Paris 07, Hop St Louis, AP HP, Serv Gastroenterol,INSERM Unite Avenir U940, Paris, France; [Louis, Edouard] Univ Hosp, CHU Liege, Liege, Belgium"	"Ternant, D (corresponding author), Univ Tours, CNRS, UMR 7292, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"NA"	"Allez, Matthieu/0000-0002-2012-7522; PAINTAUD, Gilles/0000-0003-0158-1356"	"FEDER (Fonds Europeen de Developpement Regional European funding); French Higher Education and Research Ministry under the program 'Investissements d'avenir' Grant Agreement: LabEx MAbImproveFrench National Research Agency (ANR) [ANR-10-LABX-53-01]"	"This work was a collaborative venture by GETAID (Groupe d'Etude Therapeutique des Affections Inflammatoires du Tube Digestif). The following GETAID investigators participated in patient recruitment: Amiens (J.L. Dupas), Bordeaux (D. Laharie), Caen (J.M. Reimund), Clichy-Beaujon (Y. Bouhnik), Colombes - L Mourier (P. Jouet), Gent (M. De Vos), Liege (J. Belaiche, E. Louis), Lille (J.-F. Colombel, G. Vernier-Massouille), Lyon (S. Nancey), Marseille (J.C. Grimaud), Montpellier (M. Veyrac), Nantes (A. Boureille, M. Flamant), Paris - Hopital Europeen Georges Pompidou (R. Jian), Paris - Lariboisiere (P. Marteau), Paris - St Louis (M. Lemann, M. Allez), Rouen (G. Savoye), Strasbourg (B. Duclos), and Tours (L. Picon). The authors would like to thank Jean-Yves Mary and Nicolas Azzopardi for statistical advice, Herve Watier for scientific advice, Celine Desvignes for blood-sample management, Anne-Claire Duveau, Caroline Brochon, Audrey Farnault and Marie-Noelle Marson for technical assistance with infliximab and ATI assays, and FCGR3A genotyping. The University Hospital of Tours received an FEDER (Fonds Europeen de Developpement Regional European funding for regional development) for its CePiBAc (Cetre pilote de suivi biologique des anticorps therapeutiques - Pilot centre for therapeutic antibodies monitoring). This work was partly supported by the French Higher Education and Research Ministry under the program 'Investissements d'avenir' Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01."	44	29	30	0	7	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAY"	2015	54	5	551	562	"NA"	"10.1007/s40262-014-0225-3"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CJ2TX"	"WOS:000355338600008"	25516415	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Azzopardi, N; Dupuis-Girod, S; Ternant, D; Fargeton, AE; Ginon, I; Faure, F; Decullier, E; Roux, A; Carette, MF; Gilbert-Dussardier, B; Hatron, PY; Lacombe, P; Leguy-Seguin, V; Riviere, S; Corre, R; Bailly, S; Paintaud, G"	"Azzopardi, Nicolas; Dupuis-Girod, Sophie; Ternant, David; Fargeton, Anne-Emmanuelle; Ginon, Isabelle; Faure, Frederic; Decullier, Evelyne; Roux, Adeline; Carette, Marie-France; Gilbert-Dussardier, Brigitte; Hatron, Pierre-Yves; Lacombe, Pascal; Leguy-Seguin, Vanessa; Riviere, Sophie; Corre, Romain; Bailly, Sabine; Paintaud, Gilles"	"NA"	"A"	"Dose - response relationship of bevacizumab in hereditary hemorrhagic telangiectasia"	"MABS"	"English"	"Article"	"ELISA, enzyme-linked immunosorbent assay; AVM, arterovenous malformations; VEGF, vascular endothelial growth factor; IIV, interindividual variability; PK-PD, pharmacokinetic-pharmacodynamic; CI, cardiac index; TMDD, target-mediated drug disposition; HHT, hereditary hemorrhagic telangectasia; AUC, area under the concentration vs time curve; IgG, immunoglobulin G; TGF-beta, transforming growth factor beta"	"POPULATION ANALYSIS; PHARMACOKINETICS; MODELS"	"Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI < 4 L/min/m(2) at 24 months, respectively. The fraction of patients with < 20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis."	"[Azzopardi, Nicolas; Ternant, David; Paintaud, Gilles] Univ Tours, CNRS, GICC UMR 7292, Tours, France; [Dupuis-Girod, Sophie; Fargeton, Anne-Emmanuelle] Grp Hosp Est, Hosp Civils Lyon, Dept Genet, Bron, France; [Dupuis-Girod, Sophie; Fargeton, Anne-Emmanuelle] Natl Reference Ctr Rendu Osler Dis, Bron, France; [Dupuis-Girod, Sophie; Decullier, Evelyne; Roux, Adeline] Univ Lyon 1, F-69365 Lyon, France; [Ternant, David; Paintaud, Gilles] CHRU Tours, Lab Pharmacol Toxicol, Tours, France; [Ginon, Isabelle] Ctr Hosp Lyon Sud, Dept Cardiol, Hosp Civils Lyon, F-69310 Pierre Benite, France; [Faure, Frederic] Hop Edouard Herriot, Dept Head & Neck Surg, Hosp Civils Lyon, Lyon, France; [Decullier, Evelyne; Roux, Adeline] Pole IMER, Hosp Civils Lyon, Lyon, France; [Carette, Marie-France] Univ Paris 06, Hop Tenon, Assistance Publ Hop Paris, Dept Radiol, Paris, France; [Gilbert-Dussardier, Brigitte] CHU La Miletrie, Dept Genet, Poitiers, France; [Hatron, Pierre-Yves] Univ Lille 2, CHRU Lille, Dept Internal Med, Lille, France; [Lacombe, Pascal] Univ Bourgogne, Hop Ambroise Pare, Assistance Publ Hop Paris, Dept Radiol, Paris, France; [Leguy-Seguin, Vanessa] Hop Dijon, Dept Internal Med, Dijon, France; [Riviere, Sophie] CHU Montpellier, Dept Internal Med, Montpellier, France; [Corre, Romain] Hop Pontchaillou, Dept Pneumol, Rennes, France; [Bailly, Sabine] INSERM, U1036, Biol Canc & Infect, Grenoble, France; [Bailly, Sabine] CEA, Grenoble, France; [Bailly, Sabine] Univ Grenoble Alpes, Grenoble, France"	"Paintaud, G (corresponding author), Univ Tours, CNRS, GICC UMR 7292, Tours, France."	"paintaud@med.univ-tours.fr"	"bailly, sabine/G-3540-2013; Dupuis-Girod, Sophie/D-6268-2014"	"bailly, sabine/0000-0003-1043-7030; Dupuis-Girod, Sophie/0000-0002-8834-5526; PAINTAUD, Gilles/0000-0003-0158-1356; GILBERT-DUSSARDIER, Brigitte/0000-0001-7182-9914"	"French Higher Education and Research ministry under the program Investissements d'avenirFrench National Research Agency (ANR) [LabEx MAbImprove ANR-10-LABX-53-01]"	"The present study was supported by the French Higher Education and Research ministry under the program Investissements d'avenir Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01."	18	12	13	0	8	"TAYLOR & FRANCIS INC"	"PHILADELPHIA"	"530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA"	"1942-0862"	"1942-0870"	"NA"	"MABS-AUSTIN"	"mAbs"	"MAY 4"	2015	7	3	630	637	"NA"	"10.1080/19420862.2015.1022693"	8	"Medicine, Research & Experimental"	"Research & Experimental Medicine"	"CH3VC"	"WOS:000353957600016"	25751241	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"de Mendizabal, NV; Jones, DR; Jahn, A; Bies, RR; Brown, JW"	"Velez de Mendizabal, Nieves; Jones, David R.; Jahn, Andy; Bies, Robert R.; Brown, Joshua W."	"NA"	"A"	"Nicotine and Cotinine Exposure from Electronic Cigarettes: A Population Approach"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"MODEL; DELIVERY; METABOLISM; SMOKING; HUMANS"	"Background and Objectives Electronic cigarettes (e-cigarettes) are a recent technology that has gained rapid acceptance. Still, little is known about them in terms of safety and effectiveness. A basic question is how effectively they deliver nicotine; however, the literature is surprisingly unclear on this point. Here, a population pharmacokinetic model was developed for nicotine and its major metabolite cotinine with the aim to provide a reliable framework for the simulation of nicotine and cotinine concentrations over time, based solely on inhalation airflow recordings and individual covariates [i.e., weight and breath carbon monoxide (CO) levels]. Methods This study included ten adults self-identified as heavy smokers (at least one pack of cigarettes per day). Plasma nicotine and cotinine concentrations were measured at regular 10-min intervals for 90 min while human subjects inhaled nicotine vapor from a modified e-cigarette. Airflow measurements were recorded every 200 ms throughout the session. A population pharmacokinetic model for nicotine and cotinine was developed based on previously published pharmacokinetic parameters and the airflow recordings. All of the analyses were performed with the non-linear mixed-effect modeling software NONMEM (R) version 7.2. Results The results show that e-cigarettes deliver nicotine effectively, although the pharmacokinetic profiles are lower than those achieved with regular cigarettes. Our pharmacokinetic model effectively predicts plasma nicotine and cotinine concentrations from the inhalation volume, and initial breath CO. Conclusion E-cigarettes are effective at delivering nicotine. This new pharmacokinetic model of e-cigarette usage might be used for pharmacodynamic analysis where the pharmacokinetic profiles are not available."	"[Velez de Mendizabal, Nieves; Bies, Robert R.] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA; [Velez de Mendizabal, Nieves; Jones, David R.; Bies, Robert R.] Indiana Clin & Translat Sci Inst CTSI, Indianapolis, IN USA; [Jahn, Andy; Brown, Joshua W.] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA"	"de Mendizabal, NV (corresponding author), Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, West Walnut St, Indianapolis, IN 46202 USA."	"nvelezde@iu.edu"	"NA"	"Jahn, Andrew/0000-0001-5286-049X"	"Indiana Clinical Translational Sciences Institute; CPAC Core facility grant; National Institutes of Health, National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [RR 02576]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA082709]; Eli Lilly and Company through Indiana Clinical and Translational Sciences Institute (CTSI)"	"We thank the Disease and Therapeutic Response Modeling Program for the Clinical and Translational Sciences Institute (CTSI) at Indiana University. We thank Karmen Dayhuff and Andrea Meyer for assistance with blood draws, Jeff Sturgeon for designing and implementing the custom electronic cigarette, and Ken Mackie for providing facilities to process the blood plasma. Supported by the Indiana Clinical Translational Sciences Institute, CPAC Core facility grant (JWB, DRJ). Supported by the Indiana Clinical and Translational Sciences Institute, funded in part by grant # RR 02576 from the National Institutes of Health, National Center for Research Resources. Analytical work was performed by the Clinical Pharmacology Analytical Core laboratory, a core laboratory of the Indiana University Melvin and Bren Simon Cancer Center supported by the National Cancer Institute grant P30 CA082709. NVM was supported by Eli Lilly and Company through the Indiana Clinical and Translational Sciences Institute (CTSI)."	23	12	12	0	27	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUN"	2015	54	6	615	626	"NA"	"10.1007/s40262-014-0221-7"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CJ2TQ"	"WOS:000355337900004"	25503588	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Wiczling, P; Kubik, L; Kaliszan, R"	"Wiczling, Pawel; Kubik, Lukasz; Kaliszan, Roman"	"NA"	"A"	"Maximum A Posteriori Bayesian Estimation of Chromatographic Parameters by Limited Number of Experiments"	"ANALYTICAL CHEMISTRY"	"English"	"Article"	"NA"	"PHASE LIQUID-CHROMATOGRAPHY; GRADIENT RP-HPLC; ORGANIC MODIFIER GRADIENT; RETENTION RELATIONSHIPS; IONIZABLE COMPOUNDS; MOBILE PHASES; PH; ANALYTES; MODELS; ELUTION"	"The aim of this work was to develop a nonlinear mixed-effect chromatographic model able to describe the retention times of weak acids and bases in all possible combinations of organic modifier content and mobile-phase pH. Further, we aimed to identify the influence of basic covariates, like lipophilicity (log P), dissociation constant (pK(a)), and polar surface area (PSA), on the intercompound variability of chromatographic parameters. Lastly, we aimed to propose the optimal limited experimental design to the estimation process of parameters through a maximum a posteriori (MAP) Bayesian method to facilitate the method development process. The data set comprised retention times for two series of organic modifier content collected at different pH for a large series of acids and bases. The obtained typical parameters and their distribution were subsequently used as priors to improve the estimation process from reduced design with a variable number of preliminary experiments. The MAP Bayesian estimator was validated using two external-validation data sets. The common literature model was used to relate analyte retention time with mobile-phase pH and organic modifier content. A set of QSRR-based covariate relationships was established. It turned out that four preliminary experiments and prior information that includes analyte pK(a), log P, acid/base type, and PSA are sufficient to accurately predict analyte retention in virtually all combined changes of pH and organic modifier content. The MAP Bayesian estimator of all important chromatographic parameters controlling retention in pH/organic modifier gradient was developed. It can be used to improve parameter estimation using limited experimental design."	"[Wiczling, Pawel; Kubik, Lukasz; Kaliszan, Roman] Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, PL-80416 Gdansk, Poland"	"Wiczling, P (corresponding author), Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, Gen J Hallera 107, PL-80416 Gdansk, Poland."	"wiczling@gumed.edu.pl"	"Wiczling, Pawel/T-3987-2018"	"Wiczling, Pawel/0000-0002-2878-3161"	"Ministry of Science and Higher Education of the Republic of PolandMinistry of Science and Higher Education, Poland; Polish National Science Centre [2014/13/N/NZ7/04218]"	"This Project was supported by the Ministry of Science and Higher Education of the Republic of Poland, from the quality-promoting subsidy, under the Leading National Research Centre (KNOW) programme for the years 2012-2017 and partially by the Polish National Science Centre grant 2014/13/N/NZ7/04218. We thank Academic Computer Center in Gdansk for access to the computer cluster."	31	12	12	1	14	"AMER CHEMICAL SOC"	"WASHINGTON"	"1155 16TH ST, NW, WASHINGTON, DC 20036 USA"	"0003-2700"	"1520-6882"	"NA"	"ANAL CHEM"	"Anal. Chem."	"JUL 21"	2015	87	14	7241	7249	"NA"	"10.1021/acs.analchem.5b01195"	9	"Chemistry, Analytical"	"Chemistry"	"CN6PE"	"WOS:000358555900036"	26096131	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Sahota, T; Sanderson, I; Danhof, M; Della Pasqua, O"	"Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Model-based prediction of the acute and long-term safety profile of naproxen in rats"	"BRITISH JOURNAL OF PHARMACOLOGY"	"English"	"Article"	"NA"	"SELECTIVE CYCLOOXYGENASE-2 INHIBITORS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COX-2 INHIBITORS; PHARMACOLOGY; NSAIDS; BIOMARKERS; ASPIRIN; INJURY; ISSUES; GUIDE"	"Background and PurposeDespite the increasing importance of biomarkers as predictors of drug effects, toxicology protocols continue to rely on the experimental evidence of adverse events (AEs) as a basis for establishing the link between indicators of safety and drug exposure. Furthermore, biomarkers may facilitate the translation of findings from animals to humans. Combined with a model-based approach, biomarker data have the potential to predict long-term effects arising from prolonged drug exposure. Here, we used naproxen as a paradigm to explore the feasibility of a biomarker-guided approach for the prediction of long-term AEs in humans. Experimental ApproachAn experimental toxicology protocol was set up for evaluating the effects of naproxen in rats, in which four active doses were tested (7.5, 15, 40 and 80mgkg(-1)). In addition to AE monitoring and histology, a few blood samples were also collected for the assessment of drug exposure, TXB2 and PGE(2) levels. Non-linear mixed effects modelling was used to analyse the data and identify covariate factors on the incidence and severity of AEs. Key ResultsModelling results showed that besides drug exposure, maximum PGE(2) inhibition and treatment duration were also predictors of gastrointestinal ulceration. Although PGE(2) levels were clearly linked to the incidence rates, it appeared that ulceration severity is better predicted by measures of drug exposure. Conclusions and ImplicationsThese results show that the use of a model-based approach provides the opportunity to integrate pharmacokinetics, pharmacodynamics and toxicity data, enabling optimization of the design, analysis and interpretation of toxicology experiments."	"[Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar] Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Uxbridge, Middx, England; [Della Pasqua, Oscar] UCL, Clin Pharmacol & Therapeut, London WC1H 9JP, England"	"Della Pasqua, O (corresponding author), UCL, Clin Pharmacol & Therapeut, London WC1H 9JP, England."	"o.dellapasqua@ucl.ac.uk"	"NA"	"NA"	"NA"	"NA"	51	7	7	0	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0007-1188"	"1476-5381"	"NA"	"BRIT J PHARMACOL"	"Br. J. Pharmacol."	"AUG"	2015	172	15	3861	3874	"NA"	"10.1111/bph.13167"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CM8LN"	"WOS:000357952500013"	25884765	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhou, D; Li, HS; Wang, YN; Hochhaus, G; Sinha, V; Zhao, L"	"Zhou, Di; Li, Hongshan; Wang, Yaning; Hochhaus, Guenther; Sinha, Vikram; Zhao, Liang"	"NA"	"A"	"Quantitative characterization of circadian rhythm of pulmonary function in asthmatic patients treated with inhaled corticosteroids"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Circadian rhythm; Asthma; FEV1; Pharmacodynamic model; Drug development"	"MODEL; SMOKING; FEV1; METAANALYSIS; AGONISTS; DECLINE; FEV(1)"	"The aim of this study was to characterize the circadian rhythm observed for forced expiratory volume in 1 s (FEV1) in patients with persistent asthma being treated with inhaled corticosteroids. The database included 3379 FEV1 measurements from 189 patients with mild to moderate asthma. A model using the sum of two Sine functions with periods of 12 and 24 h and a constant component of mean circadian rhythm adequately described the circadian rhythm in FEV1 measurements over time. The model adequateness was evaluated by various approaches including visual predictive check (VPC), prediction-corrected VPC, standardized VPC and normalized prediction distribution error. Covariates tested included age, body weight, height, body mass index, baseline FEV1, and sex. Age and height were found to have significant effects on the mean FEV1 level and no covariate was found to have an effect on the magnitude and timing of circadian rhythm. The model predicted that a minimum FEV1 occurred in the early morning and maximum FEV1 occurred in the early afternoon, with a population mean fluctuation of 170 mL, which is consistent with the finding that asthma symptoms usually exacerbate in the early morning for patients with persistent asthma. This developed model provides the first quantitative approach to describing FEV1 circadian rhythm with ICS background treatment and provided insight in designing future registration trials for asthma drug development."	"[Zhou, Di; Hochhaus, Guenther] Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA; [Li, Hongshan; Wang, Yaning; Sinha, Vikram; Zhao, Liang] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA"	"Zhao, L (corresponding author), US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA."	"liang.zhao@fda.hhs.gov"	"NA"	"Hochhaus, Guenther/0000-0002-7406-5558"	"NA"	"NA"	37	0	0	0	3	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"AUG"	2015	42	4	391	399	"NA"	"10.1007/s10928-015-9420-6"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CN1EN"	"WOS:000358160100005"	26099861	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Krekels, EHJ; van Ham, S; Allegaert, K; de Hoon, J; Tibboel, D; Danhof, M; Knibbe, CAJ"	"Krekels, Elke H. J.; van Ham, Saskia; Allegaert, Karel; de Hoon, Jan; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Paracetamol; Glucuronidation; Multiple dosing; Paediatrics"	"PATENT DUCTUS-ARTERIOSUS; INTRAVENOUS PARACETAMOL; PHARMACOKINETICS; PROPACETAMOL; ACETAMINOPHEN; METABOLITES; ONTOGENY"	"Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach. A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses. Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg(1.4), which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both metabolites was estimated to be 11.4 times higher than the excretion rate constant of unchanged paracetamol, yielding values of 0.580 mL/min/kg. Developmental changes were best described by bodyweight in linear relationships on the distribution volumes, the formation of paracetamol-glucuronide and the unchanged excretion of paracetamol, and in an exponential relationship on the formation of paracetamol-sulphate. There was no evidence for up-regulation or other time-varying changes in any of the model parameters. Simulations with this model illustrate how paracetamol-glucuronide recovery in urine increases over time due to the slower formation of this metabolite and in the absence of up-regulation. Developmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants."	"[Krekels, Elke H. J.; van Ham, Saskia; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Allegaert, Karel] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Allegaert, Karel] Univ Hosp, Neonatal Intens Care Unit, Leuven, Belgium; [de Hoon, Jan] Univ Hosp, Ctr Clin Pharmacol, Leuven, Belgium; [Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC, Sophia Childrens Hosp, Intens Care & Dept Pediat Surg, Rotterdam, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"allegaert, karel/C-3611-2016; de Hoon, Jan/E-3256-2018"	"allegaert, karel/0000-0001-9921-5105; de Hoon, Jan/0000-0002-5215-9836"	"Dutch Top Institute Pharma [D2-104]; Fund for Scientific Research, FlandersFWO [1700314 N]; Innovational Research Incentives Scheme (Veni grant) of the Dutch Organisation for Scientific Research (NWO)"	"EHJK received support from the Dutch Top Institute Pharma project number D2-104, KA had support from the Fund for Scientific Research, Flanders (1700314 N Fundamental Clinical Investigatorship), and CAJK received support from the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organisation for Scientific Research (NWO) for the submitted work. All authors declare that they have no conflicts of interest"	15	17	17	0	5	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"SEP"	2015	71	9	1075	1082	"NA"	"10.1007/s00228-015-1887-y"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CO8UM"	"WOS:000359447600006"	26139379	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"de Mendizabal, NV; Jimenez-Mendez, R; Cooke, E; Montgomery, CJ; Dawes, J; Rieder, MJ; Aleksa, K; Koren, G; Jacobo-Cabral, CO; Gonzalez-Ramirez, R; Castaneda-Hernandez, G; Carleton, BC"	"de Mendizabal, Nieves Velez; Jimenez-Mendez, Ricardo; Cooke, Erin; Montgomery, Carolyne J.; Dawes, Joy; Rieder, Michael J.; Aleksa, Katarina; Koren, Gideon; Jacobo-Cabral, Carlos O.; Gonzalez-Ramirez, Rodrigo; Castaneda-Hernandez, Gilberto; Carleton, Bruce C."	"NA"	"A"	"A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"BREAST-FED NEONATE; CODEINE; PHARMACOGENETICS; MODEL; PHARMACOKINETICS; POPULATION; PREDICTION; CLEARANCE; ALLELES; INFANTS"	"Background and Objectives Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. Methods The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. Results A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. Conclusion This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis."	"[de Mendizabal, Nieves Velez] Indiana Univ Sch Med, Dept Med, Div Clin Pharmacol, Indianapolis, IN 46202 USA; [de Mendizabal, Nieves Velez] Indiana Clin & Translat Sci Inst CTSI, Indianapolis, IN 46202 USA; [Jimenez-Mendez, Ricardo; Carleton, Bruce C.] Univ British Columbia, Fac Med, Dept Paediat, Div Translat Therapeut, Vancouver, BC, Canada; [Jimenez-Mendez, Ricardo; Carleton, Bruce C.] BC Childrens Hosp, Pharmaceut Outcomes Programme, Vancouver, BC, Canada; [Jimenez-Mendez, Ricardo; Carleton, Bruce C.] Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada; [Cooke, Erin; Montgomery, Carolyne J.; Dawes, Joy] Univ British Columbia, Pediat Anesthesia Res Team, Vancouver, BC V5Z 1M9, Canada; [Cooke, Erin; Montgomery, Carolyne J.; Dawes, Joy] BC Childrens Hosp, Dept Pediat Anesthesia, Vancouver, BC, Canada; [Rieder, Michael J.] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON, Canada; [Aleksa, Katarina; Koren, Gideon] Hosp Sick Children, Motherisk Program, Div Clin Pharmacol Toxicol, Toronto, ON M5G 1X8, Canada; [Jacobo-Cabral, Carlos O.; Gonzalez-Ramirez, Rodrigo; Castaneda-Hernandez, Gilberto] Inst Politecn Nacl, Dept Farmacol, Ctr Invest & Estudios Avanzados, Mexico City, DF, Mexico"	"Carleton, BC (corresponding author), Child & Family Res Inst, 950 West 28th Ave,Rm A3-207, Vancouver, BC V5Z 4H4, Canada."	"bcarleton@popi.ubc.ca"	"Rieder, Michael J/L-2397-2013; Koren, Gideon/AAG-7726-2019"	"Koren, Gideon/0000-0002-9234-0875; Gonzalez Ramirez, Rodrigo/0000-0002-9824-6679; Cooke, Erin/0000-0003-2921-1701; Dawes, Joy/0000-0003-0131-8670; Carleton, Bruce/0000-0002-4485-4054"	"NA"	"NA"	32	7	7	0	20	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"OCT"	2015	54	10	1083	1090	"NA"	"10.1007/s40262-015-0256-4"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CS0PM"	"WOS:000361764200008"	25773480	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Smits, A; De Cock, RFW; Allegaert, K; Vanhaesebrouck, S; Danhof, M; Knibbe, CAJ"	"Smits, A.; De Cock, R. F. W.; Allegaert, K.; Vanhaesebrouck, S.; Danhof, M.; Knibbe, C. A. J."	"NA"	"A"	"Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"GLOMERULAR-FILTRATION-RATE; PHARMACOKINETICS; CLEARANCE; AMINOGLYCOSIDES; MATURATION; GENTAMICIN; ERRORS"	"Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% <= 5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization."	"[Smits, A.; Allegaert, K.; Vanhaesebrouck, S.] Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium; [Smits, A.; Allegaert, K.; Vanhaesebrouck, S.] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [De Cock, R. F. W.; Danhof, M.; Knibbe, C. A. J.] Leiden Univ, LACDR, Div Pharmacol, Leiden, Netherlands; [Knibbe, C. A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Smits, A (corresponding author), Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium."	"anne.smits@uzleuven.be"	"Smits, Anne/AAG-4433-2019; allegaert, karel/C-3611-2016"	"Smits, Anne/0000-0002-0710-6698; allegaert, karel/0000-0001-9921-5105"	"Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen)FWO; Fundamental Clinical Investigatorship [1800214N]; Innovational Research Incentives Scheme of the Dutch Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG projectInstitute for the Promotion of Innovation by Science and Technology in Flanders (IWT) [IWT/SBO 130033]; Top Institute Pharma [D2-104]"	"K.A. was supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen), by a Fundamental Clinical Investigatorship (1800214N). C.A.J.K. was supported by the Innovational Research Incentives Scheme of the Dutch Organization for Scientific Research (NWO, Vidi grant, May 2013). This study was supported in part by the Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project (IWT/SBO 130033).; This study was performed within the framework of Top Institute Pharma project number D2-104."	23	24	25	0	2	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"OCT"	2015	59	10	6344	6351	"NA"	"10.1128/AAC.01157-15"	8	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"DA1YJ"	"WOS:000367591800059"	26248375	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Zhang, DL; Storme, T; Baruchel, A; Decleves, X; Jacqz-Aigrain, E"	"Zhao, Wei; Zhang, Daolun; Storme, Thomas; Baruchel, Andre; Decleves, Xavier; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Population pharmacokinetics and dosing optimization of teicoplanin in children with malignant haematological disease"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"dosing optimization; malignant haematological disease; paediatrics; pharmacokinetics; population pharmacokinetics; teicoplanin"	"NEUTROPENIC PATIENTS; PEDIATRIC-PATIENTS; VANCOMYCIN; INFANTS; THERAPY"	"AimChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high risk population. MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin were analyzed using nonmem software. The dosing regimen was optimized based on the final model. ResultsEighty-five children (age range 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n = 143) were available for analysis. With the current recommended dose of 10 mg kg(-1) day(-1), 41 children (48%) had sub-therapeutic steady-state trough concentrations (C-ss,C-min<10 mgl(-1)). A two compartment pharmacokinetic model with first order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750mgl(-1)h 18 mgkg(-1) was required for infants, 14mgkg(-1) for children and 12mgkg(-1) for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and C-ss,C-min values compared with the mg kg(-1) basis dose, making the modelling approach an important tool for dosing individualization. ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population."	"[Zhao, Wei; Jacqz-Aigrain, Evelyne] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Sinofrench Pediat Res Ctr, Jinan 250100, Peoples R China; [Zhao, Wei] Shandong Univ, Qianfoshan Hosp, Dept Pharm, Jinan 250100, Peoples R China; [Zhao, Wei; Zhang, Daolun; Jacqz-Aigrain, Evelyne] Hop Robert Debre, APHP, Dept Paediat Pharmacol & Pharmacogenet, F-75019 Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC1426, Paris, France; [Storme, Thomas] Hop Robert Debre, APHP, Dept Pharm, F-75019 Paris, France; [Baruchel, Andre] Hop Robert Debre, APHP, Dept Paediat Haematooncol, F-75019 Paris, France; [Decleves, Xavier] Hop Cochin, APHP, Dept Pharmacokinet & Pharmacochem, F-75674 Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan 250100, Peoples R China."	"wei.zhao@rdb.aphp.fr"	"DECLEVES, Xavier/S-6978-2016; Zhao, Wei/D-3322-2011"	"DECLEVES, Xavier/0000-0002-9526-2294; Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"GRiP (Global Research in Paediatrics, European Commission FP7 project) [261060]; Shandong University"	"All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare this work was supported by the GRiP (Global Research in Paediatrics, European Commission FP7 project, grant agreement number 261060) and 'The Fundamental Research Funds of Shandong University'. There are no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work."	30	21	25	2	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"NOV"	2015	80	5	1197	1207	"NA"	"10.1111/bcp.12710"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CU9UF"	"WOS:000363890400028"	26138279	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ahlers, SJGM; Valitalo, PAJ; Peeters, MYM; van Gulik, L; van Dongen, EPA; Dahan, A; Tibboel, D; Knibbe, CAJ"	"Ahlers, Sabine J. G. M.; Valitalo, Pyry A. J.; Peeters, Mariska Y. M.; van Gulik, Laura; van Dongen, Eric P. A.; Dahan, Albert; Tibboel, Dick; Knibbe, Catherijne A. J."	"NA"	"A"	"Morphine Glucuronidation and Elimination in Intensive Care Patients: A Comparison with Healthy Volunteers"	"ANESTHESIA AND ANALGESIA"	"English"	"Article"	"NA"	"CRITICALLY-ILL PATIENTS; POSTOPERATIVE PAIN; RENAL-FUNCTION; CONTROLLED-TRIAL; MORPHINE-3-GLUCURONIDE; PHARMACOKINETICS; ANALGESIA; METABOLITES; ANTINOCICEPTION; REQUIREMENTS"	"BACKGROUND: Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. METHODS: A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. RESULTS: For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. CONCLUSIONS: Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made."	"[Ahlers, Sabine J. G. M.; Peeters, Mariska Y. M.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands; [Valitalo, Pyry A. J.; Knibbe, Catherijne A. J.] Leiden Amsterdam Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [van Gulik, Laura; van Dongen, Eric P. A.] Dept Anaesthesiol Intens Care & Pain Management, Nieuwegein, Netherlands; [Dahan, Albert] Leiden Univ, Med Ctr, Dept Anesthesiol, Leiden, Netherlands; [Tibboel, Dick] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Intens Care, Rotterdam, Netherlands; [Tibboel, Dick] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Surg, Rotterdam, Netherlands"	"Ahlers, SJGM (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"sabineahlers@hotmail.com"	"NA"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NA"	"NA"	37	10	10	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0003-2999"	"NA"	"NA"	"ANESTH ANALG"	"Anesth. Analg."	"NOV"	2015	121	5	1261	1273	"NA"	"10.1213/ANE.0000000000000936"	13	"Anesthesiology"	"Anesthesiology"	"CU1QN"	"WOS:000363296500002"	26332855	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Leroux, S; Turner, MA; Barin-Le Guellec, C; Hill, H; van den Anker, JN; Kearns, GL; Jacqz-Aigrain, E; Zhao, W"	"Leroux, Stephanie; Turner, Mark A.; Barin-Le Guellec, Chantal; Hill, Helen; van den Anker, Johannes N.; Kearns, Gregory L.; Jacqz-Aigrain, Evelyne; Zhao, Wei"	"TINN Treat Infections In NeoNates"	"A"	"Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; MASS-SPECTROMETRY; SCAVENGED SAMPLES; PRETERM INFANTS; YOUNG INFANTS; ILL-PATIENTS; CIPROFLOXACIN; PIPERACILLIN; PLASMA; AGE"	"Background and Objective The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. Methods Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. Results Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC(24))/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. Conclusion Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements."	"[Leroux, Stephanie; Jacqz-Aigrain, Evelyne; Zhao, Wei] Shandong Univ, Sinofrench Pediat Res Ctr, Dept Clin Pharm, Sch Pharmaceut Sci, Jinan 250012, Peoples R China; [Leroux, Stephanie; Jacqz-Aigrain, Evelyne; Zhao, Wei] Hop Robert Debre, Dept Pediat Pharmacol & Pharmacogenet, AP HP, F-75019 Paris, France; [Leroux, Stephanie; Jacqz-Aigrain, Evelyne; Zhao, Wei] Univ Paris Diderot, EA7323, Sorbonne Paris Cite, Paris, France; [Leroux, Stephanie] CHU Rennes, Dept Neonatol, Rennes, France; [Turner, Mark A.] Univ Liverpool, Dept Womens & Childrens Hlth, Inst Translat Med, Liverpool L69 3BX, Merseyside, England; [Turner, Mark A.; Hill, Helen] Liverpool Womens Hosp, Neonatal Unit, Liverpool, Merseyside, England; [Barin-Le Guellec, Chantal] Univ Tours, Fac Med, EA4245, Tours, France; [van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Physiol & Pharmacol, Washington, DC 20052 USA; [van den Anker, Johannes N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol, Basel, Switzerland; [Kearns, Gregory L.] Childrens Mercy Hosp, Div Clin Pharmacol & Therapeut Innovat, Kansas City, MO 64108 USA; [Kearns, Gregory L.] Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA; [Jacqz-Aigrain, Evelyne; Zhao, Wei] INSERM, Clin Invest Ctr CIC1426, Paris, France; [Zhao, Wei] Shandong Univ, Qianfoshan Hosp, Dept Pharm, Jian, Jiangxi, Peoples R China"	"Zhao, W (corresponding author), Shandong Univ, Sinofrench Pediat Res Ctr, Dept Clin Pharm, Sch Pharmaceut Sci, 44 West Wenhua Rd, Jinan 250012, Peoples R China."	"wei.zhao@rdb.aphp.fr"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"TINN (Treat Infections in NeoNates, European Commission FP7 project) [223614]; GRIP (Global Research in Paediatrics, European Commission FP7 project) [261060]; Fundamental Research Funds of Shandong University"	"This work was supported by the TINN (Treat Infections in NeoNates, European Commission FP7 project, Grant Agreement Number 223614), the GRIP (Global Research in Paediatrics, European Commission FP7 project, Grant Agreement Number 261060), and The Fundamental Research Funds of Shandong University."	21	36	36	2	13	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2015	54	12	1273	1285	"NA"	"10.1007/s40262-015-0291-1"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CX5BU"	"WOS:000365716700007"	26063050	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Frechen, S; Suleiman, AA; Sigaroudi, AMN; Wachall, B; Fuhr, U"	"Frechen, Sebastian; Suleiman, Ahmed Abbas; Sigaroudi, Ali Mohammad Nejad; Wachall, Bertil; Fuhr, Uwe"	"NA"	"A"	"Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler"	"DRUG METABOLISM AND PHARMACOKINETICS"	"English"	"Article"	"Epinephrine; Anaphylaxis; Pharmacokinetics and pharmacodynamics; Mixed-effects modeling; Inhalation"	"MIXED-EFFECT MODELS; SUBCUTANEOUS INJECTION; SYSTEMIC ABSORPTION; ANAPHYLAXIS; ADRENALINE; INHALATION; NONMEM; QUANTIFICATION; CHILDREN; AEROSOL"	"Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and inter-occasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown. Copyright (C) 2015, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved."	"[Frechen, Sebastian; Suleiman, Ahmed Abbas; Sigaroudi, Ali Mohammad Nejad; Fuhr, Uwe] Cologne Univ Hosp, Dept Pharmacol, Clin Pharmacol, Cologne, Germany; [Wachall, Bertil] INFECTOPHARM Arzneimittel & Consilium GmbH, D-64646 Heppenheim, Germany"	"Frechen, S (corresponding author), Cologne Univ Hosp, Dept Pharmacol, Clin Pharmacol, Cologne, Germany."	"sebastian.frechen@uk-koeln.de"	"NA"	"Sigaroudi, Ali/0000-0002-3176-4631"	"Infectopharm Arzneimittel und Consilium GmbH"	"This study was funded by Infectopharm Arzneimittel und Consilium GmbH."	31	3	3	0	12	"JAPANESE SOC STUDY XENOBIOTICS"	"TOKYO"	"INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN"	"1347-4367"	"1880-0920"	"NA"	"DRUG METAB PHARMACOK"	"Drug Metab. Pharmacokinet."	"DEC"	2015	30	6	391	399	"NA"	"10.1016/j.dmpk.2015.08.002"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DB1DA"	"WOS:000368247000002"	26615448	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Elkomy, MH; Drover, DR; Glotzbach, KL; Galinkin, JL; Frymoyer, A; Su, F; Hammer, GB"	"Elkomy, Mohammed H.; Drover, David R.; Glotzbach, Kristi L.; Galinkin, Jeffery L.; Frymoyer, Adam; Su, Felice; Hammer, Gregory B."	"NA"	"A"	"Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery"	"AAPS JOURNAL"	"English"	"Article"	"metabolism; morphine; NONMEM; pediatric; pharmacokinetics"	"RENAL-FUNCTION; POSTOPERATIVE INFANTS; PLASMA-CONCENTRATIONS; PAIN; MORPHINE-6-GLUCURONIDE; INFUSION; KINETICS; CLEARANCE; FAILURE; CANCER"	"The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites."	"[Elkomy, Mohammed H.; Drover, David R.; Hammer, Gregory B.] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA; [Elkomy, Mohammed H.] Beni Suef Univ, Dept Pharmaceut & Ind Pharm, Bani Suwayf, Egypt; [Glotzbach, Kristi L.] Duke Univ, Med Ctr, Div Pediat Crit Care Med, Durham, NC USA; [Frymoyer, Adam; Su, Felice; Hammer, Gregory B.] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA; [Galinkin, Jeffery L.] Univ Colorado, Dept Anesthesiol, Aurora, CO USA"	"Drover, DR (corresponding author), Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, 300 Pasteur Dr, Stanford, CA 94305 USA."	"ddrover@stanford.edu"	"NA"	"Elkomy, Mohammed/0000-0003-4083-6024"	"NCCR/NICHD CTSA consortium project grant via the Stanford University Center for Clinical and Translational and Educational Research"	"This study was funded through a NCCR/NICHD CTSA consortium project grant via the Stanford University Center for Clinical and Translational and Educational Research."	43	7	9	1	7	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JAN"	2016	18	1	124	133	"NA"	"10.1208/s12248-015-9826-5"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DA1AY"	"WOS:000367529900010"	26349564	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Lin, WW; Wu, W; Jiao, Z; Lin, RF; Jiang, CZ; Huang, PF; Liu, YW; Wang, CL"	"Lin, Wei-wei; Wu, Wei; Jiao, Zheng; Lin, Rong-fang; Jiang, Chang-zhen; Huang, Pin-fang; Liu, Yi-wei; Wang, Chang-lian"	"NA"	"A"	"Population pharmacokinetics of vancomycin in adult Chinese patients with post-craniotomy meningitis and its application in individualised dosage regimens"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Vancomycin; Population pharmacokinetics; Adult Chinese patients; Post-craniotomy meningitis; Dose individualisation"	"INTENSIVE-CARE-UNIT; TARGET TROUGH CONCENTRATIONS; SERUM CYSTATIN C; PRACTICE GUIDELINES; CLINICAL-EFFICACY; RENAL-FUNCTION; RISK-FACTORS; INFECTIONS; PREDICTION; CLEARANCE"	"Purpose Vancomycin (VCM) is a first-line antibacterial drug used to treat post-craniotomy meningitis (PCM). VCM pharmacokinetic parameters are altered in PCM patients, compared to those in other patients. Although VCM population pharmacokinetics (PPK) has been reported, changes in VCM PPK in adult Chinese PCM patients remain unknown. We developed a VCM PPK model in adult Chinese PCM patients and proposed a new strategy for individualising VCM administration using this model. Methods Data was obtained from a prospective study of 100 adult PCM patients in the Neurosurgery Department of the First Affiliated Hospital of Fujian Medical University. The trough concentrations at steady state were determined by enzyme multiplied immunoassay. Nonlinear mixed-effect model software was employed to develop the PPK model. The final model was evaluated using the bootstrap method and normalised prediction error distribution and through the testing of 20 independent adult PCM patients. Results VCM clearance in PCM patients was higher than that observed in other patients. Creatinine clearance affected VCM clearance, whereas no co-administered drugs influenced VCM pharmacokinetics. Trough concentrations were accurately predicted by the final model, while the prediction errors were less than � 32 %. Moreover, a new strategy for individualising VCM regimens using the PPK model was proposed and validated. Conclusions A PPK model was developed to estimate the individual clearance in inpatients receiving intravenously infused VCM and could be used to develop individualised dosing of adult Chinese PCM patients."	"[Lin, Wei-wei; Wu, Wei; Lin, Rong-fang; Huang, Pin-fang; Liu, Yi-wei; Wang, Chang-lian] Fujian Med Univ, Affiliated Hosp 1, Dept Pharm, Fuzhou 350005, Peoples R China; [Jiang, Chang-zhen] Fujian Med Univ, Affiliated Hosp 1, Dept Neurosurg, Fuzhou 350005, Peoples R China; [Jiao, Zheng] Fudan Univ, Huashan Hosp, Dept Pharm, Shanghai 20040, Peoples R China"	"Jiao, Z (corresponding author), Fudan Univ, Huashan Hosp, Dept Pharm, 12 Wu Lu Mu Qi M Rd, Shanghai 20040, Peoples R China."	"zjiao@fudan.edu.cn; WCL@medmail.com.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162"	"Professor Fund of Fujian Medical University [JS10012]; Fujian Natural Science Fund [2013 J01370]; Fujian Medical Innovation Fund [2014-CXB-13]"	"This work was supported by the 'Professor Fund of Fujian Medical University (JS10012)', the 'Fujian Natural Science Fund (2013 J01370)' and the 'Fujian Medical Innovation Fund (2014-CXB-13)'."	53	16	24	0	16	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JAN"	2016	72	1	29	37	"NA"	"10.1007/s00228-015-1952-6"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DA3IK"	"WOS:000367690200004"	26423622	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bouazza, N; Urien, S; Neven, B; Moshous, D; Nisoy, J; Gabrion, A; Cavazzana, M; Blanche, S; Treluyer, JM; Touzot, F"	"Bouazza, Naim; Urien, Saik; Neven, Benedicte; Moshous, Despina; Nisoy, Jennifer; Gabrion, Aurelie; Cavazzana, Marina; Blanche, Stephane; Treluyer, Jean-Marc; Touzot, Fabien"	"NA"	"A"	"Evaluation of antithymocyte globulin pharmacokinetics and pharmacodynamics in children"	"JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY"	"English"	"Letter"	"NA"	"VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; MODELS"	"NA"	"[Bouazza, Naim; Urien, Saik; Blanche, Stephane; Treluyer, Jean-Marc] Univ Paris 05, Sorbonne Paris Cite, EAU08, Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Hop Tarnier, Assistance Publ Hop Paris, Unit Rech Clin, Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Cochin Necker, INSERM, CIC 0901, Paris, France; [Neven, Benedicte; Moshous, Despina] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Unite Immunol Hematol & Rhumatol Pediat, Ctr Invest Clin Integre Biotherapies, Paris, France; [Nisoy, Jennifer; Gabrion, Aurelie; Cavazzana, Marina; Touzot, Fabien] Hop Necker Enfants Malad, Assistance Publ Hop Paris, Dept Biotherapie, Ctr Invest Clin Integre Biotherapies, Paris, France; [Neven, Benedicte; Moshous, Despina; Cavazzana, Marina; Blanche, Stephane; Touzot, Fabien] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, Paris, France; [Neven, Benedicte; Moshous, Despina; Cavazzana, Marina; Touzot, Fabien] INSERM, UMR1163, Paris, France; [Treluyer, Jean-Marc] Univ Paris 05, Hop Cochin, Assistance Publ Hop Paris, Serv Pharm Clin,Sorbonne Paris Cite, Paris, France"	"Bouazza, N (corresponding author), Univ Paris 05, Sorbonne Paris Cite, EAU08, Paris, France."	"naim.bouazza@cch.aphp.fr"	"GABRION, AURELIE/K-1812-2017; treluyer, Jean-Marc/F-8036-2010; Urien, Saik/G-3240-2013; Moshous, Despina/B-7507-2017; Touzot, Fabien/T-7797-2018"	"GABRION, AURELIE/0000-0002-1885-2071; Moshous, Despina/0000-0001-6719-3693; Touzot, Fabien/0000-0002-0889-4905; Cavazzana, Marina/0000-0002-0264-0891"	"NA"	"NA"	10	2	2	0	6	"MOSBY-ELSEVIER"	"NEW YORK"	"360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA"	"0091-6749"	"1097-6825"	"NA"	"J ALLERGY CLIN IMMUN"	"J. Allergy Clin. Immunol."	"JAN"	2016	137	1	306	309	"NA"	"10.1016/j.jaci.2015.06.003"	6	"Allergy; Immunology"	"Allergy; Immunology"	"DA3UK"	"WOS:000367724300025"	26194539	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Lee, SH; Cho, SY; Yoo, KY; Jeong, S"	"Lee, Seong Heon; Cho, Soo Young; Yoo, Kyung Yeon; Jeong, Seongwook"	"NA"	"A"	"Population pharmacokinetics of ramosetron"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Population pharmacokinetics; Postoperative nausea and vomiting; NONMEM; Ramosetron; Serotonin 5-HT3 receptor antagonist"	"POSTOPERATIVE NAUSEA; ONDANSETRON; PREVENTION; MODEL; SAFETY; TOLERABILITY; MANAGEMENT; EFFICACY; ORIGIN; SIZE"	"Ramosetron is a selective serotonergic 5-hydroxy-tryptamine receptor 3 antagonist that is used to prevent and treat postoperative nausea and vomiting. This study aimed to characterize the population pharmacokinetics of ramosetron in patients undergoing surgery with general anesthesia. Patients aged 19-80 years received a single intravenous bolus of ramosetron (0.3, 0.45, or 0.6 mg) 30 min before the end of surgery. Blood samples were collected, and plasma concentrations of ramosetron were measured by high performance liquid chromatography-tandem mass spectrometry. Pooled data from 50 patients and 479 pharmacokinetic samples were used for population pharmacokinetic analysis using the nonlinear mixed effect modeling program (NONMEM). The pharmacokinetics of ramosetron was best described by a three compartment mammillary model with first -order elimination. Based on allometric principles, body weight was incorporated in the base model, along with fixed allometric exponents. The typical value of clearance was 0.19 L/h in a 60 -kg subject, and it decreased approximately 3 % for every year of age, starting at age of 57. The bootstrap method and visual predictive check showed that the final pharmacokinetic model was appropriate. A population pharmacokinetic model of ramosetron was constructed in adult surgical patients, providing a foundation for further defining the relationship between ramosetron dose and postoperative nausea and vomiting."	"[Lee, Seong Heon; Cho, Soo Young; Yoo, Kyung Yeon; Jeong, Seongwook] Chonnam Natl Univ, Sch Med, Dept Anesthesiol & Pain Med, 160 Baekseo Ro, Gwangju, South Korea"	"Jeong, S (corresponding author), Chonnam Natl Univ, Sch Med, Dept Anesthesiol & Pain Med, 160 Baekseo Ro, Gwangju, South Korea."	"anesman@gmail.com"	"NA"	"NA"	"Grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A070001]"	"This study was supported by a Grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A070001)."	41	3	3	0	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"FEB"	2016	43	1	73	83	"NA"	"10.1007/s10928-015-9455-8"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DK1VV"	"WOS:000374704000007"	26558626	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bellanti, F; Del Vecchio, GC; Putti, MC; Cosmi, C; Fotzi, I; Bakshi, SD; Danhof, M; Della Pasqua, O"	"Bellanti, Francesco; Del Vecchio, Giovanni C.; Putti, Maria C.; Cosmi, Carlo; Fotzi, Ilaria; Bakshi, Suruchi D.; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Model-Based Optimisation of Deferoxamine Chelation Therapy"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"adherence; deferoxamine; disease modelling; dose rationale; iron overload; PKPD modelling"	"BETA-THALASSEMIA MAJOR; IRON OVERLOAD; FERRITIN; COMPLICATIONS; TRANSFUSION; SURVIVAL; INDEX; MATLAB"	"Here we show how a model-based approach may be used to provide further insight into the role of clinical and demographic covariates on the progression of iron overload. The therapeutic effect of deferoxamine is used to illustrate the application of disease modelling as a means to characterising treatment response in individual patients. Serum ferritin, demographic characteristics and individual treatment data from clinical routine practice on 27 patients affected by beta-thalassaemia major were used for the purposes of this analysis. The time course of serum ferritin was described by a hierarchical nonlinear mixed effects model, in which compliance was parameterised as a covariate factor. Modelling and simulation procedures were implemented in NONMEM (7.2.0). A turnover model best described serum ferritin changes over time, with the effect of blood transfusions introduced on the ferritin conversion rate and the effect of deferoxamine on the elimination parameter (Kout) in a proportional manner. The results of the simulations showed that poor quality of execution is preferable over drug holidays; and that independently of the compliance pattern, the therapeutic intervention is not effective if > 60% of the doses are missed. Modelling of ferritin response enables characterisation of the dynamics of iron overload due to chronic transfusion. The approach can be used to support decision making in clinical practice, including personalisation of the dose for existing and novel chelating agents."	"[Bellanti, Francesco; Bakshi, Suruchi D.; Danhof, Meindert; Della Pasqua, Oscar] Leiden Acad Ctr Drug Res Leiden, Div Pharmacol, Leiden, Netherlands; [Della Pasqua, Oscar] UCL, Clin Pharmacol & Therapeut, London WC1H 9JP, England; [Del Vecchio, Giovanni C.] Azienda Osped Univ Consorziale, Policlin Bari, Bari, Italy; [Putti, Maria C.] Azienda Osped Padova, Clin Oncoematol Pediat Padova, Padua, Italy; [Cosmi, Carlo; Fotzi, Ilaria] Azienda Osped Univ, Policlin Sassari, Sassari, Italy"	"Della Pasqua, O (corresponding author), Leiden Acad Ctr Drug Res Leiden, Div Pharmacol, Leiden, Netherlands."	"o.dellapasqua@ucl.ac.uk"	"NA"	"NA"	"FP7 Framework Research Program: Off-patent medicines for children [HEALTH-2010.4.2-1]; DEEP consortium - European Union"	"This contribution is part of the DEferiprone Evaluation in Paediatrics (DEEP) consortium, supported by the FP7 Framework Research Program HEALTH-2010.4.2-1: Off-patent medicines for children. The authors would like to thank Prof. G. Derks and Dr. V. Rottschafer for their constructive input for this work. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: F.B. had financial support from the DEEP consortium (sponsored by the European Union); no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work."	37	2	2	0	8	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"FEB"	2016	33	2	498	509	"NA"	"10.1007/s11095-015-1805-0"	12	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"DA8RH"	"WOS:000368073300020"	26555666	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Janssen, EJH; Valitalo, PAJ; Allegaert, K; de Cock, RFW; Simons, SHP; Sherwin, CMT; Mouton, JW; van den Anker, JN; Knibbe, CAJ"	"Janssen, Esther J. H.; Valitalo, Pyry A. J.; Allegaert, Karel; de Cock, Roosmarijn F. W.; Simons, Sinno H. P.; Sherwin, Catherine M. T.; Mouton, Johan W.; van den Anker, Johannes N.; Knibbe, Catherijne A. J."	"NA"	"A"	"Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"RESISTANT STAPHYLOCOCCUS-AUREUS; GLOMERULAR-FILTRATION-RATE; GRAM-POSITIVE INFECTIONS; CONTINUOUS-INFUSION; CHILDREN; PHARMACODYNAMICS; MATURATION; REGIMENS; PRETERM; PREDICTION"	"Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC(24)/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate."	"[Janssen, Esther J. H.; Valitalo, Pyry A. J.; de Cock, Roosmarijn F. W.; Knibbe, Catherijne A. J.] Leiden Univ, Div Pharmacol, Leiden Acad Ctr Drug Res, Leiden, Netherlands; [Allegaert, Karel] Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium; [Simons, Sinno H. P.] Erasmus MC Sophia Childrens Hosp, Dept Pediat, Div Neonatol, Rotterdam, Netherlands; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Div Clin Pharmacol, Salt Lake City, UT USA; [Mouton, Johan W.] Erasmus MC Sophia Childrens Hosp, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA; [van den Anker, Johannes N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol, Basel, Switzerland; [van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [van den Anker, Johannes N.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, Johannes N.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, Div Pharmacol, Leiden Acad Ctr Drug Res, Leiden, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"allegaert, karel/C-3611-2016; Sherwin, Catherine Mary Turner/B-2888-2012; simons, sinno/AAC-7442-2019; mouton, johan/C-5915-2014"	"allegaert, karel/0000-0001-9921-5105; Sherwin, Catherine Mary Turner/0000-0002-0844-3207; mouton, johan/0000-0001-6736-4149; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415; Simons, Sinno/0000-0001-5219-5696"	"Top Institute Pharma (TI Pharma) [D2-501]"	"Top Institute Pharma (TI Pharma) provided funding to Esther J. H. Janssen under grant number D2-501."	67	29	29	0	10	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"FEB"	2016	60	2	1013	1021	"NA"	"10.1128/AAC.01968-15"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"DC3ZR"	"WOS:000369159800033"	26643337	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Angeli, A; Laine, F; Lavenu, A; Ropert, M; Lacut, K; Gissot, V; Sacher-Huvelin, S; Jezequel, C; Moignet, A; Laviolle, B; Comets, E"	"Angeli, Adeline; Laine, Fabrice; Lavenu, Audrey; Ropert, Martine; Lacut, Karine; Gissot, Valerie; Sacher-Huvelin, Sylvie; Jezequel, Caroline; Moignet, Aline; Laviolle, Bruno; Comets, Emmanuelle"	"NA"	"A"	"Joint Model of Iron and Hepcidin During the Menstrual Cycle in Healthy Women"	"AAPS JOURNAL"	"English"	"Article"	"hepcidin; iron; iron regulation; menstrual cycle; turnover model"	"MIXED-EFFECT MODELS; SERUM HEPCIDIN; BLOOD-LOSS; TOLERANCE; PHARMACOKINETICS; OPTIMIZATION; HOMEOSTASIS; ABSORPTION; DISORDERS; FERRITIN"	"Hepcidin regulates serum iron levels, and its dosage is used in differential diagnostic of iron-related pathologies. We used the data collected in the HEPMEN (named after HEPcidin during MENses) study to investigate the joint dynamics of serum hepcidin and iron during the menstrual cycle in healthy women. Ninety menstruating womenwere recruited after a screening visit. Six fasting blood samples for determination of iron-status variables were taken in the morning throughout the cycle, starting on the second day of the period. Non-linear mixed effect models were used to describe the evolution of iron and hepcidin. Demographic andmedical covariates were tested for their effect onmodel parameters. Parameter estimation was performed using the SAEM algorithm implemented in the Monolix software. A general pattern was observed for both hepcidin and iron, consisting of an initial decrease during menstruation, followed by a rebound and stabilising during the second half of the cycle. We developed a joint model including a menstruation-induced decrease of both molecules at the beginning of the menses and a rebound effect after menses. Iron stimulated the release of hepcidin. Several covariates, including contraception, amount of blood loss and ferritin, were found to influence the parameters. The joint model of iron and hepcidin was able to describe the fluctuations induced by blood loss from menstruation in healthy non-menopausal women and the subsequent regulation. TheHEPMENstudy showed fluctuations of iron-status variables during the menstrual cycle, which should be considered when using hepcidin measurements for diagnostic purposes in women of child-bearing potential."	"[Angeli, Adeline; Laine, Fabrice; Lavenu, Audrey; Jezequel, Caroline; Moignet, Aline; Laviolle, Bruno; Comets, Emmanuelle] INSERM, CIC 1414, Rennes, France; [Laine, Fabrice; Ropert, Martine] INSERM, U991, Rennes, France; [Laine, Fabrice; Ropert, Martine; Jezequel, Caroline; Moignet, Aline; Laviolle, Bruno] CHU, Rennes, France; [Lavenu, Audrey; Laviolle, Bruno; Comets, Emmanuelle] Univ Rennes 1, Rennes, France; [Lacut, Karine] INSERM, CIC 1412, Brest, France; [Gissot, Valerie] INSERM, CIC 1415, Tours, France; [Sacher-Huvelin, Sylvie] INSERM, CIC 1413, Nantes, France; [Sacher-Huvelin, Sylvie] CHU Hotel Dieu, IMAD, Nantes, France; [Comets, Emmanuelle] INSERM, IAME, UMR 1137, Paris, France; [Comets, Emmanuelle] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France"	"Comets, E (corresponding author), INSERM, CIC 1414, Rennes, France.; Comets, E (corresponding author), Univ Rennes 1, Rennes, France.; Comets, E (corresponding author), INSERM, IAME, UMR 1137, Paris, France.; Comets, E (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite, Paris, France."	"emmanuelle.comets@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"laine, fabrice/0000-0001-6405-2211"	"PHRC [PHRC/12-02]"	"The authors thank Ms Isabelle Leroyer, Mr Stuart Byron and Ms Amelie Martin for the management of the clinical trial, the monitoring and the management of the data sets. This work was funded by a grant from the PHRC interregional 2012 (PHRC/12-02)."	43	5	5	0	5	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"MAR"	2016	18	2	490	504	"NA"	"10.1208/s12248-016-9875-4"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DL2JN"	"WOS:000375460900002"	26842695	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Marshall, SF; Burghaus, R; Cosson, V; Cheung, SYA; Chenel, M; DellaPasqua, O; Frey, N; Hamren, B; Harnisch, L; Ivanow, F; Kerbusch, T; Lippert, J; Milligan, PA; Rohou, S; Staab, A; Steimer, JL; Tornoe, C; Visser, SAG"	"Marshall, S. F.; Burghaus, R.; Cosson, V.; Cheung, S. Y. A.; Chenel, M.; DellaPasqua, O.; Frey, N.; Hamren, B.; Harnisch, L.; Ivanow, F.; Kerbusch, T.; Lippert, J.; Milligan, P. A.; Rohou, S.; Staab, A.; Steimer, J. L.; Tornoe, C.; Visser, S. A. G."	"EFPIA MID3 Workgrp"	"M"	"Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"CLINICAL-TRIAL SIMULATION; IN-VIVO; STRUCTURAL IDENTIFIABILITY; SYSTEMS PHARMACOLOGY; INDUSTRY PERSPECTIVE; LABELING DECISIONS; PREDICTIVE CHECK; PHARMACOKINETICS; IMPACT; PHARMACOMETRICS"	"This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of good practice'' recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines."	"[Marshall, S. F.; Harnisch, L.; Milligan, P. A.] Pfizer Ltd, Pharmacometr, Sandwich, Kent, England; [Burghaus, R.; Lippert, J.] Bayer Pharma AG, Syst Pharmacol & Med, Wuppertal, Germany; [Cosson, V.; Frey, N.] F Hoffmann La Roche Ltd, Clin Pharmacometr, Basel, Switzerland; [Cheung, S. Y. A.] AstraZeneca, Quantitat Clin Pharmacol, Cambridge, England; [Chenel, M.] Servier, Inst Rech Int, Suresnes, France; [DellaPasqua, O.] GlaxoSmithKline Res & Dev Ltd, Clin Pharmacol Modelling & Simulat, Uxbridge, Middx, England; [Hamren, B.] AstraZeneca, Quantitat Clin Pharmacol, Gothenburg, Sweden; [Ivanow, F.] Janssen R&D, Global Regulatory Policy & Intelligence, High Wycombe, Bucks, England; [Kerbusch, T.] MSD, Quantitat Pharmacol & Pharmacometr, Oss, Netherlands; [Rohou, S.] AstraZeneca, Global Regulatory Affairs & Policy, Paris, France; [Staab, A.] Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany; [Steimer, J. L.] Novartis, Pharmacometr, Basel, Switzerland; [Tornoe, C.] Novo Nordisk AS, Clin Reporting, Soborg, Denmark; [Visser, S. A. G.] Merck & Co Inc, Quantitat Pharmacol & Pharmacometr, Kenilworth, NJ USA"	"Marshall, SF (corresponding author), Pfizer Ltd, Pharmacometr, Sandwich, Kent, England."	"scott.marshall@pfizer.com"	"NA"	"NA"	"NA"	"NA"	103	112	117	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"MAR"	2016	5	3	93	122	"NA"	"10.1002/psp4.12049"	30	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DT6AA"	"WOS:000381563600001"	27069774	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Acharya, C; Hookers, AC; Turkyilmaz, GY; Jonsson, S; Karlsson, MO"	"Acharya, Chayan; Hookers, Andrew C.; Turkyilmaz, Gulbeyaz Yildiz; Jonsson, Siu; Karlsson, Mats O."	"NA"	"M"	"A diagnostic tool for population models using non-compartmental analysis: The ncappc package for R"	"COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE"	"English"	"Article"	"Non-compartmental analysis (NCA); PK; NONMEM; Posterior predictive check; Simulation-based diagnostic"	"NA"	"Background and objective: Non-compartmental analysis (NCA) calculates pharmacokinetic (PK) metrics related to the systemic exposure to a drug following administration, e.g. area under the concentration time curve and peak concentration. We developed a new package in R, called ncappc, to perform (i) a NCA and (ii) simulation-based posterior predictive checks (ppc) for a population PK (PopPK) model using NCA metrics. Methods: The nca feature of ncappc package estimates the NCA metrics by NCA. The ppc feature of ncappc estimates the NCA metrics from multiple sets of simulated concentration time data and compares them with those estimated from the observed data. The diagnostic analysis is performed at the population as well as the individual level. The distribution of the simulated population means of each NCA metric is compared with the corresponding observed population mean. The individual level comparison is performed based on the deviation of the mean of any NCA metric based on simulations for an individual from the corresponding NCA metric obtained from the observed data. The ncappc package also reports the normalized prediction distribution error (NPDE) of the simulated NCA metrics for each individual and their distribution within a population. Results: The ncappc produces two default outputs depending on the type of analysis performed, i.e., NCA and PopPK diagnosis. The PopPK diagnosis feature of ncappc produces 8 sets of graphical outputs to assess the ability of a population model to simulate the concentration time profile of a drug and thereby evaluate model adequacy. In addition, tabular outputs are generated showing the values of the NCA metrics estimated from the observed and the simulated data, along with the deviation, NPDE, regression parameters used to estimate the elimination rate constant and the related population statistics. Conclusions: The ncappc package is a versatile and flexible tool-set written in R that successfully estimates NCA metrics from concentration time data and produces a comprehensive set of graphical and tabular output to summarize the diagnostic results including the model specific outliers. The output is easy to interpret and to use in evaluation of a population PK model. ncappc is freely available on CRAN (http://crantoprojectorg/web/packages/ncappc/index.html/) and GitHub (https://github.comicacha0227/ncappc/). (C) 2016 The Authors. Published by Elsevier Ireland Ltd."	"[Acharya, Chayan; Hookers, Andrew C.; Turkyilmaz, Gulbeyaz Yildiz; Jonsson, Siu; Karlsson, Mats O.] Uppsala Univ, Dept Pharmaceut Biosci, POB 591, SE-75124 Uppsala, Sweden; [Turkyilmaz, Gulbeyaz Yildiz] Ege Univ, Fac Pharm, Dept Biopharmaceut & Pharmacokinet, TR-35100 Izmir, Turkey"	"Acharya, C (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, POB 591, SE-75124 Uppsala, Sweden."	"chayan.acharya@farmbio.uu.se"	"Jonsson, Siv/U-2218-2019; Hooker, Andrew/A-7794-2015; tArkyAlmaz, gAlbeyaz yAldAz/AAF-7766-2019"	"Jonsson, Siv/0000-0001-8240-0865; Hooker, Andrew/0000-0002-2676-5912; tArkyAlmaz, gAlbeyaz yAldAz/0000-0002-8601-0263"	"Innovative Medicines Initiative Joint Undertaking under European Union [115156]; Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)"	"The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners. The authors would also like to acknowledge The Scientific and Technological Research Council of Turkey (TUBITAK) for supporting postdoctoral research of Gulbeyaz Yildiz Turkyilmaz and Ege University, Center for Drug Research & Development and Pharmacokinetic Applications (ARGEFAR), Izmir, Turkey for providing us with the license of WinNonlin."	9	18	18	0	3	"ELSEVIER IRELAND LTD"	"CLARE"	"ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND"	"0169-2607"	"1872-7565"	"NA"	"COMPUT METH PROG BIO"	"Comput. Meth. Programs Biomed."	"APR"	2016	127	"NA"	83	93	"NA"	"10.1016/j.cmpb.2016.01.013"	11	"Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics"	"Computer Science; Engineering; Medical Informatics"	"DH1CH"	"WOS:000372521500008"	27000291	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Imbert, B; Marsot, A; Liachenko, N; Simon, N"	"Imbert, Bruce; Marsot, Amelie; Liachenko, Natalia; Simon, Nicolas"	"NA"	"A"	"Population Pharmacokinetics of High-Dose Oxazepam in Alcohol-Dependent Patients: Is There a Risk of Accumulation?"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"oxazepam; population pharmacokinetics; alcohol-dependent patients; NONMEM"	"NA"	"Background: According to the guidelines, benzodiazepines with a short half-life are the reference medication to treat alcohol withdrawal syndrome. The doses of oxazepam used in this population may reach up to 300 mg per day, significantly higher than usual doses. Its use in these patients deserves further information to confirm that the half-life remains constant and that no accumulation appears. The objective of this study was to investigate the pharmacokinetics of high doses of oxazepam in alcohol-dependent patients treated for alcohol withdrawal syndrome. Methods: Overall, 63 outpatients [weight, 71.1 kg (45.0-118.0); age, 47.6 years (31-67)] followed in the addictology unit, were studied. Total mean dose of 96.0 mg per day (range, 20-300 mg/d) was administered by oral route. Therapeutic drug monitoring allowed the measurement of 96 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, gender) and biological data (creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gammaglutamyl transferase). Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model. Results: Data were modeled with a 1-compartment pharmacokinetic model. The population typical mean 90% confidence interval values for clearance, apparent volume of distribution (V), and duration of absorption (D1) were 6.8 L/h (range, 3.9-8.0 L/h), 159 L (range, 98.0-282 L), and 2 hours (fixed), respectively. The interindividual variability of clearance and V, and residual variability (90% confidence interval) were 74% (44%-96%), 69% (40%-89%), and 32% (20%-41%), respectively. The elimination half-life was 16 hours (range, 3-42 hours). Conclusions: Oxazepam exhibited a linear pharmacokinetics with a proportional relationship from 20 to 300 mg per day, the dose range currently used in alcohol-dependent patients treated for alcohol withdrawal syndrome. We did not find any evidence of drug accumulation with these doses."	"[Imbert, Bruce] Allauch Hosp Ctr, Dept Addictol, Allauch, France; [Imbert, Bruce; Simon, Nicolas] Aix Marseille Univ, INSERM U912, SESSTIM, Marseille, France; [Imbert, Bruce; Simon, Nicolas] Hop St Marguerite, APHM, Serv Pharmacol Clin, CAP TV, F-13274 Marseille, France; [Marsot, Amelie; Liachenko, Natalia] Timone Univ Hosp, Dept Clin Pharmacol, Marseille, France; [Marsot, Amelie; Liachenko, Natalia] Hop St Marguerite, APHM, Serv Pharmacol Clin, CAP TV, F-13274 Marseille, France"	"Simon, N (corresponding author), Hop St Marguerite, APHM, Dept Clin Pharmacol, CAP TV, 279 Blvd St Marguerite, F-13274 Marseille, France."	"nicolas.simon@ap-hm.fr"	"Marsot, Amelie/P-7004-2016; Simon, Nicolas/B-1235-2016; Imbert, Bruce/L-3145-2016"	"Marsot, Amelie/0000-0002-9303-8862; Simon, Nicolas/0000-0003-4393-2257; Imbert, Bruce/0000-0002-0359-6255"	"NA"	"NA"	8	2	2	0	1	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"APR"	2016	38	2	253	258	"NA"	"10.1097/FTD.0000000000000262"	6	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"DN3BT"	"WOS:000376938000009"	26580099	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Desai, A; Schmitt-Hoffmann, AH; Mujais, S; Townsend, R"	"Desai, Amit; Schmitt-Hoffmann, Anne-Hortense; Mujais, Salim; Townsend, Robert"	"NA"	"A"	"Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"NA"	"Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment."	"[Desai, Amit; Mujais, Salim; Townsend, Robert] Astellas Pharma Global Dev Inc, Northbrook, IL USA; [Schmitt-Hoffmann, Anne-Hortense] Basilea Pharmaceut Int Ltd, Basel, Switzerland"	"Desai, A (corresponding author), Astellas Pharma Global Dev Inc, Northbrook, IL USA."	"amit.desai@astellas.com"	"NA"	"NA"	"Astellas Pharma Global Development, Inc.; Basilea"	"Isavuconazole was codeveloped by Basilea Pharmaceutica International Ltd. and Astellas Pharma, Inc. The PK analysis was performed by Astellas. Editorial support was provided by Ed Parr, a medical writer at Envision Scientific Solutions, funded by Astellas Pharma Global Development, Inc.; These studies were funded by Basilea."	13	29	29	0	2	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"MAY"	2016	60	5	3025	3031	"NA"	"10.1128/AAC.02942-15"	7	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"DN4NX"	"WOS:000377045600050"	26953193	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Bernadou, G; Campone, M; Merlin, JL; Gouilleux-Gruart, V; Bachelot, T; Lokiec, F; Rezai, K; Arnedos, M; Dieras, V; Jimenez, M; Paintaud, G; Ternant, D"	"Bernadou, Guillemette; Campone, Mario; Merlin, Jean-Louis; Gouilleux-Gruart, Valerie; Bachelot, Thomas; Lokiec, Francois; Rezai, Keyvan; Arnedos, Monica; Dieras, Veronique; Jimenez, Marta; Paintaud, Gilles; Ternant, David"	"NA"	"A"	"Influence of tumour burden on trastuzumab pharmacokinetics in HER2 positive non-metastatic breast cancer"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"breast cancer; pharmacokinetics; population PK modelling; trastuzumab"	"POPULATION PHARMACOKINETICS; MONOCLONAL-ANTIBODIES; PHASE-II; RITUXIMAB; PHARMACODYNAMICS; MECHANISM; EFFICACY; SAFETY; MODEL"	"AIMS Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab. METHODS Trastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4 mg kg(-1) loading dose followed by 5 weekly 2 mg kg(-1) doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate. RESULTS A total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1 l (23%), peripheral volume of distribution =1.3 l (38%), intercompartment clearance =0.36 l day(-1), with an elimination half-life of 11.8 days. Typical clearance was 0.22 l day(-1) (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size. CONCLUSIONS In non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied."	"[Paintaud, Gilles; Ternant, David] CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France; [Bernadou, Guillemette; Gouilleux-Gruart, Valerie; Paintaud, Gilles; Ternant, David] Univ Tours, CNRS, UMR 7292, Genet Immunotherapy Chem & Canc, Tours, France; [Bernadou, Guillemette] CHRU Tours, Clin Oncol & Radiotherapie, F-37044 Tours, France; [Campone, Mario] CNRS 6299, Canc Res Ctr UMR, INSERM, Dept Med Oncol,U892,Bioinformat Unit,Inst Cancero, Nantes, France; [Merlin, Jean-Louis] Univ Lorraine, Fac Pharm Nancy, Vandoeuvre Les Nancy, France; [Merlin, Jean-Louis] CNRS, CRAN UMR7039, Vandoeuvre Les Nancy, France; [Merlin, Jean-Louis] Inst Cancerol Lorraine, Serv Biopathol, Vandoeuvre Les Nancy, France; [Gouilleux-Gruart, Valerie] CHRU Tours, Serv Immunol, F-37044 Tours, France; [Bachelot, Thomas] Ctr Leon Berard, INSERM, U1052, Dept Med Oncol, F-69373 Lyon, France; [Lokiec, Francois; Rezai, Keyvan] Rene Huguenin Hosp, Inst Curie, Dept Radiopharmacol, St Cloud, France; [Arnedos, Monica; Dieras, Veronique] Gustave Roussy, Dept Med Oncol, Villejuif, France; [Jimenez, Marta] UNICANCER, R&D Unicanc, Paris, France"	"Ternant, D (corresponding author), CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"NA"	"REZAI, Keyvan/0000-0002-3328-3102; PAINTAUD, Gilles/0000-0003-0158-1356"	"NovartisNovartis; RocheRoche Holding; Roche Pharma; JanssenJohnson & Johnson USAJanssen Biotech Inc; MSD; ServierServier; PfizerPfizer; UniCancer, Cancen (Tours, France); Roche(R); Novartis(R); European UnionEuropean Union (EU); French Higher Education and Research ministry [ANR-10-LABX-53-01]"	"All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf and declare MC, JLM, VGG, TB, FL, KR, MA, VD, MJ and GP had no support from any organization for the submitted work, DB was granted by Cancen, Tours, France, GB, VGG, FL, KR and DT had no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, MC reports grants from Novartis, JLM reports speaker activity for Roche, TB reports grants, personal fees and non-financial support from Roche and Novartis, MA reports personal fees from Novartis, VD reports honoraria for advisory boards and speaker bureau Roche Genentech, and Novartis MJ reports grants and non-financial support from Roche and Novartis and GP reports grants from Roche Pharma and Novartis, MC, JLM, VGG, TB, FL, KR, MA, VD, MJ and DT had no other relationships or activities that could appear to have influenced the submitted work. DB reports grants from Janssen during the conduct of the study and GP reports grants from MSD, Servier and Pfizer.; This study was sponsored by UniCancer, Cancen (Tours, France) and supported by Roche (R) and Novartis (R). Measurements of trastuzumab serum concentrations were carried out within the CePiBAc platform. CePiBAc was cofinanced by the European Union. Europe is committed to the region Centre with the European Regional Development Fund. This work was partly supported by the French Higher Education and Research ministry under the programme 'Investissements d'avenir' Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01. The authors thank Anne-Claire Duveau and Caroline Brochon for technical assistance with trastuzumab assays."	24	16	16	0	5	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAY"	2016	81	5	941	948	"NA"	"10.1111/bcp.12875"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DK7MG"	"WOS:000375109100013"	26714164	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, CY; Jiao, Z; Mao, JJ; Qiu, XY"	"Zhao, Chen-Yan; Jiao, Zheng; Mao, Jun-Jun; Qiu, Xiao-Yan"	"NA"	"A"	"External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"adult renal transplant recipients; external evaluation; non-linear kinetics; population pharmacokinetics; tacrolimus"	"SOLID-ORGAN TRANSPLANTATION; WHOLE-BLOOD; CLINICAL PHARMACOKINETICS; KIDNEY-TRANSPLANTATION; MYCOPHENOLIC-ACID; CYP3A5 GENOTYPE; P-GLYCOPROTEIN; CYCLOSPORINE; POLYMORPHISMS; IMMUNOASSAY"	"AIM Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors. METHODS Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. RESULTS Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within � 30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used. CONCLUSIONS The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability."	"[Zhao, Chen-Yan; Jiao, Zheng; Mao, Jun-Jun; Qiu, Xiao-Yan] Fudan Univ, Huashan Hosp, Dept Pharm, 12 Middle Urumqi Rd, Shanghai 200040, Peoples R China; [Mao, Jun-Jun] Fudan Univ, Sch Pharm, Dept Clin Pharm, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China"	"Jiao, Z (corresponding author), Fudan Univ, Huashan Hosp, Dept Pharm, 12 Middle Urumqi Rd, Shanghai 200040, Peoples R China."	"zjiao@fudan.edu.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81 072 702, 81 473 409, 81 573 505, 81 302 854]; Major Research and Development Project of Innovative Drugs, China Ministry of Science and Technology [2012ZX09303004-001]"	"All authors have completed the United Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on the request from the corresponding author) and declare Dr Z. Jiao had support from National Natural Science Foundation of China (No. 81 072 702, 81 473 409 and 81 573 505) and from Major Research and Development Project of Innovative Drugs, China Ministry of Science and Technology (2012ZX09303004-001) and Dr X.Y. Qiu had support from National Natural Science Foundation of China (No. 81 302 854), which promoted the study. There are no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work. The other authors have no conflicts of interest to declare."	73	21	25	1	11	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAY"	2016	81	5	891	907	"NA"	"10.1111/bcp.12830"	17	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DK7MG"	"WOS:000375109100009"	26574188	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Franken, LG; Masman, AD; de Winter, BCM; Koch, BCP; Baar, FPM; Tibboel, D; van Gelder, T; Mathot, RAA"	"Franken, Linda G.; Masman, Anniek D.; de Winter, Brenda C. M.; Koch, Birgit C. P.; Baar, Frans P. M.; Tibboel, Dick; van Gelder, Teun; Mathot, Ron A. A."	"NA"	"A"	"Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"CANCER-PATIENTS; CARE; INFUSION; PAIN; GLUCURONIDES; METABOLITES; PREVALENCE; PROTEINS; DELIRIUM; DISEASE"	"Background and Objective Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis. Methods Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases. Nonlinear mixed-effects modelling (NONMEM) was used to develop a population pharmacokinetic model and perform covariate analysis. Results The data were accurately described by a two-compartment model for morphine with two one-compartment models for both its metabolites. Typical morphine clearance was 48 L/h and fell exponentially by more than 10 L/h in the last week before death. Decreased albumin levels and a decreased estimated glomerular filtration rate (eGFR) resulted in lower metabolite clearance. Between-subject variability in clearance was 52 % (morphine), 75 % (M3G) and 79 % (M6G), and changed to 53, 29 and 34 %, respectively, after inclusion of the covariates. Conclusions Our results show that morphine clearance decreased up to the time of death, falling by more than 10 L/h (26 %) in the last week before death, and that M3G and M6G accumulated due to decreased renal function. Further studies are warranted to determine whether dose adjustment of morphine is required in terminally ill patients."	"[Franken, Linda G.; de Winter, Brenda C. M.; Koch, Birgit C. P.; van Gelder, Teun] Erasmus MC, Dept Hosp Pharm, Wytemaweg 80 Na 219, NL-3015 Rotterdam, Netherlands; [Masman, Anniek D.; Baar, Frans P. M.] Laurens Cadenza, Palliat Care Ctr, Rotterdam, Netherlands; [Masman, Anniek D.; Tibboel, Dick] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Intens Care, Rotterdam, Netherlands; [Tibboel, Dick] Erasmus MC Sophia Childrens Hosp, Pain Expertise Ctr, Rotterdam, Netherlands; [Mathot, Ron A. A.] Univ Amsterdam, Acad Med Ctr, Hosp Pharm Clin Pharmacol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands"	"Franken, LG (corresponding author), Erasmus MC, Dept Hosp Pharm, Wytemaweg 80 Na 219, NL-3015 Rotterdam, Netherlands."	"l.franken@erasmusmc.nl"	"Franken, Linda/AAB-1901-2020"	"Franken, Linda/0000-0001-6436-9825; koch, birgit/0000-0002-1202-3643"	"NA"	"NA"	42	15	15	0	8	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUN"	2016	55	6	697	709	"NA"	"10.1007/s40262-015-0345-4"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DM6JL"	"WOS:000376457700004"	26715216	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Bloomfield, C; Staatz, CE; Unwin, S; Hennig, S"	"Bloomfield, Celeste; Staatz, Christine E.; Unwin, Sean; Hennig, Stefanie"	"NA"	"A"	"Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"CYSTIC-FIBROSIS; AMINOGLYCOSIDE PHARMACOKINETICS; GLOMERULAR-FILTRATION; CHILDREN; NEPHROTOXICITY; OPTIMIZATION; GENTAMICIN; ADOLESCENT; PNEUMONIA; REGIMEN"	"Several population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from -0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions."	"[Bloomfield, Celeste; Staatz, Christine E.; Hennig, Stefanie] Univ Queensland, PACE, Sch Pharm, Brisbane, Qld, Australia; [Unwin, Sean] Princess Alexandra Hosp, Metro South Hlth, Infect Management Serv, Woolloongabba, Qld 4102, Australia; [Unwin, Sean] Princess Alexandra Hosp, Metro South Hlth, Dept Pharm, Woolloongabba, Qld 4102, Australia"	"Hennig, S (corresponding author), Univ Queensland, PACE, Sch Pharm, Brisbane, Qld, Australia."	"s.hennig@uq.edu.au"	"Hennig, Stefanie/E-4426-2011; Staatz, Christine E/F-3971-2010"	"Hennig, Stefanie/0000-0001-5972-3711; Staatz, Christine E/0000-0002-4595-9376"	"NA"	"NA"	44	12	12	0	3	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JUN"	2016	60	6	3407	3414	"NA"	"10.1128/AAC.02654-15"	8	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"DN4PE"	"WOS:000377048900018"	27001806	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Honma, W; Gautier, A; Paule, I; Yamaguchi, M; Lowe, PJ"	"Honma, Wataru; Gautier, Aurelie; Paule, Ines; Yamaguchi, Masayuki; Lowe, Philip J."	"NA"	"A"	"Ethnic sensitivity assessment of pharmacokinetics and pharmacodynamics of omalizumab with dosing table expansion"	"DRUG METABOLISM AND PHARMACOKINETICS"	"English"	"Article"	"Allergic asthma; Anti-immunoglobulin E; Dosing table; Modeling and simulation; Omalizumab"	"SEVERE PERSISTENT ASTHMA; SEVERE ALLERGIC-ASTHMA; E ANTIBODY OMALIZUMAB; IGE-MEDIATED ASTHMA; MONOCLONAL-ANTIBODY; POPULATION; PREDICTION; EFFICACY; THERAPY; SAFETY"	"A three-part license expansion for omalizumab (Xolair (R)), humanized anti-IgE antibody, was recently made in Japan for paediatric use, additional higher doses and revised dosing frequency in allergic asthma. The dosing level and frequency of omalizumab are guided by a dosing table based on the total serum IgE and bodyweight. Nonlinear mixed-effect pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation techniques described the binding between omalizumab and its target IgE. The population PKPD analysis was conducted using data from the nine studies included originally in the European application of dosing table expansion together with three Japanese clinical studies to assess the influence of the ethnicity. Statistically significant differences between the ethnic groups were detected. These were small, within or close to bioequivalence criteria. The model described the primary pharmacology in Caucasian and Japanese patients, both adult and paediatric, with simulations showing that the interplay between the clearance, volume and binding affinity parameters was such that there was no clinical impact of the Japanese ethnic differences on either drug PK or free IgE suppression and hence the required posology. (C) 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved."	"[Honma, Wataru; Yamaguchi, Masayuki] Novartis Pharma KK, Minato Ku, 1-23-1 Toranomon, Tokyo 1056333, Japan; [Gautier, Aurelie; Paule, Ines; Lowe, Philip J.] Novartis Pharma AG, Lichtstr 35, CH-4056 Basel, Switzerland"	"Honma, W (corresponding author), Novartis Pharma KK, Minato Ku, 1-23-1 Toranomon, Tokyo 1056333, Japan."	"wataru.honma@novartis.com; aurelie.gautier@novartis.com; ines.paule@novartis.com; masayuki.yamaguchi@novartis.com; phil.lowe@novartis.com"	"Lowe, Phil/K-8483-2019"	"NA"	"NA"	"NA"	22	4	4	1	6	"JAPANESE SOC STUDY XENOBIOTICS"	"TOKYO"	"INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN"	"1347-4367"	"1880-0920"	"NA"	"DRUG METAB PHARMACOK"	"Drug Metab. Pharmacokinet."	"JUN"	2016	31	3	173	184	"NA"	"10.1016/j.dmpk.2015.12.003"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DO4TH"	"WOS:000377776500001"	27238573	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Liu, T; Lewis, T; Gauda, E; Gobburu, J; Ivaturi, V"	"Liu, Tao; Lewis, Tamorah; Gauda, Estelle; Gobburu, Jogarao; Ivaturi, Vijay"	"NA"	"A"	"Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"morphine; diluted tincture of opium; bioavailability; population pharmacokinetic model; neonate; neonatal abstinence syndrome"	"CHILDREN; MORPHINE-6-GLUCURONIDE; PREDICTION; INFANTS; MODELS; GLUCURONIDATION; METABOLITES; VOLUNTEERS; CLEARANCE; KINETICS"	"Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population."	"[Liu, Tao; Gobburu, Jogarao; Ivaturi, Vijay] Univ Maryland, Sch Pharm, Ctr Translat Med, Pharm Hall, Baltimore, MD 21201 USA; [Lewis, Tamorah; Gauda, Estelle] Johns Hopkins Med Inst, Dept Pediat, Div Neonatol, Baltimore, MD 21205 USA"	"Ivaturi, V (corresponding author), Univ Maryland, Sch Pharm, Ctr Translat Med, Pharm Hall, Baltimore, MD 21201 USA."	"vivaturi@rx.umaryland.edu"	"Ivaturi, Vijay/J-8742-2019; Lewis, Tamorah/P-3550-2019"	"Ivaturi, Vijay/0000-0002-6433-1154; Lewis, Tamorah/0000-0003-2137-8339; Liu, Tao/0000-0002-9943-2131"	"Thomas Wilson grant; Johns Hopkins Hospital, General Clinical Research CenterUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR); National Institute on Drug AbuseUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [IR21DAO16288]; Clinical Pharmacology NIH [5T32GM066691]"	"This study was funded by a Thomas Wilson grant, an institutional research grant from Johns Hopkins Hospital, General Clinical Research Center, and was supported by National Institute on Drug Abuse grant IR21DAO16288. In addition, the Clinical Pharmacology NIH training grant 5T32GM066691 supported the second author during this work."	28	17	16	0	4	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"AUG"	2016	56	8	1009	1018	"NA"	"10.1002/jcph.696"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DR7AE"	"WOS:000380051600010"	26712409	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Bouazza, N; Urien, S; Treluyer, JM; Touzot, F"	"Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc; Touzot, Fabien"	"NA"	"A"	"Antithymocyte globulin: Importance of good clinical pharmacological practice Reply"	"JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY"	"English"	"Letter"	"NA"	"HEMATOPOIETIC-CELL TRANSPLANTATION; HOST-DISEASE PROPHYLAXIS; MODELS"	"NA"	"[Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Univ Paris 05, Sorbonne Paris Cite, EA7323, Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Hop Tarnier, AP HP, Unite Rech Clin, Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] INSERM, CIC 0901, Cochin Necker, Paris, France; [Treluyer, Jean-Marc] Univ Paris 05, Sorbonne Paris Cite, Hop Cochin, AP HP,Serv Pharmacol Clin, Paris, France; [Touzot, Fabien] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, Paris, France; [Touzot, Fabien] INSERM, UMR1163, Paris, France; [Touzot, Fabien] Hop Necker Enfants Malad, AP HP, Dept Biotherapie, Ctr Invest Clin Integre Biotherapies, Paris, France"	"Bouazza, N (corresponding author), Univ Paris 05, Sorbonne Paris Cite, EA7323, Paris, France.; Bouazza, N (corresponding author), Hop Tarnier, AP HP, Unite Rech Clin, Paris, France.; Bouazza, N (corresponding author), INSERM, CIC 0901, Cochin Necker, Paris, France."	"naim.bouazza@aphp.fr"	"Urien, Saik/G-3240-2013; Touzot, Fabien/T-7797-2018"	"Touzot, Fabien/0000-0002-0889-4905"	"NA"	"NA"	7	0	0	0	0	"MOSBY-ELSEVIER"	"NEW YORK"	"360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA"	"0091-6749"	"1097-6825"	"NA"	"J ALLERGY CLIN IMMUN"	"J. Allergy Clin. Immunol."	"AUG"	2016	138	2	633	634	"NA"	"10.1016/j.jaci.2016.02.037"	3	"Allergy; Immunology"	"Allergy; Immunology"	"DS5PY"	"WOS:000380835800050"	27215489	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Michelet, R; Dossche, L; De Bruyne, P; Colin, P; Boussery, K; Walle, JV; Van Bocxlaer, J; Vermeulen, A"	"Michelet, Robin; Dossche, Lien; De Bruyne, Pauline; Colin, Pieter; Boussery, Koen; Walle, Johan Vande; Van Bocxlaer, Jan; Vermeulen, An"	"NA"	"A"	"Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"NOCTURNAL ENURESIS; SAFETY; TABLET; MODEL"	"Introduction Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations-a tablet and a lyophilisate-in both fasted and fed children. Methods Previously published data from two studies (one in 22 children aged 6-16 years, and the other in 25 children aged 6-13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect. Results The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant. Conclusion Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model."	"[Michelet, Robin; Colin, Pieter; Boussery, Koen; Van Bocxlaer, Jan; Vermeulen, An] Univ Ghent, Fac Pharmaceut Sci, Dept Bioanal, Lab Med Biochem & Clin Anal, Ghent, Belgium; [Dossche, Lien; De Bruyne, Pauline] Univ Ghent, Dept Pediat & Med Genet, Fac Med & Hlth Sci, Ghent, Belgium; [Walle, Johan Vande] Ghent Univ Hosp, Dept Pediat Nephrol, Ghent, Belgium; [Colin, Pieter] Univ Groningen, Univ Med Ctr Groningen, Dept Anesthesiol, Groningen, Netherlands"	"Michelet, R (corresponding author), Univ Ghent, Fac Pharmaceut Sci, Dept Bioanal, Lab Med Biochem & Clin Anal, Ghent, Belgium."	"robin.michelet@ugent.be"	"Colin, Pieter/AAK-3525-2020; De Bruyne, Pauline/J-2055-2017; Walle, Johan Vande/AAG-3858-2020; Michelet, Robin/AAM-7991-2020"	"Colin, Pieter/0000-0003-3616-5539; De Bruyne, Pauline/0000-0002-3090-9755; Michelet, Robin/0000-0002-5485-607X; Dossche, Lien/0000-0003-1030-9848"	"Agency for Innovation by Science and Technology in Flanders (IWT) through SAFE-PEDRUG ProjectInstitute for the Promotion of Innovation by Science and Technology in Flanders (IWT) [IWT/SBO 130033]"	"This study was supported by the Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFE-PEDRUG Project (IWT/SBO 130033)."	39	9	9	0	13	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"SEP"	2016	55	9	1159	1170	"NA"	"10.1007/s40262-016-0393-4"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DU4AN"	"WOS:000382154200011"	27106176	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Frymoyer, A; Su, F; Grimm, PC; Sutherland, SM; Axelrod, DM"	"Frymoyer, Adam; Su, Felice; Grimm, Paul C.; Sutherland, Scott M.; Axelrod, David M."	"NA"	"A"	"Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"pediatric; aminophylline; pharmacokinetics; acute kidney injury; congenital heart defect"	"ACUTE KIDNEY INJURY; CRITICALLY-ILL CHILDREN; LENGTH-OF-STAY; CARDIAC-SURGERY; PROPHYLACTIC THEOPHYLLINE; PERINATAL ASPHYXIA; RENAL DYSFUNCTION; SERUM CREATININE; MORTALITY; INFANTS"	"Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age 5 months; 90% range 1 week to 10 years) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A 1-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in noncardiac children, theophylline clearance was markedly reduced across age. In the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50% to 75% lower than those recommended in noncardiac children were needed to achieve target serum concentrations of 5 to 10 mg/L."	"[Frymoyer, Adam; Su, Felice; Grimm, Paul C.; Sutherland, Scott M.; Axelrod, David M.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA"	"Frymoyer, A (corresponding author), Stanford Univ, Dept Pediat, 750 Welch Rd, Palo Alto, CA 94304 USA."	"frymoyer@stanford.edu"	"NA"	"NA"	"National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K23 HD079557]; Child Health Research Institute; Lucile Packard Foundation for Children's Health; Stanford Clinical Translational Science Award program - National Center for Advancing Translational Sciences at the National Institutes of Health [UL1 TR001085]"	"A.F. is supported by the National Institutes of Health (K23 HD079557) for this work. The project was also supported by the Child Health Research Institute, Lucile Packard Foundation for Children's Health, and the Stanford Clinical Translational Science Award program funded by the National Center for Advancing Translational Sciences at the National Institutes of Health (UL1 TR001085)."	48	5	6	0	9	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"SEP"	2016	56	9	1084	1093	"NA"	"10.1002/jcph.697"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DV2JO"	"WOS:000382746900006"	26712558	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Colin, P; Eleveld, DJ; Jonckheere, S; Van Bocxlaer, J; De Waele, J; Vermeulen, A"	"Colin, Pieter; Eleveld, Douglas J.; Jonckheere, Stijn; Van Bocxlaer, Jan; De Waele, Jan; Vermeulen, An"	"NA"	"M"	"What about confidence intervals? A word of caution when interpreting PTA simulations"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"TARGET ATTAINMENT ANALYSIS; CRITICALLY-ILL PATIENTS; MIXED-EFFECT MODELS; POPULATION PHARMACOKINETICS; DOSING SIMULATIONS; PHARMACODYNAMICS; EVALUATE; PIPERACILLIN; VANCOMYCIN; PREDICTION"	"In the field of antimicrobial chemotherapy, readers are increasingly confronted with population pharmacokinetic models and the ensuing simulation results with the purpose to improve the efficiency of currently used therapeutic regimens. One such type of analysis is Monte Carlo (MC) simulations in support of dose selection. At the moment, results of these MC simulations consist of predictions for the typical individual/population only. The uncertainty associated with the parameters, from which the simulations are derived, is completely ignored. Here, we highlight the importance of and the need to include parameter uncertainty in PTA simulations. Using MC simulation with parameter uncertainty, we estimated CIs around PTA curves. The added benefit of this approach was illustrated using, on the one hand, a population pharmacokinetic model developed in-house for a beta-lactam antibiotic and, on the other hand, results from a previously published PTA analysis. Our examples illustrate that proper clinical decision-making requires more than the typical PTA curve. Therefore, authors should be encouraged to provide an estimate of the uncertainty along with their simulations and to take this into account when interpreting the results. We feel that CIs around PTA curves provide this information in a comprehensive manner without requiring advanced knowledge on the underlying modelling approaches from the reader. We believe that this approach should be advocated by all stakeholders in antibiotic stewardship programmes to safeguard the quality of clinical decision-making in the future."	"[Colin, Pieter; Van Bocxlaer, Jan; Vermeulen, An] Univ Ghent, Fac Pharmaceut Sci, Lab Med Biochem & Clin Anal, Ghent, Belgium; [Colin, Pieter; Eleveld, Douglas J.] Univ Groningen, Univ Med Ctr Groningen, Dept Anesthesiol, Groningen, Netherlands; [Jonckheere, Stijn] OLVZ Aalst, Clin Lab Microbiol, Asse, Belgium; [De Waele, Jan] Ghent Univ Hosp, Dept Crit Care Med, Ghent, Belgium"	"Colin, P (corresponding author), Univ Ghent, Fac Pharmaceut Sci, Lab Med Biochem & Clin Anal, Ghent, Belgium.; Colin, P (corresponding author), Univ Groningen, Univ Med Ctr Groningen, Dept Anesthesiol, Groningen, Netherlands."	"pieter.colin@ugent.be"	"Colin, Pieter/AAK-3525-2020"	"Colin, Pieter/0000-0003-3616-5539"	"NA"	"NA"	26	9	9	0	4	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"SEP"	2016	71	9	2502	2508	"NA"	"10.1093/jac/dkw150"	7	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"DW8NB"	"WOS:000383911600020"	27147302	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Dureau, P; Charbit, B; Nicolas, N; Benhamou, D; Mazoit, JX"	"Dureau, Pauline; Charbit, Beny; Nicolas, Nathalie; Benhamou, Dan; Mazoit, Jean-Xavier"	"NA"	"A"	"Effect of Intralipid (R) on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers A Clinical and Pharmacokinetic Study"	"ANESTHESIOLOGY"	"English"	"Article"	"NA"	"BUPIVACAINE-INDUCED ASYSTOLE; INTRAVENOUS LIPID EMULSION; CARDIAC-ARREST; SUCCESSFUL RESUSCITATION; HEALTHY-VOLUNTEERS; LOCAL-ANESTHETICS; EPIDURAL INFUSION; PLEXUS BLOCK; TOXICITY; MEPIVACAINE"	"Background: Rapid intravenous administration of lipid emulsion has become the standard treatment of severe local anesthetic systemic toxicity. This experiment in volunteers aimed at determining the effect of Intralipid (R) administration on the time to neurologic symptoms. Methods: Ropivacaine or levobupivacaine was infused intravenously in 16 volunteers (8 mg/min up to 120 mg) with 120 ml Intralipid (R) 20% (Fresenius, Paris France) or placebo infused at T  2 min). Each subject received all four treatments in a crossover manner. The infusion was stopped after the intended dose had been administered or on occurrence of incipient neurologic signs of toxicity. The primary outcome was time-to-event. In addition, blood ropivacaine and levobupivacaine concentrations were measured. Results: The dose infused was not different whether volunteers received placebo (81.7 � 22.3 vs. 80.8 � 31.7 mg, ropivacaine vs. levobupivacaine) or Intralipid (R) (75.7 � 29.1 vs. 69.4 � 26.2 mg, ropivacaine vs. levobupivacaine), P = 0.755, Intralipid (R) versus placebo groups. Plasma concentrations were best modeled with an additional volume of distribution associated with Intralipid (R). Simulations suggested that decreased peak concentrations would be seen if Intralipid (R) was given during a period of increasing concentrations after extravascular administration. Conclusions: At modestly toxic doses of ropivacaine or levobupivacaine, we were unable to find any effect of the infusion of Intralipid (R) on the time to early signs of neurologic toxicity in volunteers. Peak concentration was decreased by 26 to 30% in the subjects receiving Intralipid (R). Simulations showed that Intralipid (R) might prevent the rapid increase of local anesthetic concentration after extravascular administration."	"[Benhamou, Dan; Mazoit, Jean-Xavier] Hop Univ Paris Sud, AP HP, Dept Anesthesie Reanimat, Paris, France; [Benhamou, Dan; Mazoit, Jean-Xavier] Univ Paris 11, Fac Med, Lab Anesthesie, INSERM,UMR 788, Paris, France; [Dureau, Pauline; Charbit, Beny; Nicolas, Nathalie] Hop La Pitie Salpetriere, AP HP, Ctr Invest Clin Paris Est, Paris, France; [Charbit, Beny] Ctr Hosp Univ, Dept Anesthesie Reanimat, Reims, France"	"Mazoit, JX (corresponding author), Fac Med, Lab Anesthesie, 63 Rue Gabriel Peri, F-94276 Paris, France."	"jean-xavier.mazoit@u-psud.fr"	"NA"	", Beny/0000-0002-7811-1697"	"Departement de la Recherche Clinique et du Developpement, AP-HP Hopital Saint Louis, Paris, France [CRC10035-P100501]"	"Supported by the Departement de la Recherche Clinique et du Developpement, AP-HP Hopital Saint Louis, Paris, France (Projet-CRC10035-P100501)."	46	23	23	0	3	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0003-3022"	"1528-1175"	"NA"	"ANESTHESIOLOGY"	"Anesthesiology"	"SEP"	2016	125	3	474	483	"NA"	"10.1097/ALN.0000000000001230"	10	"Anesthesiology"	"Anesthesiology"	"DY3VQ"	"WOS:000385024100011"	27404223	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Lu, YH; Chaturvedula, A; Haberer, JE; Fossler, MJ; Sale, ME; Bangsberg, D; Baeten, JM; Celum, CL; Hendrix, CW"	"Lu, Yanhui; Chaturvedula, Ayyappa; Haberer, Jessica E.; Fossler, Michael J.; Sale, Mark E.; Bangsberg, David; Baeten, Jared M.; Celum, Connie L.; Hendrix, Craig W."	"NA"	"A"	"Population Pharmacokinetics of Tenofovir in HIV-1-Uninfected Members of Serodiscordant Couples and Effect of Dose Reporting Methods"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"PREEXPOSURE PROPHYLAXIS; INFECTED PATIENTS; HIV PREVENTION; AFRICAN WOMEN; ANRS 12109; MODELS; NONMEM; ATAZANAVIR; STRATEGIES; ADHERENCE"	"Antiretroviral preexposure prophylaxis (PrEP) with once-daily dosing of tenofovir and tenofovir-emtricitabine was shown to be effective for preventing HIV-1 infection in individuals who had HIV-1-seropositive partners ( the Partners PrEP Study). We developed a population pharmacokinetic model for tenofovir and investigated the impacts of different dose reporting methods. Dosing information was collected as patient-reported dosing information ( PRDI) from 404 subjects ( corresponding to 1,280 drug concentration records) from the main trial and electronic monitoring-based adherence data collected from 211 subjects ( corresponding to 327 drug concentration records) in an ancillary adherence study. Model development was conducted with NONMEM ( 7.2), using PRDI with a steady-state assumption or using PRDI replaced with electronic monitoring records where available. A two-compartment model with first-order absorption was the best model in both modeling approaches, with the need for an absorption lag time when electronic monitoring-based dosing records were included in the analysis. Age, body weight, and creatinine clearance were significant covariates on clearance, but only creatinine clearance was retained in the final models per stepwise selection. Sex was not a significant covariate on clearance. Tenofovir population pharmacokinetic parameter estimates and the precisions of the parameters from the two final models were comparable with the point estimates of the parameters, differing from 0% to 35%, and bootstrap confidence intervals widely overlapped. These findings indicate that PRDI was sufficient for population pharmacokinetic model development in this study, with a high level of adherence per multiple measures."	"[Lu, Yanhui; Hendrix, Craig W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA; [Chaturvedula, Ayyappa; Haberer, Jessica E.] Mercer Univ, Pharmaceut Sci, Atlanta, GA 30341 USA; [Haberer, Jessica E.; Bangsberg, David] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA; [Haberer, Jessica E.; Bangsberg, David] Harvard Med Sch, Boston, MA USA; [Fossler, Michael J.] Trevena Inc, Quantitat Sci, King Of Prussia, PA USA; [Sale, Mark E.] Nuventra, Durham, NC USA; [Baeten, Jared M.; Celum, Connie L.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA; [Baeten, Jared M.; Celum, Connie L.] Univ Washington, Dept Med, Seattle, WA USA; [Baeten, Jared M.; Celum, Connie L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA; [Chaturvedula, Ayyappa] Univ North Texas, Hlth Sci Ctr, Pharmacotherapy, Ft Worth, TX 76107 USA"	"Chaturvedula, A (corresponding author), Mercer Univ, Pharmaceut Sci, Atlanta, GA 30341 USA.; Chaturvedula, A (corresponding author), Univ North Texas, Hlth Sci Ctr, Pharmacotherapy, Ft Worth, TX 76107 USA."	"ayyappa.chaturvedula@unthsc.edu"	"Haberer, Jessica/AAH-7976-2019; Hendrix, Craig/G-4182-2014"	"Haberer, Jessica/0000-0001-5845-3190; Hendrix, Craig/0000-0002-5696-8665"	"Bill & Melinda Gates FoundationBill & Melinda Gates Foundation [OOP47674]; Massachusetts General Hospital [OOP52516]; Johns Hopkins University Center for AIDS Research [5P30AI094189-04]"	"The Partners PrEP Study was funded through a research grant from the Bill & Melinda Gates Foundation (grant OOP47674), and the current analysis was supported by a subaward (grant OOP52516) from the Massachusetts General Hospital to Mercer University and by the Johns Hopkins University Center for AIDS Research (grant 5P30AI094189-04)."	29	8	8	0	0	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"SEP"	2016	60	9	5379	5386	"NA"	"10.1128/AAC.00559-16"	8	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"ED7OH"	"WOS:000389055400033"	27353269	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Knosgaard, KR; Foster, DJR; Kreilgaard, M; Sverrisdottir, E; Upton, RN; van den Anker, JN"	"Knosgaard, Katrine Rorbaek; Foster, David John Richard; Kreilgaard, Mads; Sverrisdottir, Eva; Upton, Richard Neil; van den Anker, Johannes N."	"NA"	"A"	"Pharmacokinetic models of morphine and its metabolites in neonates: Systematic comparisons of models from the literature, and development of a new meta-model"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Morphine; Morphine-6-glucuronide; Preterm neonates; Pharmacokinetics/pharmacodynamics; Modelling; Systematic model comparison"	"PROCEDURAL PAIN; RENAL-FUNCTION; PRETERM; INFANTS; CHILDREN; MORPHINE-6-GLUCURONIDE; GLUCURONIDATION; ANALGESIA; CLEARANCE"	"Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreovdr, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23-32 weeks) received a loading dose of morphine (50-100 mu g/kg), followed by a continuous infusion (5-10 mu g/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM (R) and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established. (C) 2016 Elsevier B.V. All rights reserved."	"[Knosgaard, Katrine Rorbaek; Kreilgaard, Mads; Sverrisdottir, Eva] Univ Copenhagen, Fac Hlth Sci, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark; [Foster, David John Richard; Upton, Richard Neil] Univ South Australia, Australian Ctr Pharmacometr, City East Campus,North Terrace, Adelaide, SA 5000, Australia; [Foster, David John Richard; Upton, Richard Neil] Univ South Australia, Sansom Inst, Sch Pharmaceut & Med Sci, City East Campus,North Terrace, Adelaide, SA 5000, Australia; [van den Anker, Johannes N.] Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA; [van den Anker, Johannes N.] Univ Childrens Hosp Basel, Div Paediat Pharmacol & Pharmacometr, Basel, Switzerland; [van den Anker, Johannes N.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Intens Care, Rotterdam, Netherlands; [van den Anker, Johannes N.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Surg, Rotterdam, Netherlands"	"Upton, RN (corresponding author), Univ South Australia, Sch Pharmaceut & Med Sci, Australian Ctr Pharmacometr, City East Campus,North Terrace, Adelaide, SA 5000, Australia."	"richard.upton@unisa.edu.au"	"Upton, Richard N/G-4727-2011"	"Upton, Richard N/0000-0001-9996-4886; Sverrisdottir, Eva/0000-0002-1028-3134; Foster, David/0000-0002-7345-4084"	"NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01HD048689]"	"John van den Anker was supported by a NIH grant (R01HD048689) to conduct this neonatal study; Patients were included at two institutions (Kosair Children's Hospital in Louisville, Kentucky and Children's National Health System in Washington, DC) and Drs. Jan Sullivan and Williams have been instrumental for the conduct of the study."	62	13	13	0	8	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"SEP 20"	2016	92	"NA"	117	130	"NA"	"10.1016/j.ejps.2016.06.026"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DT9PD"	"WOS:000381833900013"	27373670	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Guilhaumou, R; Marsot, A; Dupouey, J; Galambrun, C; Boulamery, A; Coze, C; Simon, N; Andre, N"	"Guilhaumou, Romain; Marsot, Amelie; Dupouey, Julien; Galambrun, Claire; Boulamery, Audrey; Coze, Carole; Simon, Nicolas; Andre, Nicolas"	"NA"	"A"	"Pediatric Patients With Solid or Hematological Tumor Disease: Vancomycin Population Pharmacokinetics and Dosage Optimization"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"vancomycin; pediatric oncology patients; population pharmacokinetics; dosage adjustment"	"CANCER; CHILDREN; NEPHROTOXICITY; INFECTIONS; MANAGEMENT; INFUSION; FEVER"	"Background:In pediatric cancer patients, determination of optimal vancomycin dosage is essential because of high risk of inadequate concentrations and bacterial resistance. The aim of this study was to determine vancomycin pharmacokinetic parameters in this population and propose dosage optimization to achieve optimal concentration.Methods:We retrospectively reviewed the use of vancomycin in pediatric cancer patients with febrile neutropenia (hematological or solid tumor disease). Vancomycin was administered by continuous infusion, and dosages were adapted according to therapeutic drug monitoring results. Blood cultures were performed before the first dose of antibiotic. Vancomycin pharmacokinetic population parameters were determined using NONMEM software, and dosage simulations were performed according to the target concentration (20-25 mg/L).Results:One hundred twenty-one patients were included in this study, representing 301 vancomycin concentrations. Blood cultures were positive in 37.5% of patients, and observed pathogens were mainly Staphylococcus spp. (43.8% methicillin resistant). Volume of distribution (95% confidence interval) was 34.7 L (17.3-48.0), and total apparent clearance (CL) (95% confidence interval) was correlated to body weight, tumor disease, and cyclosporine coadministration: CL = (CL) x (WT/70)(0.75) L/h with (CL) = 3.49 (3.02-3.96), 4.66 (3.98-5.31), and 4.97 (4.42-5.41) in patients managed for hematological malignancies with or without cyclosporine coadministration and for solid malignancies, respectively. Based on simulation results, vancomycin dosage (milligram per kilogram) should be adapted to each child on the basis of its body weight and cyclosporine coadministration.Conclusions:Our results highlight the requirement to adapt vancomycin dosage in cancer pediatric population. Simulations have allowed to describe new dosage schedules, and a chart was created for clinicians to adapt vancomycin dosage."	"[Guilhaumou, Romain; Marsot, Amelie; Dupouey, Julien] Hop la Timone, Serv Pharmacol Clin & Pharmacovigilance, Marseille, France; [Guilhaumou, Romain; Marsot, Amelie; Dupouey, Julien] Inst Neurosci Timone, Pharmacol Integree Interface Clin & Ind, Marseille, France; [Galambrun, Claire; Coze, Carole; Andre, Nicolas] Hop la Timone, Serv Hematol & Oncol Pediat, Marseille, France; [Boulamery, Audrey; Simon, Nicolas] Hop St Marguerite, Ctr Antipoison, Serv Pharmacol Clin, Marseille, France; [Boulamery, Audrey] Aix Marseille Univ, Marseille, France; [Simon, Nicolas] Aix Marseille Univ, INSERM, UMR S 912, SESSTIM, Marseille, France"	"Guilhaumou, R (corresponding author), Hop la Timone, Lab Pharmacol Clin, 264 Rue St Pierre, F-13385 Marseille 5, France."	"romain.guilhaumou@ap-hm.fr"	"Simon, Nicolas/B-1235-2016"	"Simon, Nicolas/0000-0003-4393-2257"	"NA"	"NA"	32	6	7	0	9	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"OCT"	2016	38	5	559	566	"NA"	"10.1097/FTD.0000000000000318"	8	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"DY8TQ"	"WOS:000385404400001"	27631462	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bouazza, N; Djerada, Z; Gozalo, C; Busiah, K; Beltrand, J; Berdugo, M; Urien, S; Treluyer, JM; Polak, M"	"Bouazza, Naim; Djerada, Zoubir; Gozalo, Claire; Busiah, Kanetee; Beltrand, Jacques; Berdugo, Marianne; Urien, Saik; Treluyer, Jean-Marc; Polak, Michel"	"NA"	"A"	"Evaluation of the pharmacokinetics of glibenclamide tablet given, off label, orally to children suffering from neonatal syndromic hyperglycemia"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Population pharmacokinetics; Diabetes mellitus; Glibenclamide; Children; Neonatal diabetes mellitus; Neonatal syndromic hyperglycemia"	"DIABETES-MELLITUS; GLYBURIDE; INSULIN; KIR6.2; POLYMORPHISMS; SULFONYLUREAS; MUTATIONS; CYP2C9; PHARMACODYNAMICS; IDENTIFICATION"	"Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy. Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients). A total of 229 plasma Gb concentrations and 187 blood glucose measurements were available. A population model was developed with NONMEM. Body weight was the most significant parameter on clearance and explained a substantial part of the variability. A variant genotype of CYP2C9 (i.e., *1/*2 and *1/*3) explained also a part of the remaining variability on Gb clearance. Patients carrying these allelic variants had a clearance decreased by 45 %. A link between daily area under the curve (AUC(0-24 h)) and metabolic control diabetes was found. This study evaluates for the first time the pharmacokinetics of oral Gb in children and constitutes a first step towards dose individualization of this drug in a particularly vulnerable population."	"[Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Univ Paris 05, EA 7323, Sorbonne Paris Cite, Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] Hop Tarnier, AP HP, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France; [Bouazza, Naim; Urien, Saik; Treluyer, Jean-Marc] INSERM, Cochin Necker, CIC 0901, Paris, France; [Djerada, Zoubir; Gozalo, Claire] Ctr Hosp & Univ Reims, Hop Maison Blanche, Lab Pharmacol Toxicol, Reims, France; [Busiah, Kanetee; Beltrand, Jacques; Polak, Michel] Hop Univ Necker Enfants Malades, AP HP, Endocrinol Gynecol Diabetol Pediat, Paris, France; [Beltrand, Jacques; Berdugo, Marianne] Univ Paris 05, Sorbonne Paris Cite, Inst IMAGINE, Paris, France; [Berdugo, Marianne; Polak, Michel] Univ Paris 06, Ctr Rech Cordeliers, INSERM, U1138, Paris, France; [Treluyer, Jean-Marc] Univ Paris 05, Hop Cochin, AP HP, Serv Pharmacol Clin,Sorbonne Paris Cite, Paris, France"	"Bouazza, N (corresponding author), Univ Paris 05, EA 7323, Sorbonne Paris Cite, Paris, France.; Bouazza, N (corresponding author), Hop Tarnier, AP HP, Unite Rech Clin, 89 Rue Assas, F-75006 Paris, France.; Bouazza, N (corresponding author), INSERM, Cochin Necker, CIC 0901, Paris, France."	"naim.bouazza@cch.aphp.fr"	"Kanetee, BUSIAH/AAP-8292-2020; Urien, Saik/G-3240-2013"	"Kanetee, BUSIAH/0000-0002-1059-0791; djerada, zoubir/0000-0002-4022-7889"	"Assistance Publique-Hopitaux de Paris [NCT00610038]; National Research Agency under the Investments for the Future programFrench National Research Agency (ANR) [ANR-10-IAHU-01]; Agence Nationale de la Recherche-Maladies Rares (ANR-MRAR) Research Program GrantFrench National Research Agency (ANR) [ANR-07-MRAR-000]; Transnational European Research Grant on Rare Diseases [ERANET-09-RARE-005]; Societe Francophone du Diabete (SFD)-Association Francaise du Diabete (AFD); Aide aux Jeunes Diabatiques (AJD); CIFRE grant from the French government; HRA-Pharma; French Ministry of Education and Research; Societe Francaise de Pediatrie (SFP)"	"This study was sponsored by the Assistance Publique-Hopitaux de Paris (ClinicalTrials.gov Identifier: NCT00610038) and received a government grant managed by the National Research Agency under the Investments for the Future program (reference ANR-10-IAHU-01). The work was performed within the Departement Hospitalo-Universitaire (DHU) AUToimmune and HORmonal diseaseS. It was partly funded by the Agence Nationale de la Recherche-Maladies Rares (ANR-MRAR) Research Program Grant #ANR-07-MRAR-000 (MP), the Transnational European Research Grant on Rare Diseases #ERANET-09-RARE-005 (MP), and the Societe Francophone du Diabete (SFD)-Association Francaise du Diabete (AFD) (MP). Support was also received from Aide aux Jeunes Diabatiques (AJD) (MP). KB received a CIFRE grant from the French government and was supported by HRA-Pharma, the French Ministry of Education and Research, and the Societe Francaise de Pediatrie (SFP)."	27	3	3	0	9	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"NOV"	2016	72	11	1373	1379	"NA"	"10.1007/s00228-016-2119-9"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DY5WS"	"WOS:000385175700010"	27561267	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Leroux, S; Roue, JM; Gouyon, JB; Biran, V; Zheng, H; Zhao, W; Jacqz-Aigrain, E"	"Leroux, Stephanie; Roue, Jean-Michel; Gouyon, Jean-Bernard; Biran, Valerie; Zheng, Hao; Zhao, Wei; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"DESACETYL-CEFOTAXIME; DESACETYLCEFOTAXIME; CHILDREN; SEPSIS; PHARMACODYNAMICS; ANTIBIOTICS; MODELS; ANTIBACTERIALS; INFECTIONS; NEWBORN"	"Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates ( gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants."	"[Leroux, Stephanie; Zheng, Hao; Zhao, Wei; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Leroux, Stephanie; Zhao, Wei; Jacqz-Aigrain, Evelyne] Univ Paris 05, Univ Paris Diderot, EA7323, Paris, France; [Leroux, Stephanie] CHU Rennes, Neonatal Intens Care Unit, Rennes, France; [Roue, Jean-Michel] CHU Brest, Neonatal Intens Care Unit, Brest, France; [Gouyon, Jean-Bernard] CHU Reunion, Ctr Etudes Perinat Ocean Indien EA7388, Neonatal Intens Care Unit, St Pierre, Reunion, France; [Biran, Valerie] Hop Robert Debre, AP HP, Neonatal Intens Care Unit, Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC1426, Paris, France"	"Jacqz-Aigrain, E (corresponding author), Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France.; Jacqz-Aigrain, E (corresponding author), Univ Paris 05, Univ Paris Diderot, EA7323, Paris, France.; Jacqz-Aigrain, E (corresponding author), INSERM, Clin Invest Ctr CIC1426, Paris, France."	"evelyne.jacqz-aigrain@rdb.aphp.fr"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Roue, Jean-Michel/0000-0002-5734-7254"	"GRIP project (Global Research in Pediatrics, European Commission FP7 project) [261060]"	"This work was supported by the GRIP project (Global Research in Pediatrics, European Commission FP7 project, grant agreement number 261060)."	48	14	14	0	0	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"NOV"	2016	60	11	6626	6634	"NA"	"10.1128/AAC.01045-16"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"ED7QH"	"WOS:000389063500021"	27572399	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Lavielle, M; Ribba, B"	"Lavielle, Marc; Ribba, Benjamin"	"NA"	"M"	"Enhanced Method for Diagnosing Pharmacometric Models: Random Sampling from Conditional Distributions"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"model diagnostics; modeling and simulation; pharmacokinetics and pharmacodynamics"	"GOODNESS-OF-FIT; LINEAR MIXED MODELS; TESTS"	"For nonlinear mixed-effects pharmacometric models, diagnostic approaches often rely on individual parameters, also called empirical Bayes estimates (EBEs), estimated through maximizing conditional distributions. When individual data are sparse, the distribution of EBEs can shrink towards the same population value, and as a direct consequence, resulting diagnostics can be misleading. Instead of maximizing each individual conditional distribution of individual parameters, we propose to randomly sample them in order to obtain values better spread out over the marginal distribution of individual parameters. We evaluated, through diagnostic plots and statistical tests, hypothesis related to the distribution of the individual parameters and show that the proposed method leads to more reliable results than using the EBEs. In particular, diagnostic plots are more meaningful, the rate of type I error is correctly controlled and its power increases when the degree of misspecification increases. An application to the warfarin pharmacokinetic data confirms the interest of the approach for practical applications. The proposed method should be implemented to complement EBEs-based approach for increasing the performance of model diagnosis."	"[Lavielle, Marc] Univ Paris Saclay, Ecole Polytech, Inria Saclay, St Aubin, France; [Lavielle, Marc] Univ Paris Saclay, Ecole Polytech, CMAP, St Aubin, France; [Ribba, Benjamin] Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Grenzacherstr 124, CH-4070 Basel, Switzerland"	"Ribba, B (corresponding author), Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Grenzacherstr 124, CH-4070 Basel, Switzerland."	"benjamin.ribba@roche.com"	"NA"	"NA"	"NA"	"NA"	22	22	22	0	2	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"DEC"	2016	33	12	2979	2988	"NA"	"10.1007/s11095-016-2020-3"	10	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"EB5DY"	"WOS:000387395000010"	27604892	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Auriti, C; Falcone, M; Ronchetti, MP; Goffredo, BM; Cairoli, S; Crisafulli, R; Piersigilli, F; Corsetti, T; Dotta, A; Pai, MP"	"Auriti, Cinzia; Falcone, Marco; Ronchetti, Maria Paola; Goffredo, Bianca Maria; Cairoli, Sara; Crisafulli, Rosamaria; Piersigilli, Fiammetta; Corsetti, Tiziana; Dotta, Andrea; Pai, Manjunath P."	"NA"	"A"	"High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"BIRTH-WEIGHT INFANTS; RISK-FACTORS; PHARMACOKINETICS; PREMATURE; CHILDREN; ADOLESCENTS; INFECTIONS; MANAGEMENT; CANDIDEMIA; GUIDELINE"	"High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg.h/liter (SD, 165 mg.h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect."	"[Auriti, Cinzia; Ronchetti, Maria Paola; Cairoli, Sara; Crisafulli, Rosamaria; Piersigilli, Fiammetta; Dotta, Andrea] Bambino Gesu Pediat Hosp, Dept Neonatol, Neonatal Intens Care Unit, Rome, Italy; [Falcone, Marco] Sapienza Univ, Dept Publ Hlth & Infect Dis, Infect Dis Sect, Rome, Italy; [Goffredo, Bianca Maria] Bambino Gesu Pediat Hosp, Dept Specialist Pediat, Biochem Lab, Rome, Italy; [Corsetti, Tiziana] Bambino Gesu Pediat Hosp, Unit Clin Pharm, Rome, Italy; [Pai, Manjunath P.] Univ Michigan, Coll Pharm, Dept Clin Pharm, Ann Arbor, MI USA"	"Auriti, C (corresponding author), Bambino Gesu Pediat Hosp, Dept Neonatol, Neonatal Intens Care Unit, Rome, Italy."	"cinzia.auriti@opbg.net"	"Auriti, Cinzia/I-4866-2019; piersigilli, fiammetta/I-6951-2019; Dotta, Andrea/AAA-6343-2020; Cairoli, Sara/AAI-1649-2019"	"Auriti, Cinzia/0000-0001-9820-6557; piersigilli, fiammetta/0000-0002-6581-2822; Goffredo, Bianca/0000-0001-9933-3240"	"NA"	"NA"	22	15	16	1	2	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"DEC"	2016	60	12	7333	7339	"NA"	"10.1128/AAC.01172-16"	7	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"ED7QO"	"WOS:000389064300036"	27697761	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Polito, A; Hamitouche, N; Ribot, M; Polito, A; Laviolle, B; Bellissant, E; Annane, D; Alvarez, JC"	"Polito, Andrea; Hamitouche, Noureddine; Ribot, Megane; Polito, Angelo; Laviolle, Bruno; Bellissant, Eric; Annane, Djillali; Alvarez, Jean-Claude"	"NA"	"A"	"Pharmacokinetics of oral fludrocortisone in septic shock"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Fludrocortisone; pharmacokinetics; sepsis; shock"	"SURVIVING SEPSIS CAMPAIGN; INTERNATIONAL GUIDELINES; MASS-SPECTROMETRY; QUANTIFICATION; HYDROCORTISONE; MANAGEMENT; MORTALITY; ACETATE; MODEL"	"AimThe combination of hydrocortisone and fludrocortisone improved outcomes in septic shock. However, the specific role of fludrocortisone remains controversial and its pharmacokinetics (PK) has never been investigated in septic shock. This study aimed at characterizing the PK of fludrocortisone in septic shock. MethodsThis was a single-centre ancillary PK study of a large multinational trial of crystalloids versus colloids for acute hypovolemia in intensive care unit (ICU) patients. In 21 adults with septic shock, fludrocortisone plasma concentrations were measured by liquid chromatography-mass spectrometry tandem analysis, before and repeatedly until 18h after an oral dose of 50g. PK parameters were estimated using a nonlinear mixed-effects modelling. ResultsUndetectable plasma concentrations were observed in 7 out of 21 patients. In the remaining 14 patients, plasma fludrocortisone concentrations were best described by a one-compartmental model with first-order absorption, a lag time (T-lag) before the absorption phase, and first-order elimination. Severity of illness, as quantified by Simplified Acute Physiology Score II, significantly increased T-lag and apparent clearance. There was a large inter-individual variability in PK parameters. The population estimates of PK parameters (inter-individual variability) were: T-lag 0.65h (98%), apparent clearance 40lh(-1) (49%) and apparent volume of distribution 78l (75%). Plasma half-life was estimated at 1.35h (95% CI, 0.84-2.03) and area under the curve of plasma concentrations was estimated at 1.25ghl(-1) (95% CI, 1.09-1.46). ConclusionsA single oral dose of fludrocortisone yielded undetectable plasma concentrations in one-third of adults with septic shock. Fludrocortisone PK showed a short plasma elimination half-life and a large inter-individual variability."	"[Polito, Andrea; Annane, Djillali] Hop Raymond Poincare, AP HP, Dept Intens Care, Garches, France; [Polito, Andrea; Ribot, Megane; Annane, Djillali; Alvarez, Jean-Claude] Univ Versailles St Quentin En Yvelines, Lab Cell Death Inflammat & Infect, INSERM, UMR 1173, Garches, France; [Hamitouche, Noureddine; Laviolle, Bruno; Bellissant, Eric] INSERM, Clin Invest Ctr 1414, Rennes, France; [Hamitouche, Noureddine; Laviolle, Bruno; Bellissant, Eric] Univ Rennes 1, Dept Pharmacol, Rennes, France; [Ribot, Megane; Alvarez, Jean-Claude] Univ Versailles St Quentin En Yvelines, Raymond Poincare Hosp, AP HP, Dept Pharmacol, Garches, France; [Polito, Angelo] Bambino Gesu Pediat Hosp, Dept Cardiol, Rome, Italy"	"Annane, D (corresponding author), Ctr Hosp Univ Raymond Poincare, AP HP, Serv Reanimat Med, 104 Blvd R Poincare, F-92380 Garches, France."	"djillali.annane@rpc.aphp.fr"	"Annane, Djillali/R-7947-2019"	"ALVAREZ, jean claude/0000-0001-5344-9475"	"NA"	"NA"	24	16	18	0	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2016	82	6	1509	1516	"NA"	"10.1111/bcp.13065"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EB6OQ"	"WOS:000387504500009"	27416887	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Perez-Blanco, JS; Santos-Buelga, D; de Gatta, MDF; Hernandez-Rivas, JM; Martin, A; Garcia, MJ"	"Samuel Perez-Blanco, Jonas; Santos-Buelga, Dolores; del Mar Fernandez de Gatta, Maria; Maria Hernandez-Rivas, Jesus; Martin, Alejandro; Jose Garcia, Maria"	"NA"	"A"	"Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"doxorubicin; doxorubicinol; non-Hodgkin's lymphoma; population pharmacokinetics"	"CELL LUNG-CANCER; ANTICANCER DRUGS; MAJOR METABOLITE; POTENT INHIBITOR; PHARMACODYNAMICS; CHILDREN; THERAPY; CARDIOTOXICITY; QUANTIFICATION; VARIABILITY"	"AimsThe aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematological toxicity. MethodsPopulation PK modelling (using NONMEM) was performed using DOX and DOXol plasma concentration-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematological toxicity was analysed using the Mann-Whitney-Wilcoxon test. ResultsA five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population estimates for parent drug (CL) and metabolite (CLm) clearance were 62lh(-1) and 27lh(-1), respectively. The fraction metabolized to DOXol (F-m) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm, the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUC(total)), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUC(m)), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship. ConclusionsThe PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematological toxicity of the parent drug."	"[Samuel Perez-Blanco, Jonas; Santos-Buelga, Dolores; del Mar Fernandez de Gatta, Maria; Jose Garcia, Maria] Univ Salamanca, Dept Pharmaceut Sci Pharm & Pharmaceut Technol, Avda Licenciado Mendez Nieto, Salamanca 37007, Spain; [Samuel Perez-Blanco, Jonas; Santos-Buelga, Dolores; del Mar Fernandez de Gatta, Maria; Maria Hernandez-Rivas, Jesus; Martin, Alejandro; Jose Garcia, Maria] Salamanca Inst Biomed Res IBSAL, Salamanca, Spain; [Maria Hernandez-Rivas, Jesus; Martin, Alejandro] Univ Hosp Salamanca, Dept Haematol, Salamanca, Spain; [Maria Hernandez-Rivas, Jesus; Martin, Alejandro] IBMCC, Canc Res Ctr, Salamanca, Spain"	"Perez-Blanco, JS (corresponding author), Univ Salamanca, Dept Pharmaceut Sci Pharm & Pharmaceut Technol, Avda Licenciado Mendez Nieto, Salamanca 37007, Spain."	"jsperez@usal.es"	"Martin, Alejandro/B-8611-2018; Hernandez, Jesus M/B-5459-2017; Perez-Blanco, Jonas Samuel/AAB-5010-2019; Garcia, Maria Jose/P-8475-2019"	"Martin, Alejandro/0000-0001-6330-1028; Hernandez, Jesus M/0000-0002-9661-9371; Perez-Blanco, Jonas Samuel/0000-0002-1232-1763; Garcia, Maria Jose/0000-0003-2760-7083"	"GELTAMO group (Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea)"	"All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare this work was supported in part by GELTAMO group (Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea). There are no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work."	54	9	10	0	11	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2016	82	6	1517	1527	"NA"	"10.1111/bcp.13070"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EB6OQ"	"WOS:000387504500010"	27447545	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Frymoyer, A; Bonifacio, SL; Drover, DR; Su, F; Wustoff, CJ; Van Meurs, KP"	"Frymoyer, Adam; Bonifacio, Sonia L.; Drover, David R.; Su, Felice; Wustoff, Courtney J.; Van Meurs, Krisa P."	"NA"	"A"	"Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"hypoxic ischemic encephalopathy; hypothermia; morphine; neonates; population pharmacokinetics"	"WHOLE-BODY HYPOTHERMIA; SYSTEMIC HYPOTHERMIA; YOUNG-CHILDREN; RENAL-FUNCTION; INFANTS; PHARMACOKINETICS; METABOLITES; DISPOSITION; GLUCURONIDATION; PREDICTION"	"Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, 2-center clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight, 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot liquid chromatography-tandem mass spectrometry assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. The clearance of morphine and glucuronide metabolites was best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5-kg neonate, morphine clearance was 0.77 L/h (CV, 48%), and the steady-state volume of distribution was 8.0 L (CV, 49%). Compared with previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10 and 40 ng/mL. An optimized morphine loading dose of 50 g/kg followed by a continuous infusion of 5 g/kg/h was predicted across birthweights."	"[Frymoyer, Adam; Bonifacio, Sonia L.; Su, Felice; Van Meurs, Krisa P.] Stanford Univ, Dept Pediat, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA; [Drover, David R.] Dept Anesthesiol Perioperat & Pain Med, Palo Alto, CA USA; [Wustoff, Courtney J.] Stanford Univ, Div Child Neurol, Palo Alto, CA 94304 USA"	"Frymoyer, A (corresponding author), Stanford Univ, Dept Pediat, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA."	"frymoyer@stanford.edu"	"NA"	"NA"	"Child Health Research Institute, Lucile Packard Foundation for Children's Health; Stanford Clinical Translational Science Award program - National Center for Advancing Translational Sciences at the National Institutes of Health [UL1TR001085]"	"The work was supported by the Child Health Research Institute, Lucile Packard Foundation for Children's Health; the Stanford Clinical Translational Science Award program funded by the National Center for Advancing Translational Sciences at the National Institutes of Health (grant number UL1TR001085); and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number K23HD079557)."	45	16	17	0	2	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JAN"	2017	57	1	64	76	"NA"	"10.1002/jcph.775"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EH8IB"	"WOS:000392014300006"	27225747	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Nguyen, THT; Mouksassi, MS; Holford, N; Al-Huniti, N; Freedman, I; Hooker, AC; John, J; Karlsson, MO; Mould, DR; Ruixo, JJP; Plan, EL; Savic, R; van Hasselt, JGC; Weber, B; Zhou, C; Comets, E; Mentre, F"	"Nguyen, T. H. T.; Mouksassi, M-S; Holford, N.; Al-Huniti, N.; Freedman, I.; Hooker, A. C.; John, J.; Karlsson, M. O.; Mould, D. R.; Ruixo, J. J. Perez; Plan, E. L.; Savic, R.; van Hasselt, J. G. C.; Weber, B.; Zhou, C.; Comets, E.; Mentre, F."	"Model Evaluation Grp Int Soc Pharm"	"M"	"Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"MIXED-EFFECTS MODELS; COUMARIN ANTICOAGULANT DRUGS; POPULATION PHARMACOKINETICS; PREDICTIVE CHECK; SIMULATION; WARFARIN; DROPOUT"	"This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEMs), from the International Society of Pharmacometrics (ISoP) Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons, and recalls the definition of metrics used."	"[Nguyen, T. H. T.; Comets, E.; Mentre, F.] INSERM, IAME, UMR 1137, Paris, France; [Nguyen, T. H. T.; Comets, E.; Mentre, F.; Model Evaluation Grp Int Soc Pharm] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France; [Mouksassi, M-S] Certara Strateg Consulting, Montreal, PQ, Canada; [Holford, N.] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand; [Al-Huniti, N.] AstraZeneca, Quantitat Clin Pharmacol, Waltham, MA USA; [Freedman, I.] Dr Immanuel Freedman Inc, Harleysville, PA USA; [Hooker, A. C.; Karlsson, M. O.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [John, J.] US FDA, Ctr Drug Evaluat & Res, Washington, DC USA; [Mould, D. R.] Project Res Inc, Phoenixville, PA USA; [Ruixo, J. J. Perez] Janssen Pharmaceut Companies Johnson, Beerse, Belgium; [Plan, E. L.] Pharmetheus, Uppsala, Sweden; [Savic, R.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA USA; [van Hasselt, J. G. C.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Weber, B.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT USA; [Zhou, C.] Genentech Inc, San Francisco, CA USA; [Comets, E.] Univ Rennes 1, INSERM, CIC 1414, Rennes, France"	"Mentre, F (corresponding author), INSERM, IAME, UMR 1137, Paris, France.; Mentre, F (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite, Paris, France."	"france.mentre@inserm.fr"	"Comets, Emmanuelle/C-9328-2017; van Hasselt, Coen/H-5593-2019; Ruixo, Juan Jose Perez/AAL-2987-2020; Hooker, Andrew/A-7794-2015; Ruixo, Juan Jose Perez/AAF-3160-2020; Mouksassi, Samer/AAF-7697-2020"	"Hooker, Andrew/0000-0002-2676-5912; van Hasselt, J.G.C./0000-0002-1664-7314; PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"NA"	"NA"	36	90	91	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"FEB"	2017	6	2	87	109	"NA"	"10.1002/psp4.12161"	23	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EL9QK"	"WOS:000394954900003"	27884052	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Bellanti, F; Del Vecchio, GC; Putti, MC; Maggio, A; Filosa, A; Cosmi, C; Mangiarini, L; Spino, M; Connelly, J; Ceci, A; Della Pasqua, O"	"Bellanti, Francesco; Del Vecchio, Giovanni C.; Putti, Maria C.; Maggio, Aurelio; Filosa, Aldo; Cosmi, Carlo; Mangiarini, Laura; Spino, Michael; Connelly, John; Ceci, Adriana; Della Pasqua, Oscar"	"Consortium DEferiprone Evaluation"	"A"	"Population pharmacokinetics and dosing recommendations for the use of deferiprone in children younger than 6 years"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"deferiprone; dose rationale; paediatrics; pharmacokinetic bridging; thalassaemia"	"BETA-THALASSEMIA MAJOR; CHELATION-THERAPY; IRON; MODEL; 1,2-DIMETHYL-3-HYDROXYPYRID-4-ONE; PHARMACODYNAMICS; COMPLICATIONS; PHARMACOLOGY; SAFETY; L1"	"AIMS Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children aged <6years. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients. METHODS Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis. Patients were randomised to three deferiprone dose levels (8.3, 16.7 and 33.3 mg kg(-1)). Blood samples were collected according to an optimised sampling scheme in which each patient contributed to a maximum of five samples. A population pharmacokinetic model was developed using NONMEM v.7.2. Model selection criteria were based on graphical and statistical summaries. RESULTS A one-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of deferiprone. Drug disposition parameters were affected by body weight, with both clearance and volume increasing allometrically with size. Simulation scenarios show that comparable systemic exposure (AUC) is achieved in children and adults after similar dose levels in mg kg(-1), with median (5-95(th) quantiles) AUC values, respectively, of 340.6 (223.2-520.0) mu mol l(-1) h and 318.5 (200.4-499.0) mu mol l(-1) h at 75 mg kg(-1) day(-1), and 453.7 (297.3-693.0) mu mol l(-1) h and 424.2 (266.9-664.0) mu mol l(-1) h at 100 mg kg(-1) day(-1) given as three times daily (t.i.d.) doses. CONCLUSIONS Based on the current findings, a dosing regimen of 25 mg kg(-1) t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg(-1) t.i.d."	"[Bellanti, Francesco; Della Pasqua, Oscar] Leiden Acad Ctr Drug Res, Leiden, Netherlands; [Del Vecchio, Giovanni C.] Azienda Osped Univ Consorziale Policlin Bari, Paediat Hematol Unit, Bari, Italy; [Putti, Maria C.] Azienda Osped Padova, Padua, Italy; [Maggio, Aurelio] Azienda Osped Osped Riuniti Villa Sofia, Palermo, Italy; [Filosa, Aldo] Azienda Osped Antonio Cardarelli, Naples, Italy; [Cosmi, Carlo] Clin Pediat Univ Sassari ASLI, Sassari, Italy; [Mangiarini, Laura; Ceci, Adriana] Consorzio Valutazioni Biol & Farmacol, Pavia, Italy; [Spino, Michael; Connelly, John] ApoPharma Inc, Toronto, ON, Canada; [Della Pasqua, Oscar] UCL, Clin Pharmacol & Therapeut, London WC1E 6BT, England"	"Della Pasqua, O (corresponding author), UCL, Clin Pharmacol & Therapeut, BMA House,Tavistock Sq, London, England."	"o.dellapasqua@ucl.ac.uk"	"Ceci, Adriana/D-1328-2014"	"NA"	"FP7 Framework Research Program [HEALTH-2010.4.2-1]; DEEP consortium (European Union)"	"All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: F.B. had financial support from the DEEP consortium (sponsored by the European Union); no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.; This contribution is part of the DEferiprone Evaluation in Paediatrics (DEEP) project, supported by the FP7 Framework Research Program HEALTH-2010.4.2-1: Off-patent medicines for children. We would also like to thank ApoPharma for their effort in the development of the new oral formulation, which is suitable for the young paediatric population."	32	3	3	0	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAR"	2017	83	3	593	602	"NA"	"10.1111/bcp.13134"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EK4LY"	"WOS:000393899500015"	27641003	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Suchankova, H; Lips, M; Urbanek, K; Neely, MN; Strojil, J"	"Suchankova, Hana; Lips, Michal; Urbanek, Karel; Neely, Michael N.; Strojil, Jan"	"NA"	"A"	"Is continuous infusion of imipenem always the best choice?"	"INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS"	"English"	"Article"	"Pneumonia; Critically ill; Monte Carlo simulation; Pharmacokinetics; Pharmacodynamics; Extended infusion"	"CRITICALLY-ILL PATIENTS; VENTILATOR-ASSOCIATED PNEUMONIA; 0.5 H INFUSION; POPULATION PHARMACOKINETICS; MEROPENEM; PHARMACODYNAMICS; PIPERACILLIN; INTERMITTENT; MODEL; ANTIBIOTICS"	"Monte Carlo simulations allow prediction and comparison of concentration-time profiles arising from different dosing regimens in a defined population, provided a population pharmacokinetic model has been established. The aims of this study were to evaluate the population pharmacokinetics of imipenem in critically ill patients with hospital-acquired pneumonia (HAP) and to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) using EUCAST data. A two-compartment model based on a data set of 19 subjects was employed. Various dosage regimens at 0.5-h and 3-h infusion rates and as continuous infusion were evaluated against the pharmacodynamic targets of 20%fT(>MIC), 40% fT(>MIC) and 100%fT(>MIC). For the target of 40% fT(>MIC), all 0.5-h infusion regimens achieved optimal exposures (CFR >= 90%) against Escherichia coli and Staphylococcus aureus, with nearly optimal exposure against Klebsiella pneumoniae (CFR >= 89.4%). The 3-h infusions and continuous infusion exceeded 97% CFR against all pathogens with the exception of Pseudomonas aeruginosa and Acinetobacter spp., where the maximum CFRs were 85.5% and 88.4%, respectively. For the 100%fT(>MIC) target, only continuous infusion was associated with nearly optimal exposures. Higher PTAs for the targets of 40% fT(> MIC) and 100%fT(>MIC) were achieved with 3-h infusions and continuous infusion in comparison with 0.5-h infusions; however, continuous infusion carries a risk of not reaching the MIC of less susceptible pathogens in a higher proportion of patients. In critically ill patients with HAP with risk factors for Gram-negative non-fermenting bacteria, maximum doses administered as extended infusions may be necessary. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved."	"[Suchankova, Hana; Urbanek, Karel; Strojil, Jan] Palacky Univ, Fac Med & Dent, Dept Pharmacol, Hnevotinska 3, Olomouc 77515, Czech Republic; [Lips, Michal] Charles Univ Prague, Gen Univ Hosp Prague, Fac Med 1, Dept Anaesthesiol & Intens Care, U Nemocnice 2, Prague 12808 2, Czech Republic; [Neely, Michael N.] Univ Southern Calif, Childrens Hosp Los Angeles, Lab Appl Pharmacokinet & Bioinformat, Div Pediat Infect Dis, Los Angeles, CA USA"	"Strojil, J (corresponding author), Palacky Univ, Fac Med & Dent, Dept Pharmacol, Hnevotinska 3, Olomouc 77515, Czech Republic."	"jan.strojil@upol.cz"	"Lips, Michal/N-6988-2017"	"Lips, Michal/0000-0001-9052-5123; Urbanek, Karel/0000-0002-3461-1649"	"Internal Grant Agency of Palacky University in Olomouc (Olomouc, Czech Republic) [IGA UPOL LF_2016_006]"	"This study was supported by a grant from the Internal Grant Agency of Palacky University in Olomouc (Olomouc, Czech Republic) [grant no. IGA UPOL LF_2016_006]."	32	4	4	3	10	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0924-8579"	"1872-7913"	"NA"	"INT J ANTIMICROB AG"	"Int. J. Antimicrob. Agents"	"MAR"	2017	49	3	348	354	"NA"	"10.1016/j.ijantimicag.2016.12.005"	7	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"EP1MD"	"WOS:000397148100013"	28189734	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, PAJG; Mulla, H; Desmet, S; De Somer, F; McWhinney, BC; Ungerer, JPJ; Moerman, A; Commeyne, S; Vande Walle, J; Francois, K; Van Hasselt, JGC; De Paepe, P"	"De Cock, Pieter A. J. G.; Mulla, Hussain; Desmet, Sarah; De Somer, Filip; McWhinney, Brett C.; Ungerer, Jacobus P. J.; Moerman, Annelies; Commeyne, Sabrina; Vande Walle, Johan; Francois, Katrien; Van Hasselt, Johan G. C.; De Paepe, Peter"	"NA"	"A"	"Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"SURGICAL SITE INFECTIONS; CRITICALLY-ILL CHILDREN; RISK-FACTORS; ANTIBIOTIC-PROPHYLAXIS; CARDIOVASCULAR-SURGERY; TISSUE PHARMACOKINETICS; PLASMA-CONCENTRATIONS; PEDIATRIC POPULATION; PROTEIN-BINDING; RENAL-FUNCTION"	"Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharma-cokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials. gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate(eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR < 25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis."	"[De Cock, Pieter A. J. G.; Desmet, Sarah; Commeyne, Sabrina] Ghent Univ Hosp, Dept Pharm, De Pintelaan 185, B-9000 Ghent, Belgium; [De Cock, Pieter A. J. G.; Desmet, Sarah; De Paepe, Peter] Univ Ghent, Heymans Inst Pharmacol, Ghent, Belgium; [De Cock, Pieter A. J. G.] Ghent Univ Hosp, Dept Paediat Intens Care, Ghent, Belgium; [Mulla, Hussain] Univ Hosp Leicester, Glenfield Hosp, Dept Pharm, Leicester, Leics, England; [De Somer, Filip; Francois, Katrien] Ghent Univ Hosp, Dept Cardiac Surg, Ghent, Belgium; [McWhinney, Brett C.; Ungerer, Jacobus P. J.] Pathol Queensland, Dept Chem Pathol, Queensland, Australia; [Moerman, Annelies] Ghent Univ Hosp, Dept Anaesthesiol, Ghent, Belgium; [Vande Walle, Johan] Ghent Univ Hosp, Dept Paediat Nephrol, Ghent, Belgium; [Van Hasselt, Johan G. C.] Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands"	"De Cock, PAJG (corresponding author), Ghent Univ Hosp, Dept Pharm, De Pintelaan 185, B-9000 Ghent, Belgium."	"pieter.decock@uzgent.be"	"Walle, Johan Vande/AAG-3858-2020; Ungerer, Jacobus PJ/J-3881-2017; De Cock, Pieter/F-4917-2015; van Hasselt, Coen/H-5593-2019"	"Ungerer, Jacobus PJ/0000-0003-4929-0929; De Cock, Pieter/0000-0001-7634-7471; van Hasselt, J.G.C./0000-0002-1664-7314"	"Clinical Research Fund Ghent University Hospital, Ghent Belgium [WR/1294/APO/001]; Agency for Innovation by Science and Technology, Flanders, Belgium (SAFEPEDRUG project) [IWT/SBO/130033]; European Union MSCA programme [661588]"	"This work was supported by the Clinical Research Fund Ghent University Hospital, Ghent Belgium (grant number WR/1294/APO/001 to P.A.J.G.D.C.) and the Agency for Innovation by Science and Technology, Flanders, Belgium (SAFEPEDRUG project; grant number IWT/SBO/130033). J.G.C.v.H. received funding from the European Union MSCA programme (Project ID 661588)."	48	14	14	0	3	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"MAR"	2017	72	3	791	800	"NA"	"10.1093/jac/dkw496"	10	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"EQ4IE"	"WOS:000398038800019"	27999040	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Leven, C; Fillare, P; Petitcollin, A; Verdier, MC; Laurent, J; Nesseler, N; Launey, Y; Tattevin, P; Bellissant, E; Flecher, E; Lemaitre, F"	"Leven, Cyril; Fillatre, Pierre; Petitcollin, Antoine; Verdier, Marie-Clemence; Laurent, Jerome; Nesseler, Nicolas; Launey, Yoann; Tattevin, Pierre; Bellissant, Eric; Flecher, Erwan; Lemaitre, Florian"	"NA"	"A"	"Ex Vivo Model to Decipher the Impact of Extracorporeal Membrane Oxygenation on Beta-lactam Degradation Kinetics"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"extracorporeal membrane oxygenation; pharmacokinetics; beta-lactam; antibiotics"	"STABILITY; SEQUESTRATION; DRUGS; CEFTAZIDIME; CIRCUITS; FAILURE; SODIUM"	"Background: As a consequence of drug sequestration, increase in volume of distribution, or alteration of elimination, extracorporeal membrane oxygenation (ECMO) might lead to inadequate plasma concentrations of vital drugs. The aim of this experimental study was to develop an ex vivo model to better characterize the impact of ECMO procedure on beta-lactam antibiotics pharmacokinetics. Methods: Plasma concentrations of cefotaxime, ceftazidime, cefepime, piperacillin, oxacillin, amoxicillin, and ceftriaxone were measured in an ex vivo ECMO circuit primed with whole human blood and compared with controls stored in glass tubes and polyvinyl chloride tubing. Serial blood samples were collected over 48 hours, and the concentrations of beta-lactam antibiotics were quantified using a validated high-performance liquid chromatography assay. The concentrations' decay rate over time was compared between the ECMO circuits and controls using nonlinear mixed-effect modeling. Results: Cefotaxime concentrations decreased markedly: 86% of the initial concentration remained after 4 hours and only 21% after 48 hours (P< 0.05 for the comparison in rate of decrease with both glass and polyvinyl chloride controls). There was no difference in the rate of decrease between ECMO circuit and controls for the other beta-lactam antibiotics. The average drug recoveries from the ECMO circuits at 48 hours were as follows: ceftazidime, 73%; cefepime, 67%; piperacillin, 71%; oxacillin, 46%; and amoxicillin, 72%. Concentrations of ceftriaxone remained stable throughout the 48-hour study both in ECMO circuits and in controls. Conclusions: Significant losses of cefotaxime were observed, whereas ceftazidime, cefepime, piperacillin, oxacillin, and amoxicillin decrease was moderate and similar to that of the control group, and ceftriaxone concentrations remained unchanged. These results are reassuring for the use of beta-lactam antibiotics in critically ill patients treated with ECMO."	"[Leven, Cyril; Petitcollin, Antoine; Verdier, Marie-Clemence; Bellissant, Eric; Lemaitre, Florian] Rennes Univ Hospital, Pharmacoepidemiol & Drug Informat Ctr, Dept Clin & Biol Pharmacol & Pharmacovigilance, Rennes, France; [Leven, Cyril; Petitcollin, Antoine; Verdier, Marie-Clemence; Bellissant, Eric; Lemaitre, Florian] Univ Rennes 1, Fac Med, Lab Expt & Clin Pharmacol, Rennes, France; [Leven, Cyril; Petitcollin, Antoine; Verdier, Marie-Clemence; Tattevin, Pierre; Bellissant, Eric; Flecher, Erwan; Lemaitre, Florian] INSERM, Clin Invest Ctr 1414, CIC P, Rennes, France; [Leven, Cyril] Brest Univ Hosp, Dept Biochem Pharmacol & Toxicol, Brest, France; [Fillatre, Pierre; Tattevin, Pierre] Rennes Univ Hosp, Dept Infectious Dis, Intensive Care Unit, Rennes, France; [Laurent, Jerome; Flecher, Erwan] Rennes Univ Hosp, Thorac & Cardio Vasc Surg, Rennes, France; [Nesseler, Nicolas; Launey, Yoann; Flecher, Erwan] Rennes Univ Hosp, Surg Intensive Care Unit, Rennes, France; [Flecher, Erwan] INSERM 1099, Clin Invest Ctr, CIC IT, Rennes, France"	"Lemaitre, F (corresponding author), Rennes Univ Hospital, Pharmacoepidemiol & Drug Informat Ctr, Dept Clin & Biol Pharmacol & Pharmacovigilance, Rennes, France.; Lemaitre, F (corresponding author), Univ Rennes 1, Fac Med, Lab Expt & Clin Pharmacol, Rennes, France.; Lemaitre, F (corresponding author), INSERM, Clin Invest Ctr 1414, CIC P, Rennes, France."	"florian.lemaitre@chu-rennes.fr"	"Launey, Yoann/AAN-7176-2020; Lemaitre, Florian/M-7405-2019"	"Launey, Yoann/0000-0001-9105-8862; LEVEN, Cyril/0000-0002-0697-4370; Petitcollin, Antoine/0000-0003-4811-0439"	"COmite de la RECherche Clinique et Translationelle du CHU de Rennes (CORECT); Agence de la BioMedecine (ABM)"	"Supported by the COmite de la RECherche Clinique et Translationelle du CHU de Rennes (CORECT) and by the Agence de la BioMedecine (ABM)."	21	10	11	1	7	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"APR"	2017	39	2	180	184	"NA"	"10.1097/FTD.0000000000000369"	5	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"EN3XU"	"WOS:000395942000013"	28033162	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wu, XM; Xie, HL; Lin, WW; Yang, T; Li, NN; Lin, SS; Yuan, XH; Ren, JH; Li, XF; Huang, X"	"Wu, Xuemei; Xie, Helin; Lin, Weiwei; Yang, Ting; Li, Nainong; Lin, Shanshan; Yuan, Xiaohong; Ren, Jinhua; Li, Xiaofan; Huang, Xian"	"NA"	"A"	"Population pharmacokinetics analysis of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation"	"CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY"	"English"	"Article"	"busulfan; hematopoietic stem cell transplantation; nonlinear mixed effects model; population pharmacokinetics"	"REGIMEN-RELATED TOXICITY; GST GENE POLYMORPHISMS; MARROW-TRANSPLANTATION; CONDITIONING REGIMEN; PEDIATRIC-PATIENTS; ORAL BUSULFAN; MYELOGENOUS LEUKEMIA; CLINICAL-OUTCOMES; DOSING SCHEME; CHILDREN"	"There are several reports describing population pharmacokinetic (popPK) models of busulfan (BU). However, limited information is available in Chinese hematopoietic stem cell transplantation (HSCT) patients. The present study aimed to establish a popPK model of intravenous BU in Chinese HSCT patients for individualized drug therapy. The popPK model of BU was developed from a total of 284 concentration-time points from 53 patients. The effects of demographic and biochemical covariates were investigated by nonlinear mixed effect model (NONMEM) software. Plots, visual predictive check (VPC), bootstrap and normalized prediction distribution error (NPDE) were performed to determine the stability and the reliability of the final model. A one-compartment model with first-order elimination process was confirmed as the final structural model for BU. For a typical patient whose body surface area (BSA) is 1.7m(2), the population typical values of CL and Vd were 11.86L/h, and 48.2L, respectively. The result suggested BSA showed significant influence on CL and Vd (P<.001). Plots revealed the final model was performing a goodness fit. The steady rate verified by bootstrap was 100%, relative deviation was less than 4.00%, estimated value of final model was in the 95% confidence interval (CI). The VPC results showed the observed values were almost all positioned within the 5th and 95th CIs. The mean and variance of the NPDE were 0.0363 (Wilcoxon signed-rank test, 0.298) and 0.877 (Fisher variance test, 0.134; SW test of normality, 0.108), respectively. The global adjusted P value was 0.305, which indicated that the prediction of the BU popPK model was adequate. A physician-friendly Microsoft Excel-base tool was implemented using the final popPK model for designing individualized dosing regimens."	"[Wu, Xuemei; Xie, Helin; Lin, Shanshan; Huang, Xian] Fujian Med Univ, Dept Pharm, Union Hosp, Fuzhou, Fujian, Peoples R China; [Lin, Weiwei] Fujian Med Univ, Dept Pharm, Affiliated Hosp 1, Fuzhou, Fujian, Peoples R China; [Yang, Ting; Li, Nainong; Yuan, Xiaohong; Ren, Jinhua; Li, Xiaofan] Fujian Med Univ, Dept Haematol, Union Hosp, Fuzhou, Fujian, Peoples R China"	"Wu, XM (corresponding author), Fujian Med Univ, Dept Pharm, Union Hosp, Fuzhou, Fujian, Peoples R China."	"835565695@qq.com"	", Xiaofanli/J-4497-2019"	", Xiaofanli/0000-0002-6460-7210"	"Fujian Provincal health and family planning commission [2015-ZQN-JC-14]"	"Fujian Provincal health and family planning commission, Grant/Award Number: 2015-ZQN-JC-14"	60	3	4	0	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1440-1681"	"NA"	"NA"	"CLIN EXP PHARMACOL P"	"Clin. Exp. Pharmacol. Physiol."	"MAY"	2017	44	5	529	538	"NA"	"10.1111/1440-1681.12735"	10	"Pharmacology & Pharmacy; Physiology"	"Pharmacology & Pharmacy; Physiology"	"ES9SY"	"WOS:000399902200001"	28135768	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Hamitouche, N; Comets, E; Ribot, M; Alvarez, JC; Bellissant, E; Laviolle, B"	"Hamitouche, Noureddine; Comets, Emmanuelle; Ribot, Megane; Alvarez, Jean-Claude; Bellissant, Eric; Laviolle, Bruno"	"NA"	"A"	"Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers"	"AAPS JOURNAL"	"English"	"Article"	"fludrocortisone; hydrocortisone; modeling; pharmacodynamics; pharmacokinetics"	"ADRENAL INSUFFICIENCY; SEPTIC SHOCK; HUMAN PLASMA; VARIABILITY; CORTICOSTEROIDS; QUANTIFICATION; THERAPY"	"This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95% CI [0.80;2.10]) for fludrocortisone and 2.10 h (95% CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95% CI [33.6;48]) for fludrocortisone and 30 L/h (95% CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC50) was about 200 times lower for fludrocortisone (0.08 mu g/L, 95% CI [0.035;0.125]) than for hydrocortisone (16.7 mu g/L, 95% CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered."	"[Hamitouche, Noureddine; Comets, Emmanuelle; Bellissant, Eric; Laviolle, Bruno] INSERM, CIC Clin Invest Ctr 1414, Rennes, France; [Hamitouche, Noureddine; Bellissant, Eric; Laviolle, Bruno] Rennes 1 Univ, Lab Expt & Clin Pharmacol, Rennes, France; [Ribot, Megane; Alvarez, Jean-Claude] Raymond Poincare Univ Hosp, Dept Pharmacol & Toxicol, Garches, France; [Alvarez, Jean-Claude] Versailles St Quentin Univ, INSERM, U 1173, Versailles, France; [Bellissant, Eric; Laviolle, Bruno] Rennes Univ Hosp, Dept Biol & Clin Pharmacol & Pharmacovigilance, Rennes, France"	"Laviolle, B (corresponding author), INSERM, CIC Clin Invest Ctr 1414, Rennes, France.; Laviolle, B (corresponding author), Rennes 1 Univ, Lab Expt & Clin Pharmacol, Rennes, France.; Laviolle, B (corresponding author), Rennes Univ Hosp, Dept Biol & Clin Pharmacol & Pharmacovigilance, Rennes, France."	"bruno.laviolle@chu-rennes.fr"	"Comets, Emmanuelle/C-9328-2017"	"ALVAREZ, jean claude/0000-0001-5344-9475"	"NA"	"NA"	30	11	11	0	4	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"MAY"	2017	19	3	727	735	"NA"	"10.1208/s12248-016-0041-9"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"ET8QM"	"WOS:000400565300013"	28083797	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Menard, A; Dupouey, J; Muziotti, C; Guilhaumou, R; Blin, O"	"Marsot, Amelie; Menard, Amelie; Dupouey, Julien; Muziotti, Cedric; Guilhaumou, Romain; Blin, Olivier"	"NA"	"A"	"Population pharmacokinetics of rifampicin in adult patients with osteoarticular infections: interaction with fusidic acid"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"fusidic acid; NONMEM; osteoarticular infections; population pharmacokinetics; rifampicin"	"PROSTHETIC-JOINT INFECTIONS; PROTEIN-BINDING; STAPHYLOCOCCUS-AUREUS; TUBERCULOSIS PATIENTS; MEXICAN PATIENTS; MODEL; COMBINATION; ABSORPTION; PHARMACOLOGY; FAILURE"	"AIMS Rifampicin represents the key antibiotic for the management of osteoarticular infections. An important pharmacokinetic variability has already been described, particularly for absorption and metabolism. All previous pharmacokinetic studies have been focused only on patients treated for tuberculosis. The objective of the present study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, which has not been investigated to date. METHOD Rifampicin concentrations were collected retrospectively from 62 patients treated with oral rifampicin 300 mg three times daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters. Demographic data, infection characteristics and antibiotics taken in addition to rifampicin antibiotics were investigated as covariates. RESULTS A one-compartment model, coupled to a transit absorption model, best described the rifampicin data. Fusidic acid coadministration was identified as a covariate in rifampicin pharmacokinetic parameters. The apparent clearance and apparent central volume of distribution mean values [95% confidence interval (CI)] were 5.1 1 h(-1) (1.2, 8.21 h(-1))/23.8 vertical bar(8.9, 38.7 vertical bar) and 13.7 1 h(-1) (10.6, 18.0 1 h(-1))/61.1 1 (40.8, 129.0 1) for patients with and without administration of fusidic acid, respectively. Interindividual variability (95% CI) in the apparent clearance and apparent central volume of distribution were 72.9% (49.5, 86.0%) and 59.1% (5.5, 105.4%), respectively. Residual variability was 2.3 mg l(-1) (1.6, 2.6 mg l(-1)). CONCLUSION We developed the first population pharmacokinetic model of rifampicin in patients with osteoarticular infections. Our model demonstrated that fusidic acid affects rifampicin pharmacokinetics, leading to potential high drug exposure. This finding suggests that fusidic acid dosing regimens should be reconsidered."	"[Marsot, Amelie; Dupouey, Julien; Muziotti, Cedric; Guilhaumou, Romain; Blin, Olivier] Hop La Timone, Serv Pharmacol Clin & Pharmacovigilance, 264 Rue St Pierre, F-13385 Marseille, France; [Marsot, Amelie; Dupouey, Julien; Guilhaumou, Romain; Blin, Olivier] Aix Marseille Univ, Inst Neurosci Timone, Pharmacol Integrat & Interface Clin & Ind, CNRS 7289, 27 Blvd Jean Moulin, F-13385 Marseille, France; [Menard, Amelie] CHU Conception, Fdn IHU Mediterranee Infect, Serv Malad Infect, Pole Malad Infect & Trop Clin & Biol, 147 Blvd Baille, F-13385 Marseille 05, France"	"Marsot, A (corresponding author), Serv Pharmacol Clin & Pharmacovigilance, 264 Rue St Pierre, F-13385 Marseille, France."	"amelie.marsot@ap-hm.fr"	"NA"	"Muziotti, Cedric/0000-0003-2284-7811"	"NA"	"NA"	38	5	5	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAY"	2017	83	5	1039	1047	"NA"	"10.1111/bcp.13178"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EU7SF"	"WOS:000401234300011"	27813241	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Pierre, V; Johnston, CK; Ferslew, BC; Brouwer, KLR; Gonzalez, D"	"Pierre, V.; Johnston, C. K.; Ferslew, B. C.; Brouwer, K. L. R.; Gonzalez, D."	"NA"	"A"	"Population Pharmacokinetics of Morphine in Patients With Nonalcoholic Steatohepatitis (NASH) and Healthy Adults"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"FATTY LIVER-DISEASE; PLASMA-CONCENTRATIONS; ACID; MORPHINE-6-GLUCURONIDE; MORPHINE-3-GLUCURONIDE; MODELS; DISPOSITION; METABOLITES; VOLUNTEERS; EXPRESSION"	"Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three-and one-compartment models, respectively. After accounting for the effect of total body weight on all clearance and volume of distribution parameters using an allometric scaling approach, NASH severity score (NASF; combination of fibrosis and nonalcoholic fatty liver disease activity scores) was the most significant predictor of differences in M3G exposure. The model predicted a linear decrease in the clearance of M3G with increasing NASF scores on a natural logarithmic scale. These results may provide some insight into the potential effect of NASH on the disposition of hepatic transporter substrates."	"[Pierre, V.; Johnston, C. K.; Ferslew, B. C.; Brouwer, K. L. R.; Gonzalez, D.] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA; [Johnston, C. K.] Metrum Res Grp LLC, Tariffville, CT USA"	"Gonzalez, D (corresponding author), Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA."	"daniel.gonzalez@unc.edu"	"NA"	"Gonzalez, Daniel/0000-0001-5522-5686; Brouwer, Kim/0000-0003-1945-4929"	"National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; National Institute of General Medical SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01 GM041935]; National Center for Advancing Translational Sciences (NCATS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [1UL1TR001111]; Quintiles Pharmacokinetics/Pharmacodynamics Fellowships; National Institute of Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [K23HD083465]; nonprofit organization Thrasher Research Fund"	"This project was supported in part by the National Institutes of Health (NIH), National Institute of General Medical Sciences through award number R01 GM041935 (to K.L.R.B.), National Center for Advancing Translational Sciences (NCATS), through award number 1UL1TR001111, and Quintiles Pharmacokinetics/Pharmacodynamics Fellowships (to V.P. and C.K.J.). D.G. receives support for research from the National Institute of Child Health and Human Development (K23HD083465) and the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Quintiles."	47	2	2	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"MAY"	2017	6	5	331	339	"NA"	"10.1002/psp4.12185"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EY7QF"	"WOS:000404185600008"	28417561	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Audebert, C; Attolini, L; Lacarelle, B; Micallef, J; Blin, O"	"Marsot, A.; Audebert, C.; Attolini, L.; Lacarelle, B.; Micallef, J.; Blin, O."	"NA"	"A"	"Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers"	"JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS"	"English"	"Article"	"Population pharmacokinetic; Cannabis; THC; Occasional use"	"CONTROLLED ORAL DELTA(9)-TETRAHYDROCANNABINOL; CHRONIC HEPATITIS-C; SMOKING MARIJUANA; WHOLE-BLOOD; RISK-FACTOR; PLASMA; DELTA-9-TETRAHYDROCANNABINOL; FLUID; DISPOSITION; METABOLISM"	"Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers. Twelve male volunteers (age: 20-28 years, body weight: 62.5-91.0 kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. After ad libitum smoking cannabis cigarette according a standardized procedure, 16 blood samples up to 72 h were collected. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM software. Demographic and biological data were investigated as covariates. A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants and central volume of distribution (V-1). Normal ALT concentration (6.0 to 45.0 IU/l) demonstrated a statistically significant correlation with k(10). The mean values (%Relative Standard Error (RSE)) for k(10), k(12), k(21), k(23), k(32) and V-1 were 0.408 h(-1) (48.8%), 4.070 h(-1) (21.4%), 0.022 h(-1) (27.0%), 1.070 h(-1) (14.3%), 1.060 h(-1) (16.7%) and 19.10 L (39.7%), respectively. We have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis. In addition, a linear relationship between ALT concentration and value of k10 has been described and request further investigation. (C) 2017 Elsevier Inc. All rights reserved."	"[Marsot, A.; Audebert, C.; Attolini, L.; Micallef, J.; Blin, O.] Aix Marseille Univ, Serv Pharmacol Clin & Pharmacovigilance, Pharmacol Integree & Interface Clin & Ind, AP HM,Inst Neurosci Timone,CNRS 7289, F-13385 Marseille, France; [Lacarelle, B.] AP HM, Serv Pharmacocinet Toxicocinet, Marseille, France"	"Marsot, A (corresponding author), Serv Pharmacol Clin & Pharmacovigilance, Unite Pharmacometrie, Batiment F,264 Rue St Pierre, F-13005 Marseille, France."	"amelie.marsot@ap-hm.fr"	"NA"	"NA"	"NA"	"NA"	42	6	6	0	6	"ELSEVIER SCIENCE INC"	"NEW YORK"	"360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA"	"1056-8719"	"1873-488X"	"NA"	"J PHARMACOL TOX MET"	"J. Pharmacol. Toxicol. Methods"	"MAY-JUN"	2017	85	"NA"	49	54	"NA"	"10.1016/j.vascn.2017.02.003"	6	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"FB2SN"	"WOS:000405993600005"	28167229	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Jiang, Y; Milavetz, G; James, MO; An, GH"	"Jiang, Yu; Milavetz, Gary; James, Margaret O.; An, Guohua"	"NA"	"A"	"A Mechanism-Based Pharmacokinetic Enzyme Turnover Model for Dichloroacetic Acid Autoinhibition in Rats"	"JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"pharmacokinetics; physiological model; inhibition; bioavailability"	"GLUTATHIONE TRANSFERASE ZETA; CONGENITAL LACTIC-ACIDOSIS; URINARY METABOLITES; KINETICS; CHILDREN; CANCER; MICE; DCA; TRICHLOROACETATE; INACTIVATION"	"Dichloroacetic acid (DCA), a halogenated organic acid, is a pyruvate dehydrogenase kinase inhibitor that has been used to treat congenital or acquired lactic acidosis and is currently in early-phase clinical trials for cancer treatment. DCA was found to inhibit its own metabolism by irreversibly inactivating glutathione transferase zeta 1 (GSTZ1-1), resulting in nonlinear kinetics and abnormally high accumulation ratio after repeated dosing. In this analysis, a semi-mechanistic pharmacokinetic enzyme turnover model was developed for the first time to capture DCA autoinhibition, gastrointestinal region-dependent absorption, and time-dependent change in bioavailability in rats. The maximum rate constant for DCAinduced GSTZ1-1 inactivation is estimated to be 0.96/h, which is 110 times that of the rate constant for GSTZ1-1 natural degradation (0.00875/h). The model-predicted DCA concentration that corresponds to 50% of maximum enzyme inhibition (EC50) is 4.32 mg/L. The constructed pharmacokinetic enzyme turnover model, when applied to human data, could be used to predict the accumulation of DCA after repeated oral dosing, guide selection of dosing regimens in clinical studies, and facilitate clinical development of DCA. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved."	"[Jiang, Yu; An, Guohua] Univ Iowa, Coll Pharm, Div Pharmaceut & Translat Therapeut, Iowa City, IA 52242 USA; [Milavetz, Gary] Univ Iowa, Coll Pharm, Dept Pharm Practice & Sci, Div Appl Clin Sci, Iowa City, IA 52242 USA; [James, Margaret O.] Univ Florida, Coll Pharm, Dept Med Chem, Gainesville, FL 32611 USA"	"An, GH (corresponding author), Univ Iowa, Coll Pharm, Div Pharmaceut & Translat Therapeut, Iowa City, IA 52242 USA."	"guohua-an@uiowa.edu"	"James, Margaret/A-8232-2011"	"James, Margaret/0000-0001-8778-9427"	"NIEHS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [P42 ES007375] Funding Source: Medline; NIGMS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01 GM099871] Funding Source: Medline"	"NA"	40	2	2	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0022-3549"	"1520-6017"	"NA"	"J PHARM SCI-US"	"J. Pharm. Sci."	"MAY"	2017	106	5	1396	1404	"NA"	"10.1016/j.xphs.2017.01.032"	9	"Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Pharmacology & Pharmacy; Chemistry"	"FD5WG"	"WOS:000407599900025"	28163135	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Chevance, A; Jacques, AM; Laurentie, M; Sanders, P; Henri, J"	"Chevance, A.; Jacques, A. -M.; Laurentie, M.; Sanders, P.; Henri, J."	"NA"	"A"	"The present and future of withdrawal period calculations for milk in the European Union: focus on heterogeneous, nonmonotonic data"	"JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS"	"English"	"Article"	"NA"	"MIXED-EFFECTS MODELS; NONPARAMETRIC POPULATION METHODS; TIME-ESTIMATION; VETERINARY DRUGS; PREDICTIVE CHECK; OPTIMAL-DESIGN; PHARMACOKINETICS; OPTIMIZATION; PERFORMANCE; ABSORPTION"	"Harmonization of the method for calculating the withdrawal period for milk dates from the 1990s. European harmonization has led to guidance with three accepted methods for determining the withdrawal period for milk that are currently applicable. These three methods can be used by marketing authorization holders, but, in some cases, their diversity can lead to very different withdrawal periods. This is particularly the case when concentrations in milk are nonmonotonic and heterogeneous, meaning that concentrations strictly increase and then strictly decrease with significant interindividual variability in the time to reach the maximal concentration. Here, we first describe the concepts associated with the different methods used in the harmonized approach currently applicable for the determination of milk withdrawal periods, and then, we propose the application of a modern pharmacometric tool. Finally, with a nonmonotonic heterogeneous dataset, we illustrate the usefulness of this tool in comparison with the three currently applicable methods and discuss the limitations and advantages of each method."	"[Chevance, A.; Jacques, A. -M.] ANSES ANMV, French Agcy Food Environm & Occupat Hlth & Safety, French Agcy Vet Med Prod, Fougeres, France; [Laurentie, M.; Sanders, P.; Henri, J.] ANSES, French Agcy Food Environm & Occupat Hlth & Safety, Lab Fougeres, Fougeres, France"	"Henri, J (corresponding author), ANSES, Lab Fougeres, Bioagropolis, 10B Rue Claude Bourgelat,CS 40608, F-35306 Fougeres, France."	"jerome.henri@anses.fr"	"Sanders, Pascal/C-7020-2011; HENRI, Jerome/M-5449-2019"	"Sanders, Pascal/0000-0003-4019-480X; HENRI, Jerome/0000-0002-3803-077X"	"NA"	"NA"	39	4	4	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0140-7783"	"1365-2885"	"NA"	"J VET PHARMACOL THER"	"J. Vet. Pharmacol. Ther."	"JUN"	2017	40	3	218	230	"NA"	"10.1111/jvp.12351"	13	"Pharmacology & Pharmacy; Veterinary Sciences"	"Pharmacology & Pharmacy; Veterinary Sciences"	"ET3FH"	"WOS:000400162400002"	27604508	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Janssen, EJH; Bastiaans, DET; Valitalo, PAJ; van Rossum, AMC; Jacqz-Aigrain, E; Lyall, H; Knibbe, CAJ; Burger, DM"	"Janssen, Esther J. H.; Bastiaans, Diane E. T.; Valitalo, Pyry A. J.; van Rossum, Annemarie M. C.; Jacqz-Aigrain, Evelyne; Lyall, Hermione; Knibbe, Catherijne A. J.; Burger, David M."	"NA"	"A"	"Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"human immunodeficiency virus/acquired immune deficiency syndrome; modelling and simulation; paediatrics; pharmacotherapy; therapeutic drug monitoring"	"TWICE-DAILY LAMIVUDINE; HIV-1-INFECTED CHILDREN; ZIDOVUDINE; MODEL; COMBINATION; ABACAVIR; STAVUDINE; LOPINAVIR/RITONAVIR; FORMULATION; ABSORPTION"	"AIM The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC(0-24h)) is not reached. METHODS Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4-18 years, body weight 3.4-60.5 kg); 2061 samples (median 12 per child); daily oral dose 60-300 mg (3.9-17.6 mg kg(-1))]. Steady state AUC(0-24h) was calculated per individual (adult target 8.9 mg.hl(-1)). RESULTS A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2 lh(-1) (4.2%) and 38.9l (7.0%) for a median individual of 16.6 kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14 kg and <14 kg, respectively, the target AUC(0-24h) was reached. CONCLUSION Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months-18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg(-1) day(-1) if the adult target for AUC(0-24h) is aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed."	"[Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands; [Janssen, Esther J. H.; Valitalo, Pyry A. J.; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Bastiaans, Diane E. T.] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands; [Bastiaans, Diane E. T.; Burger, David M.] Radboud Univ Nijmegen, Med Ctr, RIHS, Nijmegen, Netherlands; [van Rossum, Annemarie M. C.] Erasmus MC Sophia, Div Pediat Infect Dis & Immunol, Rotterdam, Netherlands; [Jacqz-Aigrain, Evelyne] Univ Paris VII, Hop Robert Debre, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC9202, Paris, France; [Lyall, Hermione] St Marys Hosp, Dept Pediat, London, England"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Burger, David/C-9929-2013; van Rossum, Annemarie/AAC-7050-2019"	"van Rossum, Annemarie/0000-0002-1259-477X"	"Top Institute Pharma project [D2-501]; Innovational Research Incentives Scheme (Vidi grant) of the Dutch Organization for Scientific Research (NWO)"	"This study was performed within the framework of Top Institute Pharma project number D2-501. Catherijne Knibbe is supported by the Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Dutch Organization for Scientific Research (NWO). We thank all children, families, and staff from the centres participating in the CHAPAS1, PENTA13, PENTA15, ARROW and RONDO studies."	46	4	4	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUN"	2017	83	6	1287	1297	"NA"	"10.1111/bcp.13227"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EU7SJ"	"WOS:000401234700015"	28079918	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Tout, M; Gagez, AL; Lepretre, S; Gouilleux-Gruart, V; Azzopardi, N; Delmer, A; Mercier, M; Ysebaert, L; Laribi, K; Gonzalez, H; Paintaud, G; Cartron, G; Ternant, D"	"Tout, Mira; Gagez, Anne-Laure; Lepretre, Stephane; Gouilleux-Gruart, Valerie; Azzopardi, Nicolas; Delmer, Alain; Mercier, Melanie; Ysebaert, Loic; Laribi, Kamel; Gonzalez, Hugo; Paintaud, Gilles; Cartron, Guillaume; Ternant, David"	"NA"	"A"	"Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"COLORECTAL-CANCER PATIENTS; PROGRESSION-FREE SURVIVAL; B-CELL LYMPHOMA; FC-GAMMA-RIIIA; THERAPEUTIC MONOCLONAL-ANTIBODIES; C-RECEPTOR POLYMORPHISMS; POPULATION PHARMACOKINETICS; PHASE-II; PREDICT RESPONSE; MODEL"	"Background and objectives Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the Fc gamma RIIIA genetic polymorphism on rituximab pharmacokinetics in CLL. Methods Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance. Results Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (p = 0.00046) and in patients with the FCGR3A-158VV genotype (p = 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (p = 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (p = 1.3 x 10(-5) and 0.0015, respectively). Conclusions A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab 'consumption' (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in FCGR3A-158VV patients."	"[Tout, Mira; Azzopardi, Nicolas; Paintaud, Gilles; Ternant, David] Univ Francois Rabelais Tours, CNRS, GICC, UMR 7292, Tours, France; [Gagez, Anne-Laure; Cartron, Guillaume] Univ Montpellier, CNRS, UMR 5235, Montpellier, France; [Gagez, Anne-Laure] CHU Montpellier, Dept Hematol, Montpellier, France; [Lepretre, Stephane] Henri Becquerel Ctr, Dept Hematol, Rouen, France; [Gouilleux-Gruart, Valerie] CHU Tours, Lab Immunol, Tours, France; [Delmer, Alain] CHU Reims, Dept Hematol, Reims, France; [Mercier, Melanie] CHU Angers, Dept Hematol, Angers, France; [Ysebaert, Loic] CHU Toulouse, Dept Hematol, Toulouse, France; [Laribi, Kamel] CHG Le Mans, Dept Hematol, Le Mans, France; [Gonzalez, Hugo] CHG Pontoise, Dept Hematol, Pontoise, France; [Paintaud, Gilles; Ternant, David] CHU Tours, CNRS, Lab Pharmacol Toxicol, UMR 7292, 2 Blvd Tonnelle, F-37044 Tours, France"	"Ternant, D (corresponding author), Univ Francois Rabelais Tours, CNRS, GICC, UMR 7292, Tours, France.; Ternant, D (corresponding author), CHU Tours, CNRS, Lab Pharmacol Toxicol, UMR 7292, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"NA"	"PAINTAUD, Gilles/0000-0003-0158-1356; Delmer, Alain/0000-0002-1430-2574; Cartron, Guillaume/0000-0003-0659-9635; Gagez, Anne-Laure/0000-0002-7797-3455"	"FILO Group; Roche SAS (Neuilly, France)"	"This study was funded by FILO Group and Roche SAS (Neuilly, France)."	51	10	9	1	2	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUN"	2017	56	6	635	647	"NA"	"10.1007/s40262-016-0470-8"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EU5HO"	"WOS:000401062400006"	27783363	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kleiber, N; Mathot, RAA; Ahsman, MJ; Wildschut, ED; Tibboel, D; de Wildt, SN"	"Kleiber, Niina; Mathot, Ron A. A.; Ahsman, Maurice J.; Wildschut, Enno D.; Tibboel, Dick; de Wildt, Saskia N."	"NA"	"A"	"Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"alpha-agonist; clonidine; dosing guideline; extracorporeal membrane oxygenation; paediatric intensive care; pharmacokinetics; sedation"	"CHILDREN; THERAPY; ECMO; NEWBORNS; INFANTS; SEQUESTRATION; DISPOSITION; ABSORPTION; CIRCUIT; DRUGS"	"AIMS Clonidine is used for sedation in the paediatric intensive care unit. Extracorporeal membrane oxygenation (ECMO) provides temporary support if respiratory and cardiac function is threatened. ECMO influences the pharmacokinetics of drugs. Clonidine during paediatric ECMO cannot be effectively titrated as PK data are lacking. The aim of this study is to describe clonidine PK in a particular ECMO system and propose dosing guidelines for children on this particular ECMO circuit. METHODS All children below the age of 18 years who received clonidine during ECMO were eligible. The pharmacokinetic analysis was conducted by nonlinear mixed effect modelling, which enables to establish the separate influences of determinants on drug blood level and to provide individualized dosing. RESULTS Twenty-two patients, median age 1 month (IQR 6.4) and weight at inclusion 4 kg (IQR 3.1) were included of whom 90% in addition to ECMO received pre-emptive continuous venovenous hemofiltration to optimize fluid balance. The clonidine clearance rate was two-fold that measured in patients not on ECMO. Clearance increased steeply with postnatal age: at days 6, 8 and 10, respectively 30%, 50% and 70% of the adult clearance rate was reached. The use of diuretics was associated with a lower clearance. The volume of distribution increased by 55% during ECMO support. CONCLUSION Our findings suggest that a higher dose of clonidine may be needed during ECMO. The PK parameters on ECMO and the dosing guidelines proposed hold the potential to improve sedation practices on ECMO but need to be repeated with different ECMO systems."	"[Kleiber, Niina; Ahsman, Maurice J.; Wildschut, Enno D.; Tibboel, Dick; de Wildt, Saskia N.] Erasmus MC, Intens Care, Sophia Childrens Hosp, POB 2060, NL-3000 CB Rotterdam, Netherlands; [Kleiber, Niina; Ahsman, Maurice J.; Wildschut, Enno D.; Tibboel, Dick; de Wildt, Saskia N.] Erasmus MC, Dept Pediat Surg, Sophia Childrens Hosp, POB 2060, NL-3000 CB Rotterdam, Netherlands; [Mathot, Ron A. A.] Acad Med Ctr, Dept Hosp Pharm, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands; [Ahsman, Maurice J.] LAP&P Consultants BV, Archimedesweg 3,1, NL-2333 CM Leiden, Netherlands; [de Wildt, Saskia N.] Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Nijmegen, Netherlands; [Kleiber, Niina] CHU St Justine, Dept Pediat, Montreal, PQ, Canada"	"Mathot, RAA (corresponding author), Acad Med Ctr, Dept Hosp Pharm, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands."	"r.mathot@amc.uva.nl"	"de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647; Ahsman, Maurice/0000-0002-6084-2571"	"NA"	"NA"	41	10	10	0	5	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUN"	2017	83	6	1227	1239	"NA"	"10.1111/bcp.13235"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EU7SJ"	"WOS:000401234700009"	28078682	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Frymoyer, A; Juul, SE; Massaro, AN; Bammler, TK; Wu, YW"	"Frymoyer, Adam; Juul, Sandra E.; Massaro, An N.; Bammler, Theo K.; Wu, Yvonne W."	"NA"	"A"	"High-dose erythropoietin population pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia"	"PEDIATRIC RESEARCH"	"English"	"Article"	"NA"	"WHOLE-BODY HYPOTHERMIA; RECOMBINANT ERYTHROPOIETIN; BRAIN-INJURY; SYSTEMIC HYPOTHERMIA; CEREBROSPINAL-FLUID; OUTCOMES; DARBEPOETIN; TERM; RECOVERY; NEWBORNS"	"BACKGROUND: High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxicischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies. METHODS: We performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to six doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 h of treatment (AUC(48h)) 140,000 mU*h/ml). RESULTS: Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (P < 0.001). After accounting for birth weight, variation in Epo pharmacokinetics between neonates was low (CV% 20%). All 23 neonates who received 1,000 U/kg every 24 h for the first 2 d of therapy achieved the target AUC(48h) 140,000 mU*h/ml. No neonate who received a lower dosing regimen achieved this target. CONCLUSION: In neonates with HIE receiving hypothermia, Epo 1,000 U/kg every 24 h for the first 2 d of therapy resulted in consistent achievement of target exposures associated with neuroprotection in animal models."	"[Frymoyer, Adam] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA; [Juul, Sandra E.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA; [Massaro, An N.] Childrens Natl Hlth Syst, Dept Neonatol, Washington, DC USA; [Bammler, Theo K.] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA; [Wu, Yvonne W.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA; [Wu, Yvonne W.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA"	"Frymoyer, A (corresponding author), Stanford Univ, Dept Pediat, Stanford, CA 94305 USA."	"frymoyer@stanford.edu"	"NA"	"Massaro, An/0000-0002-5543-6165"	"Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [K23HD079557]; Thrasher Research Fund, Salt Lake City, UT; Cerebral Palsy Alliance Research Foundation, Allambie Heights, Australia"	"A.F. is funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development K23HD079557. The phase I and phase II clinical studies were funded by the Thrasher Research Fund, Salt Lake City, UT and the Cerebral Palsy Alliance Research Foundation, Allambie Heights, Australia."	45	10	10	0	3	"NATURE PUBLISHING GROUP"	"NEW YORK"	"75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA"	"0031-3998"	"1530-0447"	"NA"	"PEDIATR RES"	"Pediatr. Res."	"JUN"	2017	81	6	865	872	"NA"	"10.1038/pr.2017.15"	8	"Pediatrics"	"Pediatrics"	"EX6WZ"	"WOS:000403384100004"	28099423	"Green Accepted, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Collins, TA; Hattersley, MM; Yates, JWT; Clark, E; Mondal, M; Mettetal, JT"	"Collins, T. A.; Hattersley, M. M.; Yates, J. W. T.; Clark, E.; Mondal, M.; Mettetal, J. T."	"NA"	"A"	"Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"ACUTE MYELOID-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; TOXICITY; CANCER; PHARMACOKINETICS; PHARMACODYNAMICS; BROMODOMAINS; PREDICTION; EXPOSURE; OTX015"	"In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both q.d. and b.i.d. dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses. The model was then extended to incorporate preexisting myelosuppression where bone marrow function is inhibited by acute myeloid leukemia. Under these conditions, duration of platelet count recovery has the potential to be prolonged due to drug-induced myelosuppression."	"[Collins, T. A.] AstraZeneca, Drug Safety & Metab, Cambridge, England; [Hattersley, M. M.; Clark, E.] AstraZeneca, Oncol iMED, Waltham, MA USA; [Yates, J. W. T.] AstraZeneca, Oncol iMED, Cambridge, England; [Mondal, M.; Mettetal, J. T.] AstraZeneca, Drug Safety & Metab, Waltham, MA USA"	"Collins, TA (corresponding author), AstraZeneca, Drug Safety & Metab, Cambridge, England."	"Teresa.Collins@astrazeneca.com"	"NA"	"NA"	"AstraZenecaAstraZeneca"	"This study was wholly funded by AstraZeneca, of which all the authors are employees."	33	9	9	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"JUN"	2017	6	6	357	364	"NA"	"10.1002/psp4.12194"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EY7QK"	"WOS:000404186100002"	28378926	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Methaneethorn, J"	"Methaneethorn, Janthima"	"NA"	"A"	"Population Pharmacokinetics of Valproic Acid in Patients with Mania: Implication for Individualized Dosing Regimens"	"CLINICAL THERAPEUTICS"	"English"	"Article"	"bipolar disorder; mania; pharmacokinetic properties; population pharmacokinetic model; valproate; valproic acid"	"EPILEPTIC PATIENTS; SERUM CONCENTRATIONS; CHILDREN; RISPERIDONE; CLEARANCE; MODEL; PREDICTION; GUIDELINES; CONSENSUS; DOSAGE"	"Purpose: This study characterized the population pharmacokinetic properties of valproic acid in patients with mania and determined potential factors that affect the pharmacokinetic properties of valproic acid in this population. Methods: Routine therapeutic drug monitoring of valproic acid concentrations, demographic data, and concomitant medications from 206 hospitalized patients with mania were retrospectively collected from Somdet Chaopraya Institute of Psychiatry and Srithanya Hospital, Thailand. Nonlinear mixed effect modeling was used for data analysis. Covariate model building was conducted using stepwise forward addition and stepwise backward elimination. The final model was evaluated using bootstrap analysis and normalized prediction distribution error. The results were compared with those previously reported in patients with epilepsy given that there is an evidence of a difference in valproic acid clearance between patients with mania and those with epilepsy. Findings: Valproic acid data were adequately described by a 1-compartment model. Significant predictors for valproic acid clearance included valproic acid dose and weight. The population estimates for valproic acid CL/F and V/F were 0.464 L/h and 23.3 L, respectively. Valproic acid clearance obtained from this study did not seem to be significantly different from that of patients with epilepsy. Implications: A qualified population pharmacokinetic model for valproic acid in patients with mania was developed. This model could be used to optimize valproic acid therapy in patients with mania. Valproic acid clearance could be predicted from valproic acid dose and weight of patients. This predicted clearance can subsequently be used for individualization of optimum valproic acid maintenance dose. (C) 2017 Elsevier HS Journals, Inc. All rights reserved."	"[Methaneethorn, Janthima] Naresuan Univ, Fac Pharmaceut Sci, Dept Pharm Practice, Pharmacokinet Res Unit, Phitsanulok, Thailand; [Methaneethorn, Janthima] Naresuan Univ, Ctr Excellence Environm Hlth & Toxicol, Phitsanulok, Thailand"	"Methaneethorn, J (corresponding author), Naresuan Univ, Fac Pharmaceut Sci, Phitsanulok 65000, Thailand."	"janthima.methaneethorn@gmail.com"	"NA"	"NA"	"Coordinating Center for Thai Government Science and Technology Scholarship Students (CSTS); National Science and Technology Development Agency (NSTDA)"	"This study received financial support from Coordinating Center for Thai Government Science and Technology Scholarship Students (CSTS), National Science and Technology Development Agency (NSTDA)."	29	4	4	1	7	"ELSEVIER"	"BRIDGEWATER"	"685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA"	"0149-2918"	"1879-114X"	"NA"	"CLIN THER"	"Clin. Ther."	"JUN"	2017	39	6	1171	1181	"NA"	"10.1016/j.clinthera.2017.04.005"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EZ6NN"	"WOS:000404834700009"	28483293	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Woillard, JB; Mourad, M; Neely, M; Capron, A; van Schaik, RH; van Gelder, T; Lloberas, N; Hesselink, DA; Marquet, P; Haufroid, V; Elens, L"	"Woillard, Jean-Baptiste; Mourad, Michel; Neely, Michael; Capron, Arnaud; van Schaik, Ron H.; van Gelder, Teun; Lloberas, Nuria; Hesselink, Dennis A.; Marquet, Pierre; Haufroid, Vincent; Elens, Laure"	"NA"	"A"	"Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation"	"FRONTIERS IN PHARMACOLOGY"	"English"	"Article"	"tacrolimus; kidney transplantation; CYP3A; single nucleotide polymorphisms; population pharmacokinetics; dosage recommendations"	"SINGLE-NUCLEOTIDE POLYMORPHISMS; RENAL-TRANSPLANTATION; ABCB1 POLYMORPHISMS; DOSE REQUIREMENTS; ACUTE REJECTION; CLINICAL PHARMACOKINETICS; CALCINEURIN INHIBITORS; GENETIC POLYMORPHISMS; BLOOD-CONCENTRATIONS; P450 OXIDOREDUCTASE"	"Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics (R). Patients were genotyped for the CYP3A4*22 and CYP3A5*3 alleles and were classified into 3 different categories [poor-metabolizers (PM), Intermediate-metabolizers (IM) or extensive-metabolizers (EM)]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Delta-2LL = -73). Our model estimated that tacrolimus concentrations were 33% IC95%[20-26%], 41% IC95%[36-45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile."	"[Woillard, Jean-Baptiste; Marquet, Pierre] Ctr Hosp Univ Limoges, Dept Pharmacol & Toxicol, Limoges, France; [Mourad, Michel] Catholic Univ Louvain, Kidney & Pancreas Transplantat Unit, Clin Univ St Luc, Brussels, Belgium; [Neely, Michael] Childrens Hosp Los Angeles, Lab Appl Pharmacokinet, Los Angeles, CA 90027 USA; [Capron, Arnaud; Haufroid, Vincent] Catholic Univ Louvain, Clin Univ St Luc, Dept Clin Chem, Brussels, Belgium; [van Schaik, Ron H.] Erasmus MC Univ Med Ctr Rotterdam, Dept Clin Chem, Rotterdam, Netherlands; [van Gelder, Teun] Erasmus MC Univ Med Ctr Rotterdam, Dept Hosp Pharm, Rotterdam, Netherlands; [van Gelder, Teun; Hesselink, Dennis A.] Erasmus MC Univ Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands; [Lloberas, Nuria] Univ Barcelona, Nephrol Serv, Barcelona, Spain; [Lloberas, Nuria] Univ Barcelona, Lab Expt Nephrol, Barcelona, Spain; [Haufroid, Vincent; Elens, Laure] Catholic Univ Louvain, Louvain Ctr Toxicol & Appl Pharmacol, Inst Rech Expt & Clin, Brussels, Belgium; [Elens, Laure] Catholic Univ Louvain, Dept Integrated PharmacoMetr PharmacoGen & Pharma, Louvain Drug Res Inst, Brussels, Belgium"	"Elens, L (corresponding author), Catholic Univ Louvain, Louvain Ctr Toxicol & Appl Pharmacol, Inst Rech Expt & Clin, Brussels, Belgium.; Elens, L (corresponding author), Catholic Univ Louvain, Dept Integrated PharmacoMetr PharmacoGen & Pharma, Louvain Drug Res Inst, Brussels, Belgium."	"laure.elens@uclouvain.be"	"MARQUET, Pierre/A-1727-2017; Woillard, j-Baptiste/C-4315-2016; Woillard, Jean-Baptiste/N-1934-2019"	"MARQUET, Pierre/0000-0001-7698-0760; Woillard, j-Baptiste/0000-0003-1695-0695; Woillard, Jean-Baptiste/0000-0003-1695-0695; Elens, Laure/0000-0002-0039-3583"	"NA"	"NA"	59	22	22	0	6	"FRONTIERS MEDIA SA"	"LAUSANNE"	"AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND"	"1663-9812"	"NA"	"NA"	"FRONT PHARMACOL"	"Front. Pharmacol."	"JUN 8"	2017	8	"NA"	"NA"	"NA"	358	"10.3389/fphar.2017.00358"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EW9SM"	"WOS:000402859500001"	28642710	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"De Cock, PAJG; van Dijkman, SC; de Jaeger, A; Willems, J; Carlier, M; Verstraete, AG; Delanghe, JR; Robays, H; Vande Walle, J; Della Pasqua, OE; De Paepe, P"	"De Cock, Pieter A. J. G.; van Dijkman, Sven C.; de Jaeger, Annick; Willems, Jef; Carlier, Mieke; Verstraete, Alain G.; Delanghe, Joris R.; Robays, Hugo; Vande Walle, Johan; Della Pasqua, Oscar E.; De Paepe, Peter"	"NA"	"A"	"Dose optimization of piperacillin/tazobactam in critically ill children"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"EXTENDED-INFUSION PIPERACILLIN; AUGMENTED RENAL CLEARANCE; BETA-LACTAM ANTIBIOTICS; INTENSIVE-CARE-UNIT; POPULATION PHARMACOKINETICS; CYSTATIN-C; CREATININE MEASUREMENTS; HEALTHY-VOLUNTEERS; CYSTIC-FIBROSIS; TAZOBACTAM"	"Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen. Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% fT(> MIC) > 16 mg/L). Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children > 2 months of age."	"[De Cock, Pieter A. J. G.; Robays, Hugo] Ghent Univ Hosp, Dept Pharm, Pintelaan 185, B-9000 Ghent, Belgium; [De Cock, Pieter A. J. G.; De Paepe, Peter] Univ Ghent, Heymans Inst Pharmacol, Pintelaan 185, B-9000 Ghent, Belgium; [De Cock, Pieter A. J. G.; de Jaeger, Annick; Willems, Jef] Ghent Univ Hosp, Dept Paediat Intens Care, Pintelaan 185, B-9000 Ghent, Belgium; [De Cock, Pieter A. J. G.; van Dijkman, Sven C.; Della Pasqua, Oscar E.] Leiden Acad Ctr Drug Res, Div Pharmacol, Einsteinweg 55, NL-2333 CC Leiden, Netherlands; [Carlier, Mieke; Verstraete, Alain G.; Delanghe, Joris R.] Ghent Univ Hosp, Dept Lab Med, Pintelaan 185, B-9000 Ghent, Belgium; [Verstraete, Alain G.; Delanghe, Joris R.] Univ Ghent, Dept Clin Chem Microbiol & Immunol, Pintelaan 185, B-9000 Ghent, Belgium; [Vande Walle, Johan] Ghent Univ Hosp, Dept Paediat Nephrol, Pintelaan 185, B-9000 Ghent, Belgium; [Della Pasqua, Oscar E.] GlaxoSmithKline, Clin Pharmacol & Discovery Med, Stockley Pk, Uxbridge, Middx, England; [Della Pasqua, Oscar E.] BMA House, Clin Pharmacol & Therapeut, Tavistock Sq, London WC1H 9HX, England"	"De Cock, PAJG (corresponding author), Ghent Univ Hosp, Dept Pharm, Pintelaan 185, B-9000 Ghent, Belgium.; De Cock, PAJG (corresponding author), Univ Ghent, Heymans Inst Pharmacol, Pintelaan 185, B-9000 Ghent, Belgium.; De Cock, PAJG (corresponding author), Ghent Univ Hosp, Dept Paediat Intens Care, Pintelaan 185, B-9000 Ghent, Belgium.; De Cock, PAJG (corresponding author), Leiden Acad Ctr Drug Res, Div Pharmacol, Einsteinweg 55, NL-2333 CC Leiden, Netherlands."	"pieter.decock@uzgent.be"	"Walle, Johan Vande/AAG-3858-2020; De Cock, Pieter/F-4917-2015; Verstraete, Alain/B-4150-2013"	"De Cock, Pieter/0000-0001-7634-7471; Verstraete, Alain/0000-0002-0956-3315; van Dijkman, Sven/0000-0002-2799-7643"	"Clinical Research Fund Ghent University Hospital, Ghent Belgium [WR/1294/APO/001]; Agency for Innovation by Science and Technology, Flanders, Belgium (SAFEPEDRUG project) [IWT/SBO/130033]"	"This work was supported by the Clinical Research Fund Ghent University Hospital, Ghent Belgium (grant number WR/1294/APO/001 to P.A.J.G.D.C) and the Agency for Innovation by Science and Technology, Flanders, Belgium (SAFEPEDRUG project; grant number IWT/SBO/130033)."	50	9	9	1	9	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JUL"	2017	72	7	2002	2011	"NA"	"10.1093/jac/dkx093"	10	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"EZ7JV"	"WOS:000404901100023"	28387840	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Chen, YS; Liu, ZQ; Chen, R; Wang, L; Huang, L; Zhu, X; Zhou, TY; Lu, W; Ma, P"	"Chen, Yu-si; Liu, Zi-qi; Chen, Rong; Wang, Lei; Huang, Ling; Zhu, Xiao; Zhou, Tian-yan; Lu, Wei; Ma, Ping"	"NA"	"A"	"Population pharmacokinetic analysis of tacrolimus in Chinese myasthenia gravis patients"	"ACTA PHARMACOLOGICA SINICA"	"English"	"Article"	"myasthenia gravis; immunosuppressant; tacrolimus; population pharmacokinetics; hematocrit; blood urea nitrogen; immunoglobulin treatment"	"PROTEIN-BINDING; TRANSPLANT RECIPIENTS; LIVER-TRANSPLANTATION; DOSAGE PREDICTION; INHIBITORS; CYANATE; MODELS; PLASMA"	"The importance of tacrolimus in the treatment of myasthenia gravis (MG) as a substitute for corticosteroid-dependent immunosuppressive therapy is increasing. Thus far, however, no population pharmacokinetic (PopPK) analysis of tacrolimus in treating MG patients has been published. This article aimed to construct a PopPK model of tacrolimus for Chinese MG patients with the goal of improving its performance in MG treatment. A total of 253 trough concentration records were obtained from 83 Chinese MG patients. The effects of demographics, lifestyle and health status, biochemical test data, disease progression and treatment-related information (including co-administered medications) as covariates on the various parameters were investigated. The covariate selection was based on biological plausibility, clinical significance, statistical significance and reduction in inter-individual variability (IIV). Bootstrap and normalized prediction distribution error (NPDE) analysis were performed to validate the final model. A one-compartment PopPK model with first-order elimination and a fixed absorption phase was constructed. The estimated apparent oral clearance (CL/F) and apparent oral volume of distribution (V/F) were 3.6 L/h and 1700 L, respectively, in the MG patients. Hematocrit and blood urea nitrogen were identified as two covariates that significantly influenced the CL/F. Immunoglobulin treatment (PRO) also had the potential to influence V/F, which was consistent with the clinical observations and the high protein-binding property of tacrolimus. Other covariates including age, weight, gender and co-administered medications had no obvious influence on CL/F or V/F. The first PopPK model of tacrolimus in MG patients was established. The identified covariates were of biological plausibility and clinical importance to help individualize the dosing schedule in MG patients."	"[Liu, Zi-qi; Huang, Ling; Ma, Ping] Gen Hosp PLA Rocket Force, Dept Pharm, Beijing 100088, Peoples R China; [Chen, Yu-si] Tsinghua Univ, Sch Pharmaceut Sci, Beijing 100084, Peoples R China; [Chen, Rong; Zhou, Tian-yan; Lu, Wei] Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Hlth Sci Ctr, Beijing 100191, Peoples R China; [Chen, Rong; Zhou, Tian-yan; Lu, Wei] Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China; [Wang, Lei] Gen Hosp PLA Rocket Force, Dept Neurol, Beijing 100088, Peoples R China; [Zhu, Xiao] Univ Otago, Natl Sch Pharm, Otago Pharmacometr Grp, Dunedin 9016, New Zealand"	"Ma, P (corresponding author), Gen Hosp PLA Rocket Force, Dept Pharm, Beijing 100088, Peoples R China.; Lu, W (corresponding author), Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Hlth Sci Ctr, Beijing 100191, Peoples R China.; Lu, W (corresponding author), Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China."	"luwei_pk@bjmu.edu.cn; maping691009@126.com"	"NA"	"Zhu, Xiao/0000-0003-3295-619X"	"NA"	"NA"	28	4	5	0	7	"ACTA PHARMACOLOGICA SINICA"	"SHANGHAI"	"294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA"	"1671-4083"	"1745-7254"	"NA"	"ACTA PHARMACOL SIN"	"Acta Pharmacol. Sin."	"AUG"	2017	38	8	1195	1204	"NA"	"10.1038/aps.2016.174"	10	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"FC5HJ"	"WOS:000406872200010"	28552913	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Franken, LG; Masman, AD; de Winter, BCM; Baar, FPM; Tibboel, D; van Gelder, T; Koch, BCP; Mathot, RAA"	"Franken, Linda G.; Masman, Anniek D.; de Winter, Brenda C. M.; Baar, Frans P. M.; Tibboel, Dick; van Gelder, Teun; Koch, Birgit C. P.; Mathot, Ron A. A."	"NA"	"A"	"Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect?"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"drug metabolism; NONMEM; palliative care; pharmacokinetics; sedation"	"MORBIDLY OBESE-PATIENTS; INTENSIVE-CARE PATIENTS; PALLIATIVE CARE; POPULATION PHARMACOKINETICS; DRUG-METABOLISM; CANCER-PATIENTS; SEDATION; PHARMACOLOGY; PREDICTION; LORAZEPAM"	"AimsMidazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. Because of large inter-individual variability (IIV), however, the time it takes to achieve adequate sedation varies widely. It would therefore greatly improve clinical care if an individualized dose could be determined beforehand. To find clinically relevant parameters for dose individualization, we performed a pharmacokinetic study on midazolam, 1OH-midazolam (1-OH-M) and 1OH-midazolam-glucuronide (1-OH-MG) in terminally ill patients. MethodsUsing nonlinear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 192 samples from 45 terminally ill patients who received midazolam either orally or subcutaneously. The covariates analysed were patient characteristics, co-medication and blood chemistry levels. ResultsThe data were accurately described by a one compartment model for midazolam, 1-OH-M and 1-OH-MG. The population mean estimates for midazolam, 1-OH-M and 1-OH-MG clearance were 8.4lh(-1) (RSE 9%, IIV 49%), 45.4lh(-1) (RSE 12%, IIV 60.5%) and 5.1lh(-1) (RSE 11%, IIV 49.9%), respectively. 1-OH-MG clearance was correlated with the estimated glomular filtration rate (eGFR) explaining 28.4% of the IIV in 1-OH-MG clearance. In addition, low albumin levels were associated with decreased midazolam clearance, explaining 18.2% of the IIV. ConclusionOur study indicates albumin levels and eGFR as relevant clinical parameters to optimize midazolam dosing in terminally ill patients. The correlation between low albumin levels and decreased midazolam clearance is probably a result of inflammatory response as high CRP levels were correlated in a similar way."	"[Franken, Linda G.; de Winter, Brenda C. M.; van Gelder, Teun; Koch, Birgit C. P.] Erasmus MC, Dept Hosp Pharm, Wytemaweg 80 NA 206, NL-3015 CN Rotterdam, Netherlands; [Masman, Anniek D.; Baar, Frans P. M.] Laurens Cadenza, Palliat Care Ctr, Rotterdam, Netherlands; [Masman, Anniek D.; Tibboel, Dick] Sophia Childrens Univ Hosp, Erasmus MC, Dept Paediat Surg, Intens Care, Rotterdam, Netherlands; [Tibboel, Dick] Sophia Childrens Univ Hosp, Erasmus MC, Pain Expertise Ctr, Rotterdam, Netherlands; [Mathot, Ron A. A.] Acad Med Ctr, Hosp Pharm Clin Pharmacol, Amsterdam, Netherlands"	"Franken, LG (corresponding author), Erasmus MC, Dept Hosp Pharm, Wytemaweg 80 NA 206, NL-3015 CN Rotterdam, Netherlands."	"l.franken@ersmusmc.nl"	"Franken, Linda/AAB-1901-2020"	"Franken, Linda/0000-0001-6436-9825; koch, birgit/0000-0002-1202-3643"	"NA"	"NA"	43	6	6	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"AUG"	2017	83	8	1701	1712	"NA"	"10.1111/bcp.13259"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FA6IA"	"WOS:000405545300011"	28177137	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Gertler, R; Gruber, M; Grassin-Delyle, S; Urien, S; Martin, K; Tassani-Prell, P; Braun, S; Burg, S; Wiesner, G"	"Gertler, Ralph; Gruber, Michael; Grassin-Delyle, Stanislas; Urien, Saik; Martin, Klaus; Tassani-Prell, Peter; Braun, Siegmund; Burg, Simon; Wiesner, Gunther"	"NA"	"A"	"Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"tranexamic acid; antifibrinolytic agents; pharmacokinetics; cardiac surgical procedures; congenital heart defects"	"CARDIOPULMONARY BYPASS; POPULATION PHARMACOKINETICS; CHILDREN; ADULTS; SEIZURES; FIBRINOLYSIS; PARAMETERS; MODELS"	"AimTranexamic acid (TXA) continues to be one of the antifibrinolytics of choice during paediatric cardiac surgery. However, in infants less than 1year of age, the optimal dosing based on pharmacokinetic (PK) considerations is still under discussion. MethodsForty-three children less than 1year of age were enrolled, of whom 37 required the use of cardiopulmonary bypass (CPB) and six were operated on without CPB. Administration of 50mg kg(-1) TXA intravenously at the induction of anaesthesia was followed by 50mg kg(-1) into the CPB prime in the CPB group. Plasma concentrations of TXA were analysed by gas chromatography-mass spectrometry. PK data were investigated using nonlinear mixed-effect models. ResultsA two-compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, postmenstrual age (PMA). Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h(-1); central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h(-1); V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg(-1) TXA as a bolus, a subsequent infusion of 10 mg kg(-1) h(-1), then a 4 mg kg(-1) bolus into the prime and a reduced infusion of 4 mg kg(-1) h(-1) after the start of CPB are required to maintain TXA concentrations continuously above 20 g ml(-1), the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the 10-10-4-4 rule'). ConclusionsThe introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 g ml(-1)."	"[Gertler, Ralph] Univ Med Ctr Hamburg Eppendorf, Klinikum Links Weser, Klin Anaesthesie Operat Allgemeine Intensivmed, Notfallmed, Bremen, Germany; [Gruber, Michael] Univ Hosp Regensburg, Dept Anesthesia, Regensburg, Germany; [Grassin-Delyle, Stanislas] Univ Paris Saclay, Univ Versailles St Quentin en Yvelines, Hop Foch, Dept Malad Voies Resp, F-92150 Suresnes, France; [Grassin-Delyle, Stanislas] Univ Paris Saclay, Univ Versailles St Quentin en Yvelines, UFR Sci Sante Simone Veil, Plateforme Spectrometrie Masse, F-78180 Montigny Le Bretonneux, France; [Grassin-Delyle, Stanislas] Univ Paris Saclay, Univ Versailles St Quentin en Yvelines, UFR Sci Sante Simone Veil, INSERM,UMR1173, F-78180 Montigny Le Bretonneux, France; [Urien, Saik] URC Paris Descartes Necker Cochin, AP HP, CIC1419 Inserm Necker Cochin, Paris, France; [Urien, Saik] Univ Paris 05, Sorbonne Paris Cite, EAU7323, Paris, France; [Gertler, Ralph; Martin, Klaus; Tassani-Prell, Peter; Burg, Simon; Wiesner, Gunther] Tech Univ Munich, Inst Anaesthesiol, German Heart Ctr Munich, Munich, Germany; [Braun, Siegmund] Tech Univ Munich, Inst Lab Med, German Heart Ctr Munich, Munich, Germany"	"Gertler, R (corresponding author), Univ Med Ctr Hamburg Eppendorf, Klinikum Links Weser, Klin Anaesthesie Operat Allgemeine Intensivmed, Notfallmed, Bremen, Germany."	"ralph.gertler@klinikum-bremen-ldw.de"	"Urien, Saik/G-3240-2013"	"Gertler, Ralph/0000-0002-0529-1607; Burg, Simon/0000-0003-2844-4378"	"Kommission fur klinische Forschung (KKF), Medizinische Fakultat der Technischen Universitat Munchen"	"We would like to gratefully acknowledge the work of the medical technicians at our hospital laboratory for separating the blood samples, and the University Hospital Regensburg for their expert analysis. Special thanks also to Magdalena Waldhier, Institute of Functional Genomics, University Regensburg, Germany, for providing background knowledge on chromatography-mass spectrometry. Financial support was provided from departmental sources and the Kommission fur klinische Forschung (KKF), Medizinische Fakultat der Technischen Universitat Munchen."	33	7	7	0	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"AUG"	2017	83	8	1745	1757	"NA"	"10.1111/bcp.13274"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FA6IA"	"WOS:000405545300015"	28245519	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Comets, E; Lavenu, A; Lavielle, M"	"Comets, Emmanuelle; Lavenu, Audrey; Lavielle, Marc"	"NA"	"M"	"Parameter Estimation in Nonlinear Mixed Effect Models Using saemix, an R Implementation of the SAEM Algorithm"	"JOURNAL OF STATISTICAL SOFTWARE"	"English"	"Article"	"nonlinear mixed effect models; stochastic approximation EM algorithm; pharmacokinetics; pharmacodynamics; theophylline; orange tree; S4 classes"	"MAXIMUM-LIKELIHOOD; INFORMATION MATRIX; OPTIMAL-DESIGN; APPROXIMATION; CONVERGENCE; TESTS"	"The saemix package for R provides maximum likelihood estimates of parameters in nonlinear mixed effect models, using a modern and efficient estimation algorithm, the stochastic approximation expectation maximisation (SAEM) algorithm. In the present paper we describe the main features of the package, and apply it to several examples to illustrate its use. Making use of S4 classes and methods to provide user-friendly interaction, this package provides a new estimation tool to the R community."	"[Comets, Emmanuelle; Lavenu, Audrey] U Rennes I, INSERM CIC 1414, Rennes, France; [Comets, Emmanuelle] U Paris Diderot, INSERM, IAME, UMR 1137, Paris, France; [Lavielle, Marc] U Paris Sud, INRIA Saclay, Popix, Paris, France"	"Comets, E (corresponding author), Fac Med, CIC 1414, Lab Pharmacol Expt & Clin, 2 Av Pr Leon Bernard, F-35000 Rennes, France."	"emmanuelle.comets@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"NA"	"NA"	44	15	15	1	10	"JOURNAL STATISTICAL SOFTWARE"	"LOS ANGELES"	"UCLA DEPT STATISTICS, 8130 MATH SCIENCES BLDG, BOX 951554, LOS ANGELES, CA 90095-1554 USA"	"1548-7660"	"NA"	"NA"	"J STAT SOFTW"	"J. Stat. Softw."	"AUG"	2017	80	3	1	41	"NA"	"NA"	41	"Computer Science, Interdisciplinary Applications; Statistics & Probability"	"Computer Science; Mathematics"	"FE7TR"	"WOS:000408410300001"	"NA"	"DOAJ Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Michel, F; Chasseloup, E; Paut, O; Guilhaumou, R; Blin, O"	"Marsot, Amelie; Michel, Fabrice; Chasseloup, Estelle; Paut, Olivier; Guilhaumou, Romain; Blin, Olivier"	"NA"	"A"	"Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic model"	"FUNDAMENTAL & CLINICAL PHARMACOLOGY"	"English"	"Article"	"external evaluation; pediatrics; phenobarbital; population pharmacokinetics"	"ANTIEPILEPTIC DRUGS; CHILDREN; EPILEPSY; INFANTS; SEIZURES; THERAPY; 3A4"	"An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: -8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring."	"[Marsot, Amelie; Chasseloup, Estelle; Guilhaumou, Romain; Blin, Olivier] Aix Marseille Univ, Serv Pharmacol Clin & Pharmacovigilance Pharmacol, Inst Neurosci Timone, AP HM,Hop Timone,CNRS 7289, Batiment F,264 Rue St Pierre, F-13385 Marseille, France; [Michel, Fabrice; Paut, Olivier] Hop La Timone, AP HM, Serv Reanimat Pediat, 264 Rue St pierre, F-13385 Marseille, France"	"Marsot, A (corresponding author), Aix Marseille Univ, Serv Pharmacol Clin & Pharmacovigilance Pharmacol, Inst Neurosci Timone, AP HM,Hop Timone,CNRS 7289, Batiment F,264 Rue St Pierre, F-13385 Marseille, France."	"amelie.marsot@ap-hm.fr"	"NA"	"NA"	"NA"	"NA"	41	6	6	0	10	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0767-3981"	"1472-8206"	"NA"	"FUND CLIN PHARMACOL"	"Fundam. Clin. Pharmacol."	"OCT"	2017	31	5	558	566	"NA"	"10.1111/fcp.12291"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FF6BH"	"WOS:000409087100008"	28407406	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Franken, LG; Mathot, RAA; Masman, AD; Baar, FPM; Tibboel, D; van Gelder, T; Koch, BCP; de Winter, BCM"	"Franken, L. G.; Mathot, R. A. A.; Masman, A. D.; Baar, F. P. M.; Tibboel, D.; van Gelder, T.; Koch, B. C. P.; de Winter, B. C. M."	"NA"	"A"	"Population pharmacokinetics of haloperidol in terminally ill adult patients"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Haloperidol; Pharmacokinetics; Delirium; Palliative care"	"SCHIZOPHRENIC-PATIENTS; CARE; BIOAVAILABILITY; KINETICS; CANCER; LIFE"	"Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates."	"[Franken, L. G.; van Gelder, T.; Koch, B. C. P.; de Winter, B. C. M.] Erasmus MC, Dept Hosp Pharm, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands; [Mathot, R. A. A.] Acad Med Ctr, Hosp Pharm Clin Pharmacol, Amsterdam, Netherlands; [Masman, A. D.; Baar, F. P. M.] Laurens Cadenza, Palliat Care Ctr, Rotterdam, Netherlands; [Masman, A. D.; Tibboel, D.] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Intens Care, Rotterdam, Netherlands; [Tibboel, D.] Erasmus MC Sophia Childrens Hosp, Pain Expertise Ctr, Rotterdam, Netherlands"	"Franken, LG (corresponding author), Erasmus MC, Dept Hosp Pharm, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands."	"l.franken@ersmusmc.nl"	"Franken, Linda/AAB-1901-2020"	"Franken, Linda/0000-0001-6436-9825; koch, birgit/0000-0002-1202-3643"	"NA"	"NA"	22	3	3	0	5	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"OCT"	2017	73	10	1271	1277	"NA"	"10.1007/s00228-017-2283-6"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FH0AA"	"WOS:000410800200008"	28681176	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Zhou, WD; Li, JG; Birmingham, B; Xu, HM; Lillieborg, S; Zhou, DS; Al-Huniti, N"	"Zhou, Wangda; Li, Jianguo; Birmingham, Bruce; Xu, Hongmei; Lillieborg, Stefan; Zhou, Diansong; Al-Huniti, Nidal"	"NA"	"A"	"Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"zolmitriptan; zolmitriptan nasal spray (ZNS); population pharmacokinetics; pediatrics; parent metabolite"	"NASAL SPRAY; DOUBLE-BLIND; PEDIATRIC MIGRAINEURS; CHILDHOOD MIGRAINE; DRUG DEVELOPMENT; TOLERABILITY; HEADACHE; EFFICACY; MODEL; RIZATRIPTAN"	"Zolmitriptan is a serotonin (5-HT) (1B/1D) receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5mg (50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials."	"[Zhou, Wangda; Li, Jianguo; Xu, Hongmei; Zhou, Diansong; Al-Huniti, Nidal] AstraZeneca, Quantitat Clin Pharmacol, Waltham, MA USA; [Birmingham, Bruce] AstraZeneca, Waltham, MA USA; [Lillieborg, Stefan] AstraZeneca, Global Med Dev, Gothenburg, Sweden"	"Zhou, DS (corresponding author), AstraZeneca Pharmaceut LP, 35 Gatehouse Dr, Waltham, MA 02451 USA."	"diansong.zhou@astrazeneca.com"	"NA"	"NA"	"NA"	"NA"	41	1	1	1	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"OCT"	2017	57	10	1258	1267	"NA"	"10.1002/jcph.935"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FG2CR"	"WOS:000409886500003"	28581633	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Nielsen, EI; Khan, DD; Cao, S; Lustig, U; Hughes, D; Andersson, DI; Friberg, LE"	"Nielsen, Elisabet I.; Khan, David D.; Cao, Sha; Lustig, Ulrika; Hughes, Diarmaid; Andersson, Dan I.; Friberg, Lena E."	"NA"	"A"	"Can a pharmacokinetic/pharmacodynamic (PKPD) model be predictive across bacterial densities and strains? External evaluation of a PKPD model describing longitudinal in vitro data"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"PHARMACOKINETIC-PHARMACODYNAMIC MODEL; PSEUDOMONAS-AERUGINOSA; ESCHERICHIA-COLI; TIME-KILL; PK/PD INDEXES; INOCULUM; SIMULATION; RESISTANCE; MEROPENEM; KINETICS"	"Background: Pharmacokinetic/pharmacodynamic (PKPD) models developed based on data from in vitro time-kill experiments have been suggested to contribute to more efficient drug development programmes and better dosing strategies for antibiotics. However, for satisfactory predictions such models would have to show good extrapolation properties. Objectives: To evaluate if a previously described mechanism-based PKPD model was able also to predict drug efficacy for higher bacterial densities and across bacterial strains. Methods: A PKPD model describing the efficacy of ciprofloxacin on Escherichia coli was evaluated. The predictive performance of the model was evaluated across several experimental conditions with respect to: (i) bacterial start inoculum ranging from the standard of similar to 10(6) cfu/mL up to late stationary-phase cultures; and (ii) efficacy for seven additional strains (three laboratory and four clinical strains), not included during the model development process, based only on information regarding their MIC. Model predictions were performed according to the intended experimental protocol and later compared with observed bacterial counts. Results: The mechanism-based PKPD model structure developed based on data from standard start inoculum experiments was able to accurately describe the inoculum effect. The model successfully predicted the time course of drug efficacy for additional laboratory and clinical strains based on only the MIC values. The model structure was further developed to better describe the stationary phase data. Conclusions: This study supports the use of mechanism-based PKPD models based on preclinical data for predictions of untested scenarios."	"[Nielsen, Elisabet I.; Khan, David D.; Friberg, Lena E.] Uppsala Univ, Dept Pharmaceut Biosci, Box 591, SE-75124 Uppsala, Sweden; [Cao, Sha; Lustig, Ulrika; Hughes, Diarmaid; Andersson, Dan I.] Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden"	"Nielsen, EI (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Box 591, SE-75124 Uppsala, Sweden."	"elisabet.nielsen@farmbio.uu.se"	"Hughes, Diarmaid/A-9487-2014; Nielsen, Elisabet/X-3368-2019"	"Hughes, Diarmaid/0000-0002-7456-9182; Friberg, Lena/0000-0002-2979-679X; Nielsen, Elisabet/0000-0003-0725-214X"	"Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research"	"This work was supported by grants from the Swedish Foundation for Strategic Research to D. H., D. I. A. and L. E. F."	39	6	6	0	9	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"NOV"	2017	72	11	3108	3116	"NA"	"10.1093/jac/dkx269"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"FK4KY"	"WOS:000413464200019"	28961946	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Nardotto, GHB; Lanchote, VL; Coelho, EB; Della Pasqua, O"	"Nardotto, Glauco H. B.; Lanchote, Vera L.; Coelho, Eduardo B.; Della Pasqua, Oscar"	"NA"	"A"	"Population pharmacokinetics of carvedilol enantiomers and their metabolites in healthy subjects and type-2 diabetes patients"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Carvedilol; Enantiomers; Population pharmacokinetics; Type 2 diabetes; Stereoselective metabolism"	"RANDOMIZED CONTROLLED-TRIAL; CHRONIC HEART-FAILURE; HUMAN-PLASMA; HUMAN LIVER; STEREOSELECTIVE DISPOSITION; INTESTINAL MICROSOMES; INSULIN SENSITIVITY; DRUG-INTERACTIONS; IN-VITRO; MELLITUS"	"Carvedilol, a drug available as a racemic mixture, is metabolised into hydroxyphenylcarvedilol (OHC) by CYP2D6 and O-desmethylcarvedilol (DMC) by CYP2C9 followed by conjugation to glucuronides. In contrast to other beta-adrenergic receptor antagonists, carvedilol does not induce insulin resistance or worsen glycaemic control in diabetic hypertensive patients. This study aims to investigate the implications of type 2 diabetes (T2DM) on the pharmacokinetics of carvedilol enantiomers using an integrated population pharmacokinetic modelling approach. In total, 14 T2DM patients with good glycaemic control receiving standard doses of metformin and glibenclamide were evaluated along with a control group of 13 healthy subjects. Serial blood samples were collected up to 24 h after administration of a single 25 mg dose of racemic carvedilol. A multi-compartmental population pharmacokinetic model describing the enantioselective disposition of the parent compound, OHC and DMC was developed in NONMEM v7.2. Even though data are limited, it appears that despite inhibition of CYP2C9 due to long-term glibenclamide administration to T2DM patients, overall no differences are observed in the total clearance of carvedilol when compared to healthy subjects (43.1 vs. 45.9 L/h for (S)-(-)-carvedilol and 29.0 vs. 33.1 L/h for (R)-()-carvedilol). These results provide evidence of a compensatory mechanism for the inhibition of CYP2C9, with higher contribution of CYP2D6 activity to the elimination of carvedilol. Consequently, no dose adjustment is recommended for carvedilol in T2DM patients receiving glibenclamide and metformin."	"[Nardotto, Glauco H. B.; Lanchote, Vera L.] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Sao Paulo, Brazil; [Coelho, Eduardo B.] Univ Sao Paulo, Fac Med Ribeirao Preto, Sao Paulo, Brazil; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Uxbridge, Middx, England; [Della Pasqua, Oscar] UCL, Sch Life & Med Sci, Clin Pharmacol & Therapeut Grp, London, England"	"Della Pasqua, O (corresponding author), UCL, Clin Pharmacol & Therapeut Grp, BMA House,Tavistock Sq, London WC1H 9JP, England."	"o.dellapasqua@ucl.ac.uk"	"Coelho, Eduardo B/G-3463-2012; Lanchote, Vera Lucia/P-5925-2016; Coelho, Eduardo Barbosa/M-8532-2019; Nardotto, Glauco Henrique Balthazar/AAC-8403-2020; Nardotto, Glauco Henrique Balthazar/E-1154-2016"	"Coelho, Eduardo B/0000-0003-3491-3396; Lanchote, Vera Lucia/0000-0002-0074-4953; Coelho, Eduardo Barbosa/0000-0003-3491-3396; Nardotto, Glauco Henrique Balthazar/0000-0001-7024-4252"	"National Council for Scientific and Technological Development (CNPq), BrazilNational Council for Scientific and Technological Development (CNPq) [141170/2011-5]"	"The authors are grateful to the National Council for Scientific and Technological Development (CNPq), Brazil, for the financial support provided for this investigation (grant number 141170/2011-5)."	69	3	3	1	12	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"NOV 15"	2017	109	"NA"	"S108"	"S115"	"NA"	"10.1016/j.ejps.2017.05.033"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FM7TI"	"WOS:000415283100018"	28522373	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Voller, S; Flint, RB; Stolk, LM; Degraeuwe, PLJ; Simons, SHP; Pokorna, P; Burger, DM; de Groot, R; Tibboel, D; Knibbe, CAJ"	"Voller, Swantje; Flint, Robert B.; Stolk, Leo M.; Degraeuwe, Pieter L. J.; Simons, Sinno H. P.; Pokorna, Paula; Burger, David M.; de Groot, Ronald; Tibboel, Dick; Knibbe, Catherijne A. J."	"DINO Study Grp"	"A"	"Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Neonates; Population pharmacokinetics; Phenobarbital; Dose"	"PHARMACOKINETICS; CHILDREN; SEIZURES; BIOAVAILABILITY; PREDICTION; PHENYTOIN; PRETERM; INFANTS; WEIGHT"	"Background: Particularly in the pediatric clinical pharmacology field, data-sharing offers the possibility of making the most of all available data. In this study, we utilize previously collected therapeutic drug monitoring (TDM) data of term and preterm newborns to develop a population pharmacokinetic model for phenobarbital. We externally validate the model using prospective phenobarbital data from an ongoing pharmacokinetic study in preterm neonates. Methods: TDM data from 53 neonates (gestational age (GA): 37 (24-42) weeks, bodyweight: 2.7 (0.45-4.5) kg; postnatal age (PNA): 4.5 (0 - 22) days) contained information on dosage histories, concentration and covariate data (including birth weight, actual weight, post-natal age (PNA), postmenstrual age, GA, sex, liver and kidney function, APGAR-score). Model development was carried out using NONMEM (R) 7.3. After assessment of model fit, the model was validated using data of 17 neonates included in the DINO (Drug dosage Improvement in NeOnates)-study. Results: Modelling of 229 plasma concentrations, ranging from 3.2 to 75.2 mg/L, resulted in a one compartment model for phenobarbital. Clearance (CL) and volume (V-d) for a child with a birthweight of 2.6 kg at PNA day 4.5 was 0.0091 L/h (9%) and 2.38 L (5%), respectively. Birthweight and PNA were the best predictors for CL maturation, increasing CL by 36.7% per kg birthweight and 5.3% per postnatal day of living, respectively. The best predictor for the increase in Vd was actual bodyweight (0.31 L/kg). External validation showed that the model can adequately predict the pharmacokinetics in a prospective study. Conclusion: Data-sharing can help to successfully develop and validate population pharmacokinetic models in neonates. From the results it seems that both PNA and bodyweight are required to guide dosing of phenobarbital in term and preterm neonates."	"[Voller, Swantje; Knibbe, Catherijne A. J.] Leiden Acad Ctr Drug Res, Div Pharmacol, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands; [Flint, Robert B.; Simons, Sinno H. P.] Erasmus MC Sophia Childrens Hosp, Div Neonatol, Dept Pediat, Rotterdam, Netherlands; [Flint, Robert B.; Burger, David M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands; [Flint, Robert B.] Erasmus MC, Dept Pharm, Rotterdam, Netherlands; [Stolk, Leo M.] Maastricht UMC, Dept Clin Pharm, Maastricht, Netherlands; [Pokorna, Paula] Charles Univ Prague, Fac Med 1, Gen Univ Hosp, Dept Pediat PICU NICU, Prague, Czech Republic; [Pokorna, Paula] Charles Univ Prague, Fac Med 1, Gen Univ Hosp, Dept Pharmacol, Prague, Czech Republic; [Pokorna, Paula; Tibboel, Dick] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Dept Pediat, Intens Care, Rotterdam, Netherlands; [de Groot, Ronald] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Pediat, Lab Pediat Infect Dis,Med Ctr, Nijmegen, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands; [Degraeuwe, Pieter L. J.] Maastricht UMC, Div Neonatol, Dept Pediat, Maastricht, Netherlands"	"Voller, S (corresponding author), Leiden Acad Ctr Drug Res, Div Pharmacol, Gorlaeus Labs, Einsteinweg 55, NL-2333 CC Leiden, Netherlands."	"s.voller@lacdr.leidenuniv.nl"	"Pokorna, Pavla/N-3785-2017; Degraeuwe, Pieter LJ/C-7853-2013; Flint, Robert B/A-1862-2016; simons, sinno/AAC-7442-2019; Burger, David/C-9929-2013"	"Pokorna, Pavla/0000-0001-6803-7350; Flint, Robert B/0000-0002-3658-594X; Simons, Sinno/0000-0001-5219-5696; Voller, Swantje/0000-0003-0587-2775; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Netherlands Organisation for Health Research and Development ZonMwNetherlands Organization for Health Research and Development [80-83600-98-10190]; General University Hospital RV-project [64-165/2012]; Intensive Care of the ErasmusMC-Sophia Childrens Hospital"	"The DINO study and all accompanying research were funded by the Netherlands Organisation for Health Research and Development ZonMw (Grant number: 80-83600-98-10190). All authors have no conflicts of interest to declare. Paula Pokorna is supported by the General University Hospital RV-project (64-165/2012) and an unrestricted research grant of the Intensive Care of the ErasmusMC-Sophia Childrens Hospital."	38	9	9	0	8	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"NOV 15"	2017	109	"NA"	"S90"	"S97"	"NA"	"10.1016/j.ejps.2017.05.026"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FM7TI"	"WOS:000415283100016"	28506869	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Pressiat, C; Mea-Assande, V; Yonaba, C; Treluyer, JM; Dahourou, DL; Amorissani-Folquet, M; Blanche, S; Eboua, F; Ye, D; Lui, G; Malateste, K; Zheng, Y; Leroy, V; Hirt, D"	"Pressiat, Claire; Mea-Assande, Veronique; Yonaba, Caroline; Treluyer, Jean-Marc; Dahourou, Desire-Lucien; Amorissani-Folquet, Madeleine; Blanche, Stephane; Eboua, Francois; Ye, Diarra; Lui, Gabrielle; Malateste, Karen; Zheng, Yi; Leroy, Valeriane; Hirt, Deborah"	"MONOD Study Grp"	"A"	"Suboptimal cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"children; HIV; pharmacokinetics; sulfamethoxazole; trimethoprim"	"PNEUMOCYSTIS-CARINII-PNEUMONIA; HUMAN-IMMUNODEFICIENCY-VIRUS; TRIMETHOPRIM-SULFAMETHOXAZOLE; GENETIC POLYMORPHISMS; ZAMBIAN CHILDREN; COTE-DIVOIRE; PHARMACOKINETICS; TRIAL; METABOLISM; PREVENTION"	"AimsA clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole [sulfamethoxazole (SMX) and trimethoprim (TMP)] advised by the WHO. MethodsChildren received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200mg of SMX/40mg of TMP once daily). A nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Factors that could impact the pharmacokinetic profile were investigated. The model was subsequently used to simulate individual exposure and evaluate different administration schemes. ResultsThe cohort comprised 136 children [average age: 1.9 years (range: [0.7-4]), average weight: 9.5kg (range: [6-16.3])]. A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetics. SMX and TPM clearance were estimated at 0.49lh(-1)/9.5kg and 3.06lh(-1)/9.5kg, respectively. The simulated exposures obtained after administration of oral dosing recommended by the WHO for children from 10 to 15kg were significantly lower than in adults for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30mgkg(-1) of SMX and 6mgkg(-1) of TMP in the 5-10kg group and 25mgkg(-1) of SMX and 5mgkg(-1) of TMP in the 10-15kg group are more suitable doses. ConclusionsIn this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed."	"[Pressiat, Claire; Treluyer, Jean-Marc; Blanche, Stephane; Lui, Gabrielle; Zheng, Yi; Hirt, Deborah] Paris Descartes Univ, EA 7323, Paris, France; [Mea-Assande, Veronique] MONOD Project, PACCI Programme, Site ANRS, Abidjan, Cote Ivoire; [Yonaba, Caroline] Ctr Hosp Univ Yalgado Ouedraogo, Dept Pediat, Ouagadougou, Burkina Faso; [Treluyer, Jean-Marc; Zheng, Yi; Hirt, Deborah] Paris Ctr Hosp Grp, AP HP, Clin Pharmacol Dept, Paris, France; [Dahourou, Desire-Lucien] Ctr Rech Int Sante, MONOD Project, ANRS 12206, Ouagadougou, Burkina Faso; [Dahourou, Desire-Lucien] Ctr Muraz, Bobo Dioulasso, Burkina Faso; [Dahourou, Desire-Lucien; Malateste, Karen] Univ Bordeaux, INSERM, Unite U1219, Bordeaux, France; [Amorissani-Folquet, Madeleine] Ctr Hospitalier Univ Cocody, Dept Pediat, Abidjan, Cote Ivoire; [Blanche, Stephane] Hop Necker Enfants Malad, AP HP, Immunol Hematol Pediat Unit, Paris, France; [Eboua, Francois] Ctr Hosp Univ Yopougon, Dept Pediat, Abidjan, Cote Ivoire; [Ye, Diarra] Univ Ouagadougou, Dept Paediat, CHU Charles de Gaulle, Ouagadougou, Burkina Faso; [Leroy, Valeriane] Univ Paul Sabatier Toulouse 3, INSERM, Unite U1027, Toulouse, France"	"Pressiat, C (corresponding author), Paris Descartes Univ, EA 7323, Paris, France."	"claire.pressiat@gmail.com"	"DAHOUROU, Desire Lucien/AAC-5059-2019; , Leroy/F-8129-2013; Leroy, Valeriane/AAO-5175-2020"	", Leroy/0000-0003-3542-8616; Leroy, Valeriane/0000-0003-3542-8616; Seguin-Devaux, Carole/0000-0003-0636-5222; , YI/0000-0002-1115-7121"	"NA"	"NA"	42	1	1	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2017	83	12	2729	2740	"NA"	"10.1111/bcp.13397"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FN5QW"	"WOS:000416063700016"	28800382	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Rodrigues, C; Chiron, C; Rey, E; Dulac, O; Comets, E; Pons, G; Jullien, V"	"Rodrigues, Christelle; Chiron, Catherine; Rey, Elisabeth; Dulac, Olivier; Comets, Emmanuelle; Pons, Gerard; Jullien, Vincent"	"NA"	"A"	"Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"childhood epilepsy; monohydroxy derivative; oxcarbazepine; population pharmacokinetics"	"MIXED-EFFECT MODELS; FILM-COATED TABLET; ANTIEPILEPTIC DRUGS; VALPROIC ACID; CLINICAL PHARMACOKINETICS; PEDIATRIC-PATIENTS; ACTIVE METABOLITE; CHINESE CHILDREN; HEALTHY-SUBJECTS; YOUNG-CHILDREN"	"AimsOxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (C-trough) of MHD (3-35mgl(-1)). MethodsA total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain C-trough between 3-35mgl(-1) was determined by Monte Carlo simulations for doses ranging from 10 to 90mgkg(-1)day(-1). ResultsA parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140lh(-1)70kg(-1), 337l70kg(-1), 60.7l and 62.5lh(-1), respectively. Typical values for MHD clearance and distribution volume were 4.11lh(-1)70kg(-1) and 54.8l70kg(-1) respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30mgkg(-1)day(-1) instead of the recommended target maintenance dose (30-45mgkg(-1)day(-1)) to obtain C-trough within the reference range. By contrast, 10-kg children with EIAEDs would need 90mgkg(-1)day(-1) instead of the maximum recommended dose of 60mgkg(-1)day(-1). ConclusionThis population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs."	"[Rodrigues, Christelle; Chiron, Catherine; Rey, Elisabeth; Dulac, Olivier; Pons, Gerard; Jullien, Vincent] INSERM, U1129, Paris, France; [Rodrigues, Christelle; Chiron, Catherine; Rey, Elisabeth; Dulac, Olivier; Pons, Gerard; Jullien, Vincent] Paris Descartes Univ, CEA, Gif Sur Yvette, France; [Comets, Emmanuelle] Univ Paris Diderot, Sorbonne Paris Cite, INSERM, IAME,UMR1137, F-UMR1137 Paris, France; [Comets, Emmanuelle] Univ Rennes 1, INSERM, CIC 1414, Rennes, France; [Jullien, Vincent] Hop Europeen Georges Pompidou, Serv Pharmacol, 20 Rue Leblanc, F-75015 Paris, France"	"Jullien, V (corresponding author), Hopital Europeen Georges Pompidou, 20 Rue Leblanc, F-75015 Paris, France."	"vincent.jullien@aphp.fr"	"Chiron, Catherine/E-8506-2016; Comets, Emmanuelle/C-9328-2017"	"Chiron, Catherine/0000-0002-9096-1694; Rodrigues, Christelle/0000-0001-6681-5542"	"CIBA-GEIGY"	"All authors have completed the United Competing Interest form at http://www.icmje.org/conflicts-of-interest/ and declare: C.R. reports personal fees from BIOCODEX, outside the submitted work; C.C. reports personal fees and nonfinancial support from BIOCODEX, personal fees from BRABANT, personal fees from UCB-PHARMA, personal fees from BIAL, personal fees from ZOGENIX, personal fees from VIROPHARMA, outside the submitted work; E.R., O.D., E.C. and G.P. had nothing to disclose; V.J. reports grants from BIOCODEX, personal fees from ZOGENIX, outside the submitted work. A grant from CIBA-GEIGY was obtained for the conductance of the initial PK study."	54	7	7	0	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2017	83	12	2695	2708	"NA"	"10.1111/bcp.13392"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FN5QW"	"WOS:000416063700013"	28771787	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Brown, RT; Nicholas, CR; Cozzi, NV; Gassman, MC; Cooper, KM; Muller, D; Thomas, CD; Hetzel, SJ; Henriquez, KM; Ribaudo, AS; Hutson, PR"	"Brown, Randall T.; Nicholas, Christopher R.; Cozzi, Nicholas V.; Gassman, Michele C.; Cooper, Karen M.; Muller, Daniel; Thomas, Chantelle D.; Hetzel, Scott J.; Henriquez, Kelsey M.; Ribaudo, Alexandra S.; Hutson, Paul R."	"NA"	"A"	"Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"LIFE-THREATENING CANCER; RECEPTOR; ANXIETY; 5-HT2A; MODEL; QUANTIFICATION; HALLUCINOGENS; DEPRESSION; PROFILES; TRIAL"	"Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose."	"[Brown, Randall T.; Nicholas, Christopher R.; Thomas, Chantelle D.] Univ Wisconsin Madison, Sch Med & Publ Hlth, Dept Family Med, Madison, WI USA; [Cozzi, Nicholas V.] Univ Wisconsin Madison, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Madison, WI USA; [Gassman, Michele C.; Cooper, Karen M.; Henriquez, Kelsey M.; Ribaudo, Alexandra S.; Hutson, Paul R.] Univ Wisconsin Madison, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA; [Muller, Daniel] Univ Wisconsin Madison, Sch Med & Publ Hlth, Dept Med, Madison, WI USA; [Hetzel, Scott J.] Univ Wisconsin Madison, Sch Med & Publ Hlth, Dept Biostatist & Med Informat, Madison, WI USA"	"Hutson, PR (corresponding author), Univ Wisconsin Madison, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA."	"paul.hutson@wisc.edu"	"Cozzi, Nicholas/AAT-1633-2020"	"NA"	"Psilocybin Research Fund at the University of Wisconsin-Madison Foundation; Usona Research Institute"	"This study was funded by gifts from the Psilocybin Research Fund at the University of Wisconsin-Madison Foundation, and by the Usona Research Institute."	37	16	17	4	38	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2017	56	12	1543	1554	"NA"	"10.1007/s40262-017-0540-6"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FN4JO"	"WOS:000415971900009"	28353056	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Hwang, MF; Beechinor, RJ; Wade, KC; Benjamin, DK; Smith, PB; Hornik, CP; Capparelli, EV; Duara, S; Kennedy, KA; Cohen-Wolkowiez, M; Gonzalez, D"	"Hwang, Michael F.; Beechinor, Ryan J.; Wade, Kelly C.; Benjamin, Daniel K., Jr.; Smith, P. Brian; Hornik, Christoph P.; Capparelli, Edmund V.; Duara, Shahnaz; Kennedy, Kathleen A.; Cohen-Wolkowiez, Michael; Gonzalez, Daniel"	"NA"	"A"	"External Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"external evaluation; fluconazole; infant; pediatrics; pharmacokinetics"	"BIRTH-WEIGHT INFANTS; NEONATAL CANDIDIASIS; PREMATURE-INFANTS; RISK-FACTORS"	"Fluconazole is an antifungal agent used for the treatment of invasive candidiasis, a leading cause of morbidity and mortality in premature infants. Population pharmacokinetic (PK) models of fluconazole in infants have been previously published by Wade et al. (Antimicrob Agents Chemother 52: 4043-4049, 2008, https:// doi. org/10.1128/AAC.00569-08) and Momper et al. (Antimicrob Agents Chemother 60: 5539 -5545, 2016, https://doi. org/10.1128/AAC. 00963-16). Here we report the results of the first external evaluation of the predictive performance of both models. We used patient-level data from both studies to externally evaluate both PK models. The predictive performance of each model was evaluated using the model prediction error (PE), mean prediction error (MPE), mean absolute prediction error (MAPE), predictioncorrected visual predictive check (pcVPC), and normalized prediction distribution errors (NPDE). The values of the parameters of each model were reestimated using both the external and merged data sets. When evaluated with the external data set, the model proposed by Wade et al. showed lower median PE, MPE, and MAPE (0.429 mu g/ml, 41.9%, and 57.6%, respectively) than the model proposed by Momper et al. (2.45 mu g/ml, 188%, and 195%, respectively). The values of the majority of reestimated parameters were within 20% of their respective original parameter values for all model evaluations. Our analysis determined that though both models are robust, the model proposed by Wade et al. had greater accuracy and precision than the model proposed by Momper et al., likely because it was derived from a patient population with a wider age range. This study highlights the importance of the external evaluation of infant population PK models."	"[Hwang, Michael F.; Beechinor, Ryan J.; Gonzalez, Daniel] Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA; [Wade, Kelly C.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA; [Benjamin, Daniel K., Jr.; Smith, P. Brian; Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA; [Benjamin, Daniel K., Jr.; Smith, P. Brian; Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA; [Capparelli, Edmund V.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA; [Capparelli, Edmund V.] Skaggs Sch Pharm, La Jolla, CA USA; [Duara, Shahnaz] Univ Miami, Miller Sch Med, Miami, FL 33136 USA; [Kennedy, Kathleen A.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA"	"Gonzalez, D (corresponding author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA."	"daniel.gonzalez@unc.edu"	"NA"	"Gonzalez, Daniel/0000-0001-5522-5686"	"QuintilesIMS pharmacometrics fellowship; National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [T32GM086330]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [2K24HD058735-06, 1R01-HD076676-01A1, NIH-1R21HD080606-01A1]; National Center for Advancing Translational Sciences award [UL1TR001117]; National Institute of Child Health and Human Development [NICHD]United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HHSN275201000003I]; National Institute of Allergy and Infectious Diseases [NIAID]United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [HHSN272201500006I]; National Center for Advancing Translational Sciences of the NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1TR001117]; NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [HHSN272201500006I, HHSN272201300017I]; NICHDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HHSN275201000003I, K23HD083465]; Biomedical Advanced Research and Development Authority (BARDA) [HHSO100201300009C]; U.S. Government for his work in pediatric and neonatal clinical pharmacology [HHSN267200700051C]; Food and Drug AdministrationUnited States Department of Health & Human Services [1R18-FD005292-01]"	"M.F.H. is funded by a QuintilesIMS pharmacometrics fellowship. R.J.B. is supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under award T32GM086330. D.K.B. receives support from NIH (award 2K24HD058735-06, National Center for Advancing Translational Sciences award UL1TR001117, National Institute of Child Health and Human Development [NICHD] contract HHSN275201000003I, and National Institute of Allergy and Infectious Diseases [NIAID] contract HHSN272201500006I). M.C-W. receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), NIAID (HHSN272201500006I and HHSN272201300017I), NICHD (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (BARDA; HHSO100201300009C), and other sponsors for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). C.P.H. receives salary support for research from the National Center for Advancing Translational Sciences of the NIH (UL1TR001117) and the U.S. Government for his work in pediatric and neonatal clinical pharmacology (government contract HHSN267200700051C; principal investigator, D.K. Benjamin, Jr., under the Best Pharmaceuticals for Children Act). P.B.S. receives salary support for research from the NIH (NIH-1R21HD080606-01A1) and the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), NICHD (HHSN275201000003I), and the Food and Drug Administration (1R18-FD005292-01). D.G. receives support for research from NICHD (K23HD083465), the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org), and industry (Cempra, Inc., and Jacobus Pharmaceutical Company, Inc.) for drug development in adults and children."	23	1	1	0	3	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"DEC"	2017	61	12	"NA"	"NA"	"e01352-17"	"10.1128/AAC.01352-17"	13	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"FO2CH"	"WOS:000416578900044"	28893774	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Zhi, LJ; Wang, L; Chen, XK; Zhai, XY; Wen, L; Dong, L; Jacqz-Aigrain, E; Shi, ZR; Zhao, W"	"Zhi, Li-Juan; Wang, Li; Chen, Xing-Kai; Zhai, Xiao-Ying; Wen, Li; Dong, Lei; Jacqz-Aigrain, Evelyne; Shi, Zhong-Ren; Zhao, Wei"	"NA"	"A"	"Population pharmacokinetics and dosing optimization of cefathiamidine in children with hematologic infection"	"DRUG DESIGN DEVELOPMENT AND THERAPY"	"English"	"Article"	"cefathiamidine; pharmacokinetics; dosing; children"	"PHARMACODYNAMICS; RESISTANCE; INFANTS; AMOXICILLIN; VANCOMYCIN; HOSPITALS; EVALUATE; DISEASE; IMPACT"	"Purpose: Cefathiamidine, a first-generation cephalosporin, has approval from the China Food and Drug Administration for the treatment of infections caused by susceptible bacteria in both adults and children. As pharmacokinetic data are limited in the pediatric population, we aimed to evaluate the population pharmacokinetics of cefathiamidine in children and to define the appropriate dose in order to optimize cefathiamidine treatment. Methods: Blood samples were collected from children treated with cefathiamidine, and concentrations were quantified by high-performance liquid chromatography and tandem mass spectrometry. Population pharmacokinetic analysis was conducted using NONMEM software. Results: Fifty-four children (age range: 2.0-11.8 years) were included. Sparse pharmacokinetic samples (n=20) were available for analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that bodyweight had a significant impact on cefathiamidine pharmacokinetics. Monte Carlo simulation demonstrated that the currently used dosing regimen of 100 mg/kg/day q12h was associated with a high risk of underdosing in pediatric patients. To reach the target 70% fT>MIC,a dose of 100 mg/kg/day cefathiamidine q6h is required for effective treatment against Haemophilus influenzae. Conclusion: A population pharmacokinetics model of cefathiamidine in children with hematologic disease was established. A dosing regimen of 100 mg/kg/day cefathiamidine q6h should be used in clinical practice against H. influenza infections."	"[Zhi, Li-Juan; Dong, Lei; Zhao, Wei] Childrens Hosp Hebei Prov, Dept Pharm, Shijiazhuang, Hebei, Peoples R China; [Zhi, Li-Juan; Wang, Li; Dong, Lei; Shi, Zhong-Ren; Zhao, Wei] Childrens Hosp Hebei Prov, Pediat Res Inst, Shijiazhuang 050000, Hebei, Peoples R China; [Wang, Li; Zhai, Xiao-Ying; Wen, Li] Childrens Hosp Hebei Prov, Dept Pediat Hematol Oncol, Shijiazhuang, Hebei, Peoples R China; [Chen, Xing-Kai; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr, CIC 1426, Paris, France"	"Shi, ZR; Zhao, W (corresponding author), Childrens Hosp Hebei Prov, Pediat Res Inst, Shijiazhuang 050000, Hebei, Peoples R China."	"hbseryyeys@163.com; zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"Science and Technology Planning Project of Hebei Province [15277705D]; Health and Family Planning Commission of Hebei Province [20150100]; Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security) [CG2016030001]; Hundred-Talent Program (People's Government of Hebei Province) [E2015100010]"	"This study was supported by the Science and Technology Planning Project of Hebei Province (grant no 15277705D); Health and Family Planning Commission of Hebei Province (grant no 20150100); Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (grant no CG2016030001; Ministry of Human Resources and Social Security); and the Hundred-Talent Program (grant no E2015100010; The People's Government of Hebei Province)."	28	0	1	0	1	"DOVE MEDICAL PRESS LTD"	"ALBANY"	"PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND"	"1177-8881"	"NA"	"NA"	"DRUG DES DEV THER"	"Drug Des. Dev. Ther."	"NA"	2018	12	"NA"	855	862	"NA"	"10.2147/DDDT.S160329"	8	"Chemistry, Medicinal; Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GD2JY"	"WOS:000430327100001"	29713143	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Mao, JJ; Jiao, Z; Yun, HY; Zhao, CY; Chen, HC; Qiu, XY; Zhong, MK"	"Mao, Jun-Jun; Jiao, Zheng; Yun, Hwi-Yeol; Zhao, Chen-Yan; Chen, Han-Chao; Qiu, Xiao-Yan; Zhong, Ming-Kang"	"NA"	"A"	"External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"ciclosporin; external evaluation; nonlinear kinetics; population pharmacokinetics"	"BAYESIAN-ESTIMATION; ORAL CYCLOSPORINE; MICROEMULSION; METABOLISM; ABSORPTION; PLASMA; PHARMACOLOGY; DISPOSITION; VARIABILITY; PERFORMANCE"	"AimsSeveral population pharmacokinetic (popPK) models for ciclosporin (CsA) in adult renal transplant recipients have been constructed to optimize the therapeutic regimen of CsA. However, little is known about their predictabilities when extrapolated to different clinical centres. Therefore, this study aimed to externally evaluate the predictive ability of CsA popPK models and determine the potential influencing factors. MethodsA literature search was conducted and the predictive performance was determined for each selected model using an independent data set of 62 patients (471 predose and 500 2-h postdose concentrations) from our hospital. Prediction-based diagnostics and simulation-based normalized prediction distribution error were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Additionally, potential factors influencing model predictability were investigated. ResultsSeventeen models extracted from 17 published popPK studies were assessed. Prediction-based diagnostics showed that ethnicity potentially influenced model transferability. Simulation-based normalized prediction distribution error analyses indicated misspecification in most of the models, especially regarding variance. Bayesian forecasting demonstrated that the predictive performance of the models substantially improved with 2-3 prior observations. The predictability of nonlinear Michaelis-Menten models was superior to that of linear compartmental models when evaluating the impact of structural models, indicating the underlying nonlinear kinetics of CsA. Structural model, ethnicity, covariates and prior observations potentially affected model predictability. ConclusionsStructural model is the predominant factor influencing model predictability. Incorporation of nonlinear kinetics in CsA popPK modelling should be considered. Moreover, Bayesian forecasting substantially improved model predictability."	"[Mao, Jun-Jun; Jiao, Zheng; Zhao, Chen-Yan; Chen, Han-Chao; Qiu, Xiao-Yan; Zhong, Ming-Kang] Fudan Univ, Huashan Hosp, Dept Pharm, Shanghai, Peoples R China; [Yun, Hwi-Yeol] Chungnam Natl Univ, Coll Pharm, Daejeon, South Korea"	"Jiao, Z (corresponding author), Fudan Univ, Huashan Hosp, Dept Pharm, Clin Pharm, 12 Middle Urumqi Rd, Shanghai 200040, Peoples R China."	"zjiao@fudan.edu.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162; Yun, Hwi-yeol/0000-0001-8793-2449"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81573505, 81 072 702, 81302854]; Shanghai Municipal Commission of Health and Family Planning [2016ZB0301-01]"	"All authors have completed the United Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on the request from the corresponding author). Z.J. was supported by grants from the National Natural Science Foundation of China (No. 81573505 and 81 072 702), the 2016 Key Clinical Program of Clinical Pharmacy, and Weak Discipline Construction Project (No. 2016ZB0301-01) of Shanghai Municipal Commission of Health and Family Planning. X.-Y.Q. received support from the National Natural Science Foundation of China (No. 81302854), which promoted this study. There are no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. The other authors have no conflicts of interest to declare."	64	9	10	1	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JAN"	2018	84	1	153	171	"NA"	"10.1111/bcp.13431"	19	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FQ5HV"	"WOS:000418390400014"	28891596	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Cerou, M; Lavielle, M; Brendel, K; Chenel, M; Comets, E"	"Cerou, M.; Lavielle, M.; Brendel, K.; Chenel, M.; Comets, E."	"NA"	"M"	"Development and performance of npde for the evaluation of time-to-event models"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"model evaluation; npde; PSA; time-to-event"	"MIXED-EFFECT MODELS; PROSTATE-CANCER; SURVIVAL; RESIDUALS; KINETICS; METRICS; MEN"	"Purpose Normalised prediction distribution errors (npde) are used to graphically and statistically evaluate mixed-effect models for continuous responses. In this study, our aim was to extend npde to time-to-event (TTE) models and evaluate their performance. Methods Let V denote a dataset with censored TTE observations. The null hypothesis (H-0) is that observations in V can be described by model M. We extended npde to TTE models using imputations to take into account censoring. We then evaluated their performance in terms of type I error and power to detect model misspecifications for TTE data by means of a simulation study with different sample sizes. Results Type I error was found to be close to the expected 5% significance level for all sample sizes tested. The npde were able to detect misspecifications in the baseline hazard as well as in the link between the longitudinal variable and the survival function. The ability to detect model misspecifications increased as the difference in the shape of the survival function became more apparent. As expected, the power also increased as the sample size increased. Imputing the censored events tended to decrease the percentage of rejections. Conclusions We have shown that npde can be readily extended to TTE data and that they perform well with an adequate type I error."	"[Cerou, M.; Comets, E.] INSERM, CIC 1414, F-35700 Rennes, France; [Cerou, M.; Comets, E.] Univ Rennes 1, F-35700 Rennes, France; [Cerou, M.; Comets, E.] INSERM, IAME, UMR 1137, F-75018 Paris, France; [Cerou, M.; Comets, E.] Univ Paris Diderot, Sorbonne Paris Cite, IAME, UMR 1137, F-75018 Paris, France; [Cerou, M.; Brendel, K.; Chenel, M.] Inst Rech Int Servier, Div Clin Pharmacokinet & Pharmacometr, Suresnes, France; [Lavielle, M.] Ecole Polytech, Inria Saclay, Palaiseau, France; [Lavielle, M.] Ecole Polytech, CMAP, Palaiseau, France"	"Cerou, M (corresponding author), INSERM, CIC 1414, F-35700 Rennes, France.; Cerou, M (corresponding author), Univ Rennes 1, F-35700 Rennes, France.; Cerou, M (corresponding author), INSERM, IAME, UMR 1137, F-75018 Paris, France.; Cerou, M (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite, IAME, UMR 1137, F-75018 Paris, France."	"marc.cerou@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"Cerou, Marc/0000-0001-6792-2526"	"Institut de Recherches Internationales ServierServier"	"Marc Cerou received funding from Institut de Recherches Internationales Servier. The authors thank Herve Le Nagard and Francois Cohen for the use of the computer cluster services hosted on the Centre de Biomodelisation UMR1137 and Solene Desmee for her help with setting up the simulation study."	39	1	1	0	2	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"FEB"	2018	35	2	"NA"	"NA"	30	"10.1007/s11095-017-2291-3"	15	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"FV1JP"	"WOS:000424317700005"	29368033	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Santacana, E; Rodriguez-Alonso, L; Padulles, A; Guardiola, J; Rodriguez-Moranta, F; Serra, K; Bas, J; Morandeira, F; Colom, H; Padulles, N"	"Santacana, Eugenia; Rodriguez-Alonso, Lorena; Padulles, Ariadna; Guardiola, Jordi; Rodriguez-Moranta, Francisco; Serra, Katja; Bas, Jordi; Morandeira, Francisco; Colom, Helena; Padulles, Nuria"	"NA"	"A"	"External Evaluation of Population Pharmacokinetic Models of Infliximab in Patients With Inflammatory Bowel Disease"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"infliximab; population pharmacokinetics; inflammatory bowel disease; dose individualization"	"SCHEDULED MAINTENANCE TREATMENT; ANTI-TNF TREATMENTS; CROHNS-DISEASE; SERUM INFLIXIMAB; TROUGH LEVELS; ANTIBODIES; METAANALYSIS; CHILDREN; THERAPY; METRICS"	"Background: Infliximab (IFX) trough levels vary markedly between patients with inflammatory bowel disease (IBD), which is important for clinical response. The aim of this study was to evaluate the performance of previously developed population pharmacokinetic models in patients with IBD for dose individualization for Crohn disease (CD) and ulcerative colitis in our clinical setting. Methods: The authors collected 370 trough levels prospectively from 100 adult patients with IBD who were undergoing IFX treatment between July 2013 and August 2016. The external evaluation included prediction-and simulation-based diagnostics [prediction-corrected visual predictive check, prediction-and variability-corrected visual predictive check, and normalized prediction distribution error tests]. Results: In prediction-based diagnostics, the authors observed a nonsignificant overall mean relative bias of -6.87% and an acceptable imprecision of 8.45%. Approximately 100% of the prediction error was within � 30%, indicating satisfactory predictability. Simulation-based diagnostics indicated model misspecification; thus, the model may not be appropriate for simulation-based applications. Conclusions: While simulation-based diagnostics provided unsatisfactory results, the prediction-based diagnostics demonstrate that the population pharmacokinetic model developed by Fasanmade et al for CD can be used to predict and design individualized IFX dose regimens that meet the individual needs of patients with CD and ulcerative colitis."	"[Santacana, Eugenia; Padulles, Ariadna; Padulles, Nuria] Hosp Univ Bellvitge Idibell, Hosp Llobregat, Dept Pharm, Feixa Llarga S-N, Barcelona 08907, Spain; [Rodriguez-Alonso, Lorena; Guardiola, Jordi; Rodriguez-Moranta, Francisco; Serra, Katja] Hosp Univ Bellvitge Idibell, Hosp Llobregat, Dept Gastroenterol, Barcelona, Spain; [Bas, Jordi; Morandeira, Francisco] Hosp Univ Bellvitge Idibell, Hosp Llobregat, Dept Immunol, Barcelona, Spain; [Colom, Helena] Univ Barcelona, Sch Pharm, Dept Pharm & Pharmaceut Technol, Barcelona, Spain"	"Padulles, N (corresponding author), Hosp Univ Bellvitge Idibell, Hosp Llobregat, Dept Pharm, Feixa Llarga S-N, Barcelona 08907, Spain."	"npadulles@bellvitgehospital.cat"	"Rodriguez-Moranta, Francisco/AAB-8082-2019; BAS, JORDI/P-6689-2019; Padulles Zamora, Ariadna/E-8806-2019"	"Rodriguez-Moranta, Francisco/0000-0003-4025-5510; BAS, JORDI/0000-0002-4478-421X; Rodriguez Alonso, Lorena/0000-0003-0498-4804; Padulles Zamora, Ariadna/0000-0003-1541-6001; Guardiola, Jordi/0000-0002-0464-241X"	"COFB (Col.legi Oficial de Farmaceutics de Barcelona); Agaur (Agencia de Gestio d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya) [2014 SGR 1650]; MSD; General Electrics; Kern Pharma"	"Supported in part by Grants from COFB 2013 (Col.legi Oficial de Farmaceutics de Barcelona) and from Agaur (2014 SGR 1650) (Agencia de Gestio d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya).; J. Guardiola has served as a speaker for Abbvie, Takeda, MSD, General Electrics, Kern Pharma, and Pfizer and has received Investigator Research Grants from MSD, General Electrics, and Kern Pharma. F. Rodriguez-Moranta has served as a speaker for Abbvie, Takeda, and MSD. The remaining authors declare no conflict of interest."	36	4	4	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"FEB"	2018	40	1	120	129	"NA"	"NA"	10	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"GB5JC"	"WOS:000429099400014"	29200097	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Brussee, JM; Vet, NJ; Krekels, EHJ; Valkenburg, AJ; Jacqz-Aigrain, E; van Gerven, JMA; Swart, EL; van den Anker, JN; Tibboel, D; de Hoog, M; de Wildt, SN; Knibbe, CAJ"	"Brussee, Janneke M.; Vet, Nienke J.; Krekels, Elke H. J.; Valkenburg, Abraham J.; Jacqz-Aigrain, Evelyne; van Gerven, Joop M. A.; Swart, Eleonora L.; van den Anker, Johannes N.; Tibboel, Dick; de Hoog, Matthijs; de Wildt, Saskia N.; Knibbe, Catherijne A. J."	"NA"	"A"	"Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"children; cytochrome P450; drug metabolism"	"PEDIATRIC INTENSIVE-CARE; POPULATION PHARMACOKINETICS; CONTROLLED-TRIAL; DRUG-METABOLISM; IN-VITRO; PHARMACODYNAMICS; SEDATION; CLEARANCE; SURGERY; MODELS"	"AimsInflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. MethodsThe model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90kg, C-reactive protein level 0.1-341mg l(-1) and 0-4 failing organs) using graphical and numerical diagnostics. ResultsThe pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). ConclusionThe recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates."	"[Brussee, Janneke M.; Krekels, Elke H. J.; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Vet, Nienke J.; Tibboel, Dick; de Hoog, Matthijs] Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat, Rotterdam, Netherlands; [Valkenburg, Abraham J.; van den Anker, Johannes N.; de Wildt, Saskia N.] Sophia Childrens Univ Hosp, Erasmus MC, Intens Care, Rotterdam, Netherlands; [Valkenburg, Abraham J.; van den Anker, Johannes N.; de Wildt, Saskia N.] Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat Surg, Rotterdam, Netherlands; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [van Gerven, Joop M. A.] Ctr Human Drug Res, Leiden, Netherlands; [Swart, Eleonora L.] Vrije Univ Amsterdam, Med Ctr, Dept Clin Pharmacol & Pharm, Amsterdam, Netherlands; [van den Anker, Johannes N.] Univ Basel, Childrens Hosp, Div Paediat Pharmacol & Pharmacometr, Basel, Switzerland; [van den Anker, Johannes N.] Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA; [de Wildt, Saskia N.] Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, Nijmegen, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, Gorlaeus Labs, Div Syst Biomed & Pharmacol, Leiden Acad Ctr Drug Res, POB 9502, NL-2300 RA Leiden, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647; Brussee, Janneke/0000-0002-0813-4463; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NWO/Vidi grantNetherlands Organization for Scientific Research (NWO); Netherlands Organization for Health Research and Development, ZonMw Priority Medicines for Children [113 202 002, 92 003 549]; Erasmus MC Cost-Effectiveness Research"	"This study was supported by a NWO/Vidi grant to Catherijne A. J. Knibbe (2013), and project grants from the Netherlands Organization for Health Research and Development, ZonMw Priority Medicines for Children (grant numbers 113 202 002 and 92 003 549), and Erasmus MC Cost-Effectiveness Research."	49	11	11	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"FEB"	2018	84	2	358	368	"NA"	"10.1111/bcp.13459"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FX4IE"	"WOS:000426035900014"	29072785	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Michelet, R; Dossche, L; Van Herzeele, C; Van Bocxlaer, J; Vermeulen, A; Vande Walle, J"	"Michelet, Robin; Dossche, Lien; Van Herzeele, Charlotte; Van Bocxlaer, Jan; Vermeulen, An; Vande Walle, Johan"	"Safe-Pedrug consortium"	"M"	"Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population PKPD analysis"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Bioequivalence; 1-Deamino-8-D-arginine vasopressin (dDAVP); Children; Tablet; Lyophilisate; PKPD modeling"	"ORAL DESMOPRESSIN; PHARMACOKINETICS; TABLET; FORMULATION; MODELS; VASOPRESSIN; FOOD"	"For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, children are not small adults, and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication. Population pharmacokinetic and pharmacodynamic modeling was used to analyze previously published desmopressin data of 18 children suffering from nocturnal enuresis. The main objective was the comparison of the therapeutic equivalence of two desmopressin formulations: tablet and lyophilisate. The measurements for pharmacokinetics and pharmacodynamics were respectively plasma desmopressin concentration and urine osmolality and diuresis. The half maximal inhibitory concentration for inhibition of urine production was 0.7 pg/mL lower for the lyophilisate than for the tablet. The effect of formulation on the half maximal inhibitory concentration seems to suggest that the 120-mu g lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-mu g tablet, even when the same exposure is achieved. A new indirect response model for desmopressin was constructed and validated, using a previously built pharmacokinetic model and additional pharmacodynamic data. In order to draw solid conclusions regarding the efficacy and safety of desmopressin in children, pharmacokinetics and pharmacodynamics data should be analyzed together. This study adds proof to potential differences in pediatric and adult pharmacokinetic and pharmacodynamic properties of desmopressin and exemplifies the need for pediatric clinical trials, not only for every new drug but also for every new formulation."	"[Michelet, Robin; Van Bocxlaer, Jan; Vermeulen, An] Univ Ghent, Fac Pharmaceut Sci, Dept Bioanal, Lab Med Biochem & Clin Anal, Ottergemsesteenweg 460, B-9000 Ghent, Belgium; [Dossche, Lien; Van Herzeele, Charlotte; Vande Walle, Johan] Ghent Univ Hosp, Dept Pediat Nephrol, De Pintelaan 185, B-9000 Ghent, Belgium"	"Michelet, R (corresponding author), Univ Ghent, Fac Pharmaceut Sci, Dept Bioanal, Lab Med Biochem & Clin Anal, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.; Dossche, L (corresponding author), Ghent Univ Hosp, Dept Pediat Nephrol, De Pintelaan 185, B-9000 Ghent, Belgium."	"robin.michelet@ugent.be; lien.dossche@ugent.be"	"Michelet, Robin/AAM-7991-2020; Walle, Johan Vande/AAG-3858-2020"	"Michelet, Robin/0000-0002-5485-607X;"	"Agency for Innovation by Science and Technology in Flanders (IWT)Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT) [IWT-SBO 130033]"	"This study was funded by the Agency for Innovation by Science and Technology in Flanders (IWT) through the SAFE-PEDRUG project (IWT-SBO 130033)."	32	5	5	0	5	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"MAR"	2018	74	3	297	305	"NA"	"10.1007/s00228-017-2386-0"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FV6RC"	"WOS:000424708300005"	29198064	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Cazaubon, Y; Mauprivez, C; Feliu, C; Binet, L; Oget, O; Gozalo, C; Djerada, Z"	"Cazaubon, Yoann; Mauprivez, Cedric; Feliu, Catherine; Binet, Laurent; Oget, Olivier; Gozalo, Claire; Djerada, Zoubir"	"NA"	"A"	"Population pharmacokinetics of articaine with 1:200,000 epinephrine during third molar surgery and simulation of high-dose regimens"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Articaine; Pharmacokinetics; Local anesthetic; Third molar; Submucosal infiltration"	"DIFFERENT LOCAL-ANESTHETICS; NEUROBLASTOMA-CELL LINE; 4-PERCENT ARTICAINE; INFERIOR ALVEOLAR; DRUG ARTICAINE; NERVE; LIDOCAINE; PLASMA; PARESTHESIA; IMPAIRMENT"	"Background and objectives: Articaine is more and more used in third molar surgery under local anesthesia (LA). The objectives of this analysis were to characterize the pharmacokinetics of articaine for this type of surgery and to simulate dosing regimens. Methods: Non-linear mixed-effects modeling conducted in Monolix 4.4.0 was used to describe articaine plasma concentration-time data from 20 patients. Monte Carlo simulations were then performed to evaluate the probability of cardiotoxic target attainment (PCTA) of various dosage regimens. Results: Articaine concentration data were best described by a linear one-compartment model, with an additional depot compartment for submucosal route with a zero-order transfer to central compartment. Age and gender were found to influence duration transfer (Tk0) and elimination rate constant (Ke), respectively. Simulated maximum recommended dose regimen (7 mg/kg) had a PCTA of 0%. Simulated higher doses of 10 mg/kg and 15 mg/kg had a PCTA of 0% and about 1-4%, respectively. Conclusions: The model adequately described the articaine pharmacokinetics. This is the first PK model qualified for articaine administered by submucosal route. The simulations suggest that maximum recommended dose regimen is safe concerning the cardiotoxicity in healthy patients."	"[Cazaubon, Yoann; Feliu, Catherine; Binet, Laurent; Oget, Olivier; Gozalo, Claire; Djerada, Zoubir] Reims Univ Hosp, Pharmacol & Toxicol Lab, Dept Pharmacol & Toxicol, 45 Rue Cognacq Jay, F-51092 Reims, France; [Cazaubon, Yoann; Feliu, Catherine; Djerada, Zoubir] URCA Reims Univ, SFR CAP Sante, EA3801, Dept Pharmacol, F-51100 Reims, France; [Mauprivez, Cedric] Reims Univ Hosp, Dept Odontol, 45 Rue Cognacq Jay, F-51092 Reims, France; [Mauprivez, Cedric] URCA Reims Univ, Biomat & Inflammat Site Osseux, EA4691, 51 Rue Cognacq Jay, F-51092 Reims, France"	"Djerada, Z (corresponding author), Reims Univ Hosp, SFR CAP Sante, EA 3801, Dept Pharmacol, 45 Rue Cognacq Jay, F-51092 Reims, France."	"zoubir.djerada@univ-reims.fr"	"Cazaubon, Yoann/J-5628-2019"	"Cazaubon, Yoann/0000-0003-1032-0879; Feliu, Catherine/0000-0002-3928-8908; djerada, zoubir/0000-0002-4022-7889"	"NA"	"NA"	52	5	5	1	5	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"MAR 1"	2018	114	"NA"	38	45	"NA"	"10.1016/j.ejps.2017.11.027"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FW0IN"	"WOS:000424977500005"	29197630	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Shi, ZR; Chen, XK; Tian, LY; Wang, YK; Zhang, GY; Dong, L; Jirasomprasert, T; Jacqz-Aigrain, E; Zhao, W"	"Shi, Zhong-Ren; Chen, Xing-Kai; Tian, Li-Yuan; Wang, Ya-Kun; Zhang, Gu-Ying; Dong, Lei; Jirasomprasert, Totsapol; Jacqz-Aigrain, Evelyne; Zhao, Wei"	"NA"	"A"	"Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"ceftazidime; pharmacokinetics; dosing; infants"	"ANTIBACTERIAL AGENTS; ANTIMICROBIAL AGENTS; CHILDREN; PHARMACODYNAMICS; HEMODIALYSIS; METAANALYSIS; VANCOMYCIN; RESISTANCE; INFUSION; EFFICACY"	"Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software (version 7.2.0). Fifty-one infants (age range, 0.1 to 2.0 years) were included. Sparse pharmacokinetic samples (n = 90) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CLCR) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg/kg twice daily was associated with a high risk of under-dosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT(>MIC)), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation."	"[Shi, Zhong-Ren; Dong, Lei; Zhao, Wei] Childrens Hosp Hebei Prov, Pediat Res Inst, Shijiazhuang, Hebei, Peoples R China; [Chen, Xing-Kai; Jirasomprasert, Totsapol; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Tian, Li-Yuan; Wang, Ya-Kun] Childrens Hosp Hebei Prov, Dept Resp Care, Shijiazhuang, Hebei, Peoples R China; [Zhang, Gu-Ying; Dong, Lei] Childrens Hosp Hebei Prov, Dept Pharm, Shijiazhuang, Hebei, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC1426, Paris, France"	"Zhao, W (corresponding author), Childrens Hosp Hebei Prov, Pediat Res Inst, Shijiazhuang, Hebei, Peoples R China.; Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China."	"zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"Science and Technology Planning Project of Hebei Province [15277705D]; Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security) [CG2016030001]; Hundred-Talent Program (The People's Government of Hebei Province) [E2015100010]"	"This study was supported by the Science and Technology Planning Project of Hebei Province (grant agreement number 15277705D), the Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security; grant agreement number CG2016030001), and the Hundred-Talent Program (The People's Government of Hebei Province; grant agreement number E2015100010)."	34	4	4	1	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2018	62	4	"NA"	"NA"	"e02486-17"	"10.1128/AAC.02486-17"	8	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"GA5RU"	"WOS:000428392100083"	29378703	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Chevillard, L; Sabo, N; Tod, M; Labat, L; Chasport, C; Chevaleyre, C; Thibaut, F; Barre, J; Azuar, J; Questel, F; Vorspan, F; Bloch, V; Bellivier, F; Granger, B; Barrault, C; Decleves, X"	"Chevillard, Lucie; Sabo, Naomi; Tod, Michel; Labat, Laurence; Chasport, Celine; Chevaleyre, Celine; Thibaut, Florence; Barre, Jerome; Azuar, Julien; Questel, Franck; Vorspan, Florence; Bloch, Vanessa; Bellivier, Frank; Granger, Bernard; Barrault, Camille; Decleves, Xavier"	"NA"	"A"	"Population pharmacokinetics of oral baclofen at steady-state in alcoholic-dependent adult patients"	"FUNDAMENTAL & CLINICAL PHARMACOLOGY"	"English"	"Article"	"alcohol dependence; baclofen; inter-individual variability; population pharmacokinetics"	"MIXED-EFFECT MODELS; PEDIATRIC-PATIENTS; TOLERABILITY; PREDICTION; DISEASE"	"Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m(2), respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h(-1), respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data."	"[Chevillard, Lucie; Labat, Laurence; Questel, Franck; Vorspan, Florence; Bloch, Vanessa; Bellivier, Frank; Decleves, Xavier] Univ Paris Descartes Paris Diderot, INSERM, UMR S 1144, Variabilite Reponse Psychotropes, F-75006 Paris, France; [Sabo, Naomi; Labat, Laurence; Chasport, Celine; Chevaleyre, Celine; Decleves, Xavier] Hop Cochin, AP HP, Biol Medicament & Toxicol, F-75014 Paris, France; [Tod, Michel] Univ Lyon 1, EMR 3738, Ciblage Therapeut Oncol, Fac Med & Maieut Lyon Sud, F-69600 Oullins, France; [Tod, Michel] Hosp Civils Lyon, Hop Croix Rousse, Pharm, F-69000 Lyon, France; [Thibaut, Florence; Azuar, Julien; Questel, Franck; Vorspan, Florence; Bellivier, Frank] Hop Lariboisiere, AP HP, Serv Psychiat & Med Addictol, F-75010 Paris, France; [Barre, Jerome; Barrault, Camille] Ctr Hosp Intercommunal Creteil, Serv Ctr Ressources Biol, F-94000 Creteil, France; [Granger, Bernard] Hop Tarnier, AP HP, Serv Psychiat, F-75014 Paris, France; [Barrault, Camille] Ctr Hosp Intercommunal Creteil, Serv Addictol & Hepatogastroenterol, F-94000 Creteil, France"	"Decleves, X (corresponding author), Univ Paris Descartes Paris Diderot, INSERM, UMR S 1144, Variabilite Reponse Psychotropes, F-75006 Paris, France.; Decleves, X (corresponding author), Hop Cochin, AP HP, Biol Medicament & Toxicol, F-75014 Paris, France."	"xavier.decleves@aphp.fr"	"DECLEVES, Xavier/S-6978-2016; Bloch, Vanessa VB/L-9407-2017; Chevillard, Lucie M/S-5942-2016"	"DECLEVES, Xavier/0000-0002-9526-2294; Chevillard, Lucie M/0000-0003-2910-9117; Bloch, Vanessa/0000-0002-2582-6349"	"NA"	"NA"	22	7	7	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0767-3981"	"1472-8206"	"NA"	"FUND CLIN PHARMACOL"	"Fundam. Clin. Pharmacol."	"APR"	2018	32	2	239	248	"NA"	"10.1111/fcp.12330"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GA9EH"	"WOS:000428643600016"	29091319	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Andrews, LM; Hesselink, DA; van Gelder, T; Koch, BCP; Cornelissen, EAM; Bruggemann, RJM; van Schaik, RHN; de Wildt, SN; Cransberg, K; de Winter, BCM"	"Andrews, Louise M.; Hesselink, Dennis A.; van Gelder, Teun; Koch, Birgit C. P.; Cornelissen, Elisabeth A. M.; Bruggemann, Roger J. M.; van Schaik, Ron H. N.; de Wildt, Saskia N.; Cransberg, Karlien; de Winter, Brenda C. M."	"NA"	"A"	"A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"SOLID-ORGAN TRANSPLANTATION; CYP3A5 GENOTYPE; KIDNEY-TRANSPLANTATION; LIVER-TRANSPLANTATION; CLINICAL PHARMACOKINETICS; IMMUNOSUPPRESSIVE DRUGS; STEROID WITHDRAWAL; DOSAGE PREDICTION; UNITED-STATES; TROUGH LEVELS"	"Background Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. Objectives The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis. Methods A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM (R)) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines. Results The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day. Conclusion During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor."	"[Andrews, Louise M.; van Gelder, Teun; Koch, Birgit C. P.; de Winter, Brenda C. M.] Univ Med Ctr Rotterdam, Dept Hosp Pharm, Erasmus Med Ctr, POB 2040, NL-3000 CA Rotterdam, Netherlands; [Hesselink, Dennis A.; van Gelder, Teun] Univ Med Ctr Rotterdam, Dept Internal Med, Erasmus Med Ctr, Rotterdam, Netherlands; [Cornelissen, Elisabeth A. M.] Radboud Univ Nijmegen, Amalia Childrens Hosp, Dept Pediat Nephrol, Med Ctr, Nijmegen, Netherlands; [Bruggemann, Roger J. M.] Radboud Univ Nijmegen, Dept Hosp Pharm, Nijmegen, Netherlands; [van Schaik, Ron H. N.] Univ Med Ctr Rotterdam, Dept Clin Chem, Erasmus Med Ctr, Rotterdam, Netherlands; [de Wildt, Saskia N.] Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Nijmegen, Netherlands; [Cransberg, Karlien] Sophia Childrens Univ Hosp, Dept Pediat Nephrol, Erasmus Med Ctr, Rotterdam, Netherlands"	"Andrews, LM (corresponding author), Univ Med Ctr Rotterdam, Dept Hosp Pharm, Erasmus Med Ctr, POB 2040, NL-3000 CA Rotterdam, Netherlands."	"l.andrews@erasmusmc.nl"	"de Wildt, Saskia/A-9589-2008; Cornelissen, Elisabeth AM/F-3618-2015; Bruggemann, Roger JM/A-7057-2015"	"de Wildt, Saskia/0000-0002-0502-0647; Cornelissen, Elisabeth AM/0000-0002-1156-5264; Bruggemann, Roger JM/0000-0002-7618-725X; koch, birgit/0000-0002-1202-3643"	"NA"	"NA"	54	29	29	1	4	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"APR"	2018	57	4	475	489	"NA"	"10.1007/s40262-017-0567-8"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FZ7BJ"	"WOS:000427754200005"	28681225	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Rodrigues, C; Chhun, S; Chiron, C; Dulac, O; Rey, E; Pons, G; Jullien, V"	"Rodrigues, Christelle; Chhun, Stephanie; Chiron, Catherine; Dulac, Olivier; Rey, Elisabeth; Pons, Gerard; Jullien, Vincent"	"NA"	"A"	"A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Childhood epilepsy; Valproate; Population pharmacokinetics; Protein binding"	"STEADY-STATE PHARMACOKINETICS; ANTIEPILEPTIC DRUGS; SODIUM VALPROATE; SERUM CONCENTRATIONS; PEDIATRIC-PATIENTS; MONITORING-DATA; CLEARANCE; DOSAGE; STIRIPENTOL; DISPOSITION"	"Purpose The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (C-trough) within the target range (50-100 mg/L). Methods Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain C-trough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. Results A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a C-trough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30-and >= 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. Conclusions If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA."	"[Rodrigues, Christelle; Chiron, Catherine; Dulac, Olivier; Rey, Elisabeth; Pons, Gerard; Jullien, Vincent] Paris Descartes Univ, CEA, INSERM U1129, Paris, France; [Chhun, Stephanie] Hop Necker Enfants Malad Enfants Malad, AP HP, Lab Immunol Biol, Inserm U1151,INEM, Paris, France; [Jullien, Vincent] Hop Europeen Georges Pompidou, Serv Pharmacol, 20 Rue Leblanc, F-75015 Paris, France"	"Jullien, V (corresponding author), Paris Descartes Univ, CEA, INSERM U1129, Paris, France.; Jullien, V (corresponding author), Hop Europeen Georges Pompidou, Serv Pharmacol, 20 Rue Leblanc, F-75015 Paris, France."	"vincent.jullien@aphp.fr"	"Chiron, Catherine/E-8506-2016"	"Chiron, Catherine/0000-0002-9096-1694; Rodrigues, Christelle/0000-0001-6681-5542"	"Sanofi Aventis FranceSanofi-Aventis [NCT00385411]; Biocodex [2007-001784-30]"	"Study 1 (VAPOP) was funded by Sanofi Aventis France (registration NCT00385411) and study 2 (STIPOP) was funded by Biocodex (EudraCT number: 2007-001784-30). The present work was returned independently from Biocodex."	57	3	3	0	6	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JUN"	2018	74	6	793	803	"NA"	"10.1007/s00228-018-2444-2"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GF4CI"	"WOS:000431907000012"	29564480	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bastos, ACM; Vandecasteele, SJ; Spinewine, A; Tulkens, PM; Van Bambeke, F"	"Bastos, Ana C. Miranda; Vandecasteele, Stefaan J.; Spinewine, Anne; Tulkens, Paul M.; Van Bambeke, Francoise"	"NA"	"A"	"Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"IMPAIRED RENAL-FUNCTION; IN-VITRO ACTIVITY; SPECTRUM BETA-LACTAMASES; TISSUE PENETRATION; BELGIAN HOSPITALS; ENTEROBACTERIACEAE; DIALYSIS; BACTEREMIA; PARAMETERS; INFUSION"	"Objectives: To develop a population model describing temocillin pharmacokinetics (PK) in patients undergoing haemodialysis and investigate how pharmacokinetic/pharmacodynamic (PD) targets can be met with different dosage regimens. Patients and methods: Sixteen patients received the currently licenced dosing of 1, 2 or 3 g of temocillin (total of 61 doses) corresponding to an inter-dialytic period of 20, 44 or 68 h, respectively, and a dialysis period of 4 h. A non-linear mixed-effects model was developed jointly for total and unbound temocillin serum concentrations. The performance of clinically feasible dosing regimens was evaluated using a 5000-subject Monte Carlo (MC) simulation for determining the highest MIC for which the PK/PD target of 40% fT(>MIC) would be reached in 90% of patients [probability of target attainment (PTA)]. This PK study was registered at ClinicalTrials. gov (NCT02285075). Results: Temocillin unbound and total serum concentrations (429 samples) were used to fit an open two-compartment model with non-linear albumin binding and first-order elimination. In addition to total body clearance, dialysis clearance was modelled using the Michaels function. The currently licenced dosing achieved a 90% PTA for an MIC up to 8 mg/L. A new temocillin dosage regimen was designed that would achieve a 90% PTA for an MIC of 16 mg/L (MIC90 of target organisms) adjusted to patient weight and inter-dialytic period. Conclusions: Currently licensed dosage regimen is suboptimal for MICs>8 mg/L (frequently found in clinical isolates). Model-based simulations allowed suggestion of a new dosage regimen with improved probability of microbiological success, applicability in routine clinical practice and more appropriate for empirical therapy."	"[Bastos, Ana C. Miranda; Tulkens, Paul M.; Van Bambeke, Francoise] Catholic Univ Louvain, Louvain Drug Res Inst, Pharmacol Cellulaire & Mol, Brussels, Belgium; [Bastos, Ana C. Miranda; Spinewine, Anne] Catholic Univ Louvain, Louvain Drug Res Inst, Clin Pharm Res Grp, Brussels, Belgium; [Vandecasteele, Stefaan J.] AZ Sint Jan Brugge Oostende AV, Dept Nephrol & Infect Dis, Brugge, Belgium"	"Van Bambeke, F (corresponding author), Catholic Univ Louvain, Louvain Drug Res Inst, Pharmacol Cellulaire & Mol, Brussels, Belgium."	"francoise.vanbambeke@uclouvain.be"	"NA"	"Van Bambeke, Francoise/0000-0002-0052-7991"	"Region Wallonne [TEMOEXPAND 1217668]"	"This work was supported in part by the Region Wallonne (project TEMOEXPAND 1217668)."	43	2	2	0	1	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JUN"	2018	73	6	1630	1638	"NA"	"10.1093/jac/dky078"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"GI0SL"	"WOS:000434079600024"	29579214	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Li, ZL; Liu, YX; Jiao, Z; Qiu, G; Huang, JQ; Xiao, YB; Wu, SJ; Wang, CY; Hu, WJ; Sun, HJ"	"Li, Zhi-ling; Liu, Yi-xi; Jiao, Zheng; Qiu, Gang; Huang, Jian-quan; Xiao, Yu-bo; Wu, Shu-jin; Wang, Chen-yu; Hu, Wen-juan; Sun, Hua-jun"	"NA"	"A"	"Population Pharmacokinetics of Vancomycin in Chinese ICU Neonates: Initial Dosage Recommendations"	"FRONTIERS IN PHARMACOLOGY"	"English"	"Article"	"neonate; vancomycin; population pharmacokinetic; Monte Carlo simulation; individualized therapy"	"DOSING OPTIMIZATION; PRACTICE GUIDELINES; MODEL; PREDICTION; CHILDREN; PRETERM; SOCIETY; ADULT; SIMULATIONS; PERFORMANCE"	"The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population. The study population consisted of 80 neonates in the neonatal intensive care unit (ICU) from which 165 trough and peak concentrations of vancomycin were obtained. Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin. The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errors and the bootstrap method. Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin. The average clearance was 0.309 Uh for a neonate with Scr of 23.3 mu mol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15 mu mol/L, current guideline recommendations would likely not achieve therapeutic area under the concentration-time curve over 24 h/minimum inhibitory concentration (AUC(24h)/MIC) >= 400. The exceptions to this are British National Formulary (2016-2017), Blue Book (2016) and Neofax (2017). Recommended dose regimens for neonates with different Scr levels and postmenstrual ages were estimated based on Monte Carlo simulations and the established model. These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting."	"[Li, Zhi-ling; Huang, Jian-quan; Hu, Wen-juan; Sun, Hua-jun] Shanghai Jiao Tong Univ, Dept Pharm, Shanghai Childrens Hosp, Shanghai, Peoples R China; [Liu, Yi-xi; Jiao, Zheng; Xiao, Yu-bo; Wu, Shu-jin; Wang, Chen-yu] Fudan Univ, Dept Pharm, Huashan Hosp, Shanghai, Peoples R China; [Liu, Yi-xi] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing, Jiangsu, Peoples R China; [Qiu, Gang] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Dept Neonatol, Shanghai, Peoples R China; [Xiao, Yu-bo] Wuhan Univ, Dept Pharm, Renmin Hosp, Wuhan, Hubei, Peoples R China; [Wu, Shu-jin] Gansu Prov Hosp, Dept Pharm, Lanzhou, Gansu, Peoples R China"	"Sun, HJ (corresponding author), Shanghai Jiao Tong Univ, Dept Pharm, Shanghai Childrens Hosp, Shanghai, Peoples R China.; Jiao, Z (corresponding author), Fudan Univ, Dept Pharm, Huashan Hosp, Shanghai, Peoples R China."	"zjao@fudan.edu.cn; sunhj1@shchildren.com.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162; wang, chenyu/0000-0003-1808-361X"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81603199]; Shanghai Municipal Population and Family Planning Commission [20154Y0019]; Weak Discipline Construction Project of Shanghai Municipal Population and Family Planning Commission [2016ZB0305-01, 2016ZB0301-01]; Shanghai Jiaotong University [YG2015QN29]"	"This work was supported by the National Natural Science Foundation of China (No. 81603199), Shanghai Municipal Population and Family Planning Commission (No.20154Y0019), Weak Discipline Construction Project of Shanghai Municipal Population and Family Planning Commission (No.2016ZB0305-01& 2016ZB0301-01), and Cross-fund for medical and engineering workers in Shanghai Jiaotong University (YG2015QN29)."	48	2	2	0	6	"FRONTIERS MEDIA SA"	"LAUSANNE"	"AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND"	"1663-9812"	"NA"	"NA"	"FRONT PHARMACOL"	"Front. Pharmacol."	"JUN 26"	2018	9	"NA"	"NA"	"NA"	603	"10.3389/fphar.2018.00603"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GK6DN"	"WOS:000436273000001"	29997498	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Chen, YW; Wu, D; Dong, M; Zhu, YQ; Lu, JM; Li, XX; Chen, C; Li, ZP"	"Chen, Yewei; Wu, Dan; Dong, Min; Zhu, Yiqing; Lu, Jinmiao; Li, Xiaoxia; Chen, Chao; Li, Zhiping"	"NA"	"A"	"Population pharmacokinetics of vancomycin and AUC-guided dosing in Chinese neonates and young infants"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Vancomycin; Pharmacokinetics; NONMEM; AUC; Infants"	"GLOMERULAR-FILTRATION-RATE; INTENSIVE-CARE-UNIT; CHILDREN; INFECTIONS; PHARMACODYNAMICS; PHARMACOLOGY; PREDICTION; MODELS; DOSAGE; ADULTS"	"To develop a population pharmacokinetic (PK) model for vancomycin in Chinese neonates and infants less than 2 months of age (young infants) with a wide gestational age range, in order to determine the appropriate dosing regimen for this population. We performed a retrospective chart review of patients from the neonatal intensive care unit (NICU) at Children's Hospital of Fudan University to identify neonates and young infants treated with vancomycin from May 2014 to May 2017. Vancomycin concentrations and covariates were utilized to develop a one-compartment model with first-order elimination. The predictive performance of the final model was assessed by both internal and external evaluation, and the relationship between trough concentration and AUC(0-24) was investigated. Monte Carlo simulations were performed to design an initial dosing schedule targeting an AUC(0-24) 400. The analysis included a total of 330 concentration-time data points from 213 neonates and young infants with gestational age (GA) and body weight of 25-42 weeks and 0.88-5.1 kg, respectively. Body weight, postmenstrual age (PMA) and serum creatinine level were found to be important factors explaining the between-subject variability in vancomycin PK parameters for this population. Both internal and external evaluation supported the prediction of the final vancomycin PK model. The typical population parameter estimates of clearance and distribution volume for an infant weighing 2.73 kg with a PMA of 39.8 weeks and serum creatinine of 0.28 mg/dL were 0.103 L/h/kg and 0.58 L/kg, respectively. Although vancomycin serum trough concentrations were predictive of the AUC, considerable variability was observed in the achievement of an AUC(0-24)/MIC of 400. For MIC values of 0.5 mg/L, AUC(0-24)/MIC 400 was achieved for 95% of the newborn infants with vancomycin troughs of 5-10 mg/L. When the MIC increased to 1 mg/L, only 15% of the patients with troughs of 5-10 mg/L achieved AUC(0-24)/MIC 400. For MIC values of 2 mg/L, no infants achieved the target. Simulations predicted that a dose of at least 14 and 15 mg/kg every 12 h was required to attain the target AUC(0-24) 400 in 90% of infants with a PMA of 30-32 and 32-34 weeks, respectively. This target was also achieved in 93% of simulated infants in the oldest PMA groups (36-38 and 38-40 weeks, respectively) when the dosing interval was extended to 8 h. For infants with a PMA 44 weeks, a dose increase to 18 mg/kg every 8 h was needed. The trough concentrations of 5-15 mg/L were highly predictive of an AUC(0-24) of 400 when treating invasive MRSA infections with an MIC of 1 mg/L. The PK parameters for vancomycin in Chinese infants younger than 2 months of age were estimated using the model developed herein. This model has been used to predict individualized dosing regimens in this vulnerable population in our hospital. A large external evaluation of our model will be conducted in future studies."	"[Chen, Yewei; Wu, Dan; Zhu, Yiqing; Lu, Jinmiao; Li, Xiaoxia; Li, Zhiping] Fudan Univ, Dept Pharm, Childrens Hosp, 399 Wanyuan Rd, Shanghai 201102, Peoples R China; [Dong, Min] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA; [Chen, Chao] Fudan Univ, Dept Neonatol, Childrens Hosp, Shanghai, Peoples R China"	"Li, ZP (corresponding author), Fudan Univ, Dept Pharm, Childrens Hosp, 399 Wanyuan Rd, Shanghai 201102, Peoples R China."	"zplifudan@126.com"	"NA"	"NA"	"NA"	"NA"	33	8	9	0	12	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JUL"	2018	74	7	921	930	"NA"	"10.1007/s00228-018-2454-0"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GJ4GZ"	"WOS:000435339900008"	29602981	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Liu, T; Ivaturi, V; Sabato, P; Gobburu, JVS; Greer, JM; Wright, JJ; Smith, BD; Pratz, KW; Rudek, MA"	"Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V. S.; Greer, Jacqueline M.; Wright, John J.; Smith, B. Douglas; Pratz, Keith W.; Rudek, Michelle A."	"ETCTN-6745 Study Team"	"A"	"Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship"	"CTS-CLINICAL AND TRANSLATIONAL SCIENCE"	"English"	"Article"	"NA"	"PHASE-I; KINASE INHIBITOR; MYELODYSPLASTIC SYNDROME; YOUNGER PATIENTS; SOLID TUMORS; FLT3; TRIALS; DISPOSITION; CHEMOTHERAPY; MECHANISMS"	"Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E-max) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC50 of 69.3ng/mL and ERK activity by 84% with an IC50 of 85.7ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400mg b.i.d. and is recommended in further clinical trials in patients with AML."	"[Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V. S.] Univ Maryland Baltimore, Ctr Translat Med, Baltimore, MD 21201 USA; [Greer, Jacqueline M.; Smith, B. Douglas; Pratz, Keith W.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA; [Wright, John J.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA; [Smith, B. Douglas; Pratz, Keith W.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA; [Rudek, Michelle A.; ETCTN-6745 Study Team] Johns Hopkins Univ, Dept Med, Div Clin Pharmacol, Baltimore, MD USA"	"Ivaturi, V (corresponding author), Univ Maryland Baltimore, Ctr Translat Med, Baltimore, MD 21201 USA.; Rudek, MA (corresponding author), Johns Hopkins Univ, Dept Med, Div Clin Pharmacol, Baltimore, MD USA."	"vivaturi@rx.umaryland.edu; mrudek2@jhmi.edu"	"NA"	"Liu, Tao/0000-0002-9943-2131"	"National Cancer Institute (NCI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA070095, UM1CA186691]; Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (National Institutes of Health (NIH)) [P30CA006973, UL1TR001079]; National Center for Advancing Translational Sciences (NCATS) a component of the NIH [UL1TR 001079]; NIH Roadmap for Medical ResearchUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [UL1TR 001079]"	"The project described was supported in part by the National Cancer Institute (NCI) Cooperative Agreement U01CA070095, and UM1CA186691 (B.D.S., K.W.P., and M.A.R.) and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (National Institutes of Health (NIH) grants P30CA006973 and UL1TR001079). Grant number UL1TR 001079 is from the National Center for Advancing Translational Sciences (NCATS) a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS, or NIH."	44	8	8	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1752-8054"	"1752-8062"	"NA"	"CTS-CLIN TRANSL SCI"	"CTS-Clin. Transl. Sci."	"JUL"	2018	11	4	435	443	"NA"	"10.1111/cts.12555"	9	"Medicine, Research & Experimental"	"Research & Experimental Medicine"	"GM3QW"	"WOS:000438023100013"	29702736	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Marsot, A; Gallais, F; Galambrun, C; Coze, C; Blin, O; Andre, N; Guilhaumou, R"	"Marsot, Amelie; Gallais, F.; Galambrun, C.; Coze, C.; Blin, O.; Andre, N.; Guilhaumou, R."	"NA"	"A"	"Vancomycin in Pediatric Patients with Solid or Hematological Malignant Disease: Predictive Performance of a Population Pharmacokinetic Model and New Optimized Dosing Regimens"	"PEDIATRIC DRUGS"	"English"	"Article"	"NA"	"AUGMENTED RENAL CLEARANCE; FEBRILE NEUTROPENIA; EFFICACY; INFUSION; CHILDREN"	"Background The application of population pharmacokinetic models and Bayesian methods offers the potential to develop individualized therapeutic approaches. Objectives The current study presents an external evaluation of a vancomycin pharmacokinetic model in a pediatric cancer population and proposes an easy-to-use chart for clinicians for a priori vancomycin schedule adaptation to achieve target concentration. Methods External evaluation of a population pharmacokinetic model of vancomycin administered via continuous infusion was realized in a new retrospective dataset of pediatric patients with cancer. The published population pharmacokinetic model was implemented in NONMEM 7.3 with the structural and variance parameter values set equal to estimates previously reported. Predictive performance was assessed by quantifying bias and accuracy of model prediction. Normalized prediction distribution errors were also evaluated. Dosage simulations were performed according to the target concentration. Results A total of 77 patients were included in this study, representing 146 vancomycin courses and 289 concentrations. The model adequately predicted vancomycin concentrations (median prediction error % of - 9.4%, median vertical bar PE vertical bar% of 24.1%). Based on simulation results, vancomycin dosage (mg/kg) should be adapted for each child on the basis of body weight and cyclosporine coadministration. Conclusion The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage."	"[Marsot, Amelie; Blin, O.; Guilhaumou, R.] Hop La Timone, Serv Pharmacol Clin & Pharmacovigilance, 264 Rue St Pierre, F-13385 Marseille 5, France; [Marsot, Amelie; Gallais, F.; Blin, O.; Guilhaumou, R.] Aix Marseille Univ, Inst Neurosci Timone, CNRS 7289, Pharmacol Integree Interface Clin & Ind, F-13385 Marseille, France; [Galambrun, C.; Coze, C.; Andre, N.] Hop La Timone, Serv Hematol & Oncol Pediat, Marseille, France; [Andre, N.] Aix Marseille Univ, Ctr Rech Oncol Biol & Oncopharmacol, UMR 911, INSERM, Marseille, France"	"Marsot, A (corresponding author), Hop La Timone, Serv Pharmacol Clin & Pharmacovigilance, 264 Rue St Pierre, F-13385 Marseille 5, France."	"amelie.marsot@ap-hm.fr"	"NA"	"NA"	"NA"	"NA"	22	2	1	3	6	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"1174-5878"	"1179-2019"	"NA"	"PEDIATR DRUGS"	"Pediatr. Drugs"	"AUG"	2018	20	4	375	381	"NA"	"10.1007/s40272-018-0295-z"	7	"Pediatrics; Pharmacology & Pharmacy"	"Pediatrics; Pharmacology & Pharmacy"	"GL2EE"	"WOS:000436928100008"	29736878	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Li, AN; Ji, SM; Yue, WH; Yan, H; Dong, F; Ruan, CJ; Li, WB; Lu, W; Zhang, D; Wang, CY"	"Li, Anning; Ji, Shuangmin; Yue, Weihua; Yan, Hao; Dong, Fang; Ruan, Canjun; Li, Wenbiao; Lu, Wei; Zhang, Dai; Wang, Chuanyue"	"NA"	"A"	"Development of a population pharmacokinetic model of olanzapine for Chinese health volunteers and patients with schizophrenia"	"BMJ OPEN"	"English"	"Article"	"olanzapine; population pharmacokinetics; therapeutic drug monitoring; individualized therapy"	"PARAMETERS; DISORDER"	"Objective Olanzapine is an atypical antipsychotic drug commonly used for the treatment of schizophrenia. However, there are still many complications associated with the use of olanzapine, and researchers continually strive to improve the handling of data from regular therapeutic drug monitoring (TDM). The objective of this study is to optimise the individualised treatment of olanzapine by establishing a population pharmacokinetics (PopPK) model in Chinese patients with schizophrenia. Methods This study integrates an extensive collection of concentration data from healthy volunteers after a single dose and a less extensive collection of samples from patients undergoing TDM. A PopPK model was developed using non-linear mixed-effects modelling. Potential covariates, including the olanzapine manufacturer and patient gender and age, were assessed during model development. A total of 616 plasma concentration levels from 22 healthy male individuals in China and 458 concentration levels from 112 male and 122 female patients with schizophrenia undergoing TDM at 12 hospitals in China were included in the analysis. The concentration profile could be best described using a two-compartment model with first-order absorption and elimination. Results The absorption rate (Ka) of olanzapine ranged from 2.85h(-1) to 5.39h(-1) for the different formulations. The typical absorption time delay was 0.877hour. Body weight had a considerable effect on the apparent volume of the centre compartment and showed a power relationship. Conclusions A PopPK model of olanzapine in Chinese patients with schizophrenia was developed in this study. After determining the PK parameters of olanzapine, the results suggested that body weight exhibited a considerable impact effect on V-C/F. The impact of subjects and formulations requires further study. The PopPK model established in this study is likely to provide some information for the individualised therapy of olanzapine. Trial registration number ChiCTR-TRC-10000934; Results."	"[Li, Anning; Dong, Fang; Ruan, Canjun; Li, Wenbiao; Wang, Chuanyue] Capital Med Univ, Beijing Anding Hosp, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China; [Li, Anning; Dong, Fang; Ruan, Canjun; Li, Wenbiao; Wang, Chuanyue] Capital Med Univ, Beijing Anding Hosp, Beijing Key Lab Mental Disorders, Beijing Inst Brain Disorders,Ctr Schizophrenia, Beijing, Peoples R China; [Ji, Shuangmin] China Food & Drug Adm, Ctr Drug Evaluat, Beijing, Peoples R China; [Yue, Weihua; Yan, Hao; Zhang, Dai] Peking Univ, Hosp 6, Inst Mental Hlth, Minist Hlth,Key Lab Mental Hlth, Beijing, Peoples R China; [Lu, Wei] Peking Univ, Sch Pharmaceut Sci, Beijing, Peoples R China; [Zhang, Dai] Peking Univ, McGovern Inst Brain Res, PKU IDG, Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China"	"Wang, CY (corresponding author), Capital Med Univ, Beijing Anding Hosp, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China.; Wang, CY (corresponding author), Capital Med Univ, Beijing Anding Hosp, Beijing Key Lab Mental Disorders, Beijing Inst Brain Disorders,Ctr Schizophrenia, Beijing, Peoples R China."	"wang_cy@ccmu.edu.cn"	"Yan, Hao/AAH-7406-2019; Wang, Chuan-Yue/C-9369-2015"	"Yan, Hao/0000-0003-0376-9037; Wang, Chuan-Yue/0000-0001-6549-3713"	"Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding [ZY201403]; Capital Medical Research Development Fund of China [2014-2-2122]; National Key Project [2009AA022702]; Beijing Science and Technology Plan Project [Z151100004015180]"	"This work was supported by the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding, grant number ZY201403; the Capital Medical Research Development Fund of China, grant number 2014-2-2122; the National Key Project, grant number 2009AA022702 and the Beijing Science and Technology Plan Project, grant number Z151100004015180."	18	1	2	8	14	"BMJ PUBLISHING GROUP"	"LONDON"	"BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND"	"2044-6055"	"NA"	"NA"	"BMJ OPEN"	"BMJ Open"	"AUG"	2018	8	8	"NA"	"NA"	"e020070"	"10.1136/bmjopen-2017-020070"	8	"Medicine, General & Internal"	"General & Internal Medicine"	"GV9IO"	"WOS:000446470200021"	30121590	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Hao, GX; Huang, X; Zhang, DF; Zheng, Y; Shi, HY; Li, Y; Jacqz-Aigrain, E; Zhao, W"	"Hao, Guo-Xiang; Huang, Xin; Zhang, Dong-Feng; Zheng, Yi; Shi, Hai-Yan; Li, Yan; Jacqz-Aigrain, Evelyne; Zhao, Wei"	"NA"	"A"	"Population pharmacokinetics of tacrolimus in children with nephrotic syndrome"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"children; nephrotic syndrome; pharmacokinetics; tacrolimus"	"KIDNEY-TRANSPLANT RECIPIENTS; PEDIATRIC LIVER-TRANSPLANTATION; STEROID-RESISTANT; CYP3A5 GENOTYPE; LONG-TERM; MYCOPHENOLIC-ACID; MODEL EVALUATION; IN-VITRO; CHILDHOOD; POLYMORPHISM"	"AimsNephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen. MethodsBlood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC-MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene. ResultsThe data from 28 children were used for PPK analysis. A one-compartment model and first-order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10mgkg(-1)dose(-1) twice daily and NS children with CYP3A5*1 receiving 0.25mgkg(-1)dose(-1) twice daily TAC could achieve the target concentrations of 5-10ngml(-1). ConclusionThe PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations."	"[Hao, Guo-Xiang; Zheng, Yi; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Huang, Xin; Shi, Hai-Yan; Li, Yan; Zhao, Wei] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Zhang, Dong-Feng; Jacqz-Aigrain, Evelyne] Childrens Hosp Hebei Prov, Dept Pediat Nephrol, Shijiazhuang, Hebei, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, APHP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Jinan 250012, Shandong, Peoples R China."	"zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81503163]; National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002]; Young Taishan Scholars Program and Young Scholars Program of Shandong University"	"All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). None of the authors have any other relationships or activities that could appear to have influenced the submitted work. This work is supported by the National Natural Science Foundation of China (81503163), National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002) and Young Taishan Scholars Program and Young Scholars Program of Shandong University."	57	11	12	1	13	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"AUG"	2018	84	8	1748	1756	"NA"	"10.1111/bcp.13605"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GN1AH"	"WOS:000438713800012"	29637588	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Brussee, JM; Yu, HX; Krekels, EHJ; Palic, S; Brill, MJE; Barrett, JS; Rostami-Hodjegan, A; de Wildt, SN; Knibbe, CAJ"	"Brussee, Janneke M.; Yu, Huixin; Krekels, Elke H. J.; Palic, Semra; Brill, Margreke J. E.; Barrett, Jeffrey S.; Rostami-Hodjegan, Amin; de Wildt, Saskia N.; Knibbe, Catherijne A. J."	"NA"	"A"	"Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"CYP3A; extraction ratio; absorption; first-pass metabolism; gut wall; liver; pediatrics"	"ORAL-DRUG ABSORPTION; CYTOCHROME-P450 3A; IN-VITRO; PEDIATRIC-PATIENTS; HUMAN LIVER; PREDICTION; INFANTS; ONTOGENY; CLEARANCE; WEIGHT"	"Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults."	"[Brussee, Janneke M.; Yu, Huixin; Krekels, Elke H. J.; Palic, Semra; Knibbe, Catherijne A. J.] Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Yu, Huixin] Novartis, Basel, Switzerland; [Palic, Semra] Netherlands Canc Inst NKI, Amsterdam, Netherlands; [Brill, Margreke J. E.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Barrett, Jeffrey S.] Sanofi, Translat Informat, Bridgewater, NJ USA; [Barrett, Jeffrey S.] Childrens Hosp Philadelphia, Dept Pediat, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA; [Rostami-Hodjegan, Amin] Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England; [Rostami-Hodjegan, Amin] Simcyp Ltd, Sheffield, S Yorkshire, England; [de Wildt, Saskia N.] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [de Wildt, Saskia N.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [de Wildt, Saskia N.] Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.; Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands."	"brusseejm@lacdr.leidenuniv.nl; c.knibb@antoniusziekenhuis.nl"	"de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647; Brussee, Janneke/0000-0002-0813-4463; Rostami-Hodjegan, Amin/0000-0003-3917-844X; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NWONetherlands Organization for Scientific Research (NWO); NIH / NICHD, Pediatric Pharmacology Research UnitUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HD037255-06]"	"CAJ Knibbe was supported by an NWO Vidi grant (Knibbe 2013). The authors would like to thank Anthony Gebhart (LACDR, Leiden University) for the code review. Drs. Jeff Galinken and Peter Adamson were the PIs on the original study conducted at CHOP and the study was supported by NIH / NICHD, Pediatric Pharmacology Research Unit, Grant # HD037255-06."	51	9	9	1	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"SEP"	2018	35	9	"NA"	"NA"	182	"10.1007/s11095-018-2458-6"	13	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"GO8NN"	"WOS:000440347600001"	30062590	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Ibrahim, MMA; Nordgren, R; Kjellsson, MC; Karlsson, MO"	"Ibrahim, Moustafa M. A.; Nordgren, Rikard; Kjellsson, Maria C.; Karlsson, Mats O."	"NA"	"M"	"Model-Based Residual Post-Processing for Residual Model Identification"	"AAPS JOURNAL"	"English"	"Article"	"conditional weighted residuals; diagnostics; model evaluation; nonlinear mixed effects models; residual error model"	"POPULATION PHARMACOKINETICS; GLUCOSE; ERRORS"	"The purpose of this study was to investigate if model-based post-processing of common diagnostics can be used as a diagnostic tool to quantitatively identify model misspecifications and rectifying actions. The main investigated diagnostic is conditional weighted residuals (CWRES). We have selected to showcase this principle with residual unexplained variability (RUV) models, where the new diagnostic tool is used to scan extended RUV models and assess in a fast and robust way whether, and what, extensions are expected to provide a superior description of data. The extended RUV models evaluated were autocorrelated errors, dynamic transform both sides, inter-individual variability on RUV, power error model, t-distributed errors, and time-varying error magnitude. The agreement in improvement in goodness-of-fit between implementing these extended RUV models on the original model and implementing these extended RUV models on CWRES was evaluated in real and simulated data examples. Real data exercise was applied to three other diagnostics: conditional weighted residuals with interaction (CWRESI), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE). CWRES modeling typically predicted (i) the nature of model misspecifications, (ii) the magnitude of the expected improvement in fit in terms of difference in objective function value (Delta OFV), and (iii) the parameter estimates associated with the model extension. Alternative metrics (CWRESI, IWRES, and NPDE) also provided valuable information, but with a lower predictive performance of Delta OFV compared to CWRES. This method is a fast and easily automated diagnostic tool for RUV model development/evaluation process; it is already implemented in the software package PsN."	"[Ibrahim, Moustafa M. A.; Nordgren, Rikard; Kjellsson, Maria C.; Karlsson, Mats O.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Ibrahim, Moustafa M. A.] Helwan Univ, Dept Pharm Practice, Cairo, Egypt"	"Karlsson, MO (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden."	"mats.karlsson@farmbio.uu.se"	"NA"	"Ibrahim, Moustafa/0000-0002-2084-1531"	"NA"	"NA"	32	4	4	0	1	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"SEP"	2018	20	5	"NA"	"NA"	81	"10.1208/s12248-018-0240-7"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GL5FG"	"WOS:000437188800001"	29968184	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Jacobs, A; Taccone, FS; Roberts, JA; Jacobs, F; Cotton, F; Wolff, F; Creteur, J; Vincent, JL; Hites, M"	"Jacobs, Alexandra; Taccone, Fabio Silvio; Roberts, Jason A.; Jacobs, Frederique; Cotton, Frederic; Wolff, Fleur; Creteur, Jacques; Vincent, Jean-Louis; Hites, Maya"	"NA"	"A"	"beta-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"creatinine clearance; meropenem; ceftazidime; cefepime; piperacillin-tazobactam; critically ill; pharmacokinetics"	"CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; PIPERACILLIN-TAZOBACTAM; CREATININE CLEARANCE; DOSE OPTIMIZATION; PHARMACODYNAMICS; INFECTIONS; MEROPENEM; DRUG; POPULATION"	"Augmented renal clearance is commonly observed in septic patients and may result in insufficient beta-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of beta-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of >= 120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient beta-lactam serum concentrations to treat infections due to Pseudomonas aeruginosa. There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r = -0.21, P = 0.01), trough concentrations of piperacillin (r = -0.28, P = 0.0071), concentrations at 50% of the dosage interval (r = -0.41, P < 0.0001), and total body clearance of piperacillin (r = 0.39, P = 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain beta-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens."	"[Jacobs, Alexandra; Taccone, Fabio Silvio; Creteur, Jacques; Vincent, Jean-Louis] Univ Libre Bruxelles, CUB Erasme, Dept Intens Care, Brussels, Belgium; [Jacobs, Alexandra; Jacobs, Frederique; Hites, Maya] Univ Libre Bruxelles, CUB Erasme, Dept Infect Dis, Brussels, Belgium; [Roberts, Jason A.] Univ Queensland, Royal Brisbane & Womens Hosp, Ctr Clin Res, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Ctr Translat Antiinfect Pharmacodynam, Woolloongabba, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia; [Cotton, Frederic; Wolff, Fleur] Univ Libre Bruxelles, CUB Erasme, Dept Clin Biochem, Brussels, Belgium"	"Hites, M (corresponding author), Univ Libre Bruxelles, CUB Erasme, Dept Infect Dis, Brussels, Belgium."	"maya.hites@erasme.ulb.ac.be"	"Roberts, Jason A/F-6272-2010; Hites, Maya/AAS-2969-2020"	"Roberts, Jason A/0000-0001-6218-435X; Vincent, Jean-Louis/0000-0001-6011-6951; Cotton, Frederic/0000-0002-7356-7417"	"Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [APP1099452, APP1117065]"	"J.A.R. acknowledges funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and Practitioner Fellowship (APP1117065). No funding was received to carry out this study."	39	15	15	1	3	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"SEP"	2018	62	9	"NA"	"NA"	"e02534-17"	"10.1128/AAC.02534-17"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"GR6NN"	"WOS:000442771200082"	29987138	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Zheng, Y; Liu, SP; Xu, BP; Shi, ZR; Wang, K; Yang, JB; Huang, X; Tang, BH; Chen, XK; Shi, HY; Zhou, Y; Wu, YE; Qi, H; Jacqz-Aigrain, E; Shen, AD; Zhao, W"	"Zheng, Yi; Liu, Shu-Ping; Xu, Bao-Ping; Shi, Zhong-Ren; Wang, Kai; Yang, Jin-Bin; Huang, Xin; Tang, Bo-Hao; Chen, Xing-Kai; Shi, Hai-Yan; Zhou, Yue; Wu, Yue-E; Qi, Hui; Jacqz-Aigrain, Evelyne; Shen, A-Dong; Zhao, Wei"	"NA"	"A"	"Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"azithromycin; pharmacokinetics; children; dosing regimen; community-acquired pneumonia"	"LC-MS/MS METHOD; PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; MICROBIAL RESPONSE; COLONIZATION; MACROLIDE; OUTCOMES; THERAPY; DISEASE; MODELS"	"Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation."	"[Zheng, Yi; Tang, Bo-Hao; Chen, Xing-Kai; Zhou, Yue; Wu, Yue-E; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Liu, Shu-Ping; Qi, Hui; Shen, A-Dong] Capital Med Univ, Beijing Childrens Hosp,Beijing Ky Lab Pediat Resp, Natl Ctr Childrens Hlth,Key Lab Major Dis Childre, Natl Clin Res Ctr Resp Dis,Beijing Pediat Res Ins, Beijing, Peoples R China; [Xu, Bao-Ping] Capital Med Univ, Beijing Childrens Hosp, Natl Ctr Childrens Hlth, China Natl Clin Res Ctr Resp Dis,Resp Dept, Beijing, Peoples R China; [Shi, Zhong-Ren] Childrens Hosp Hebei Prov, Pediat Res Inst, Shijiazhuang, Hebei, Peoples R China; [Wang, Kai] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Resp Dis, Jinan, Shandong, Peoples R China; [Yang, Jin-Bin] Xingtai Peoples Hosp, Dept Pharm, Xintai, Peoples R China; [Huang, Xin; Shi, Hai-Yan; Zhao, Wei] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dep Pediat Pharmacol & Pharmacogenet, Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China.; Shen, AD (corresponding author), Capital Med Univ, Beijing Childrens Hosp,Beijing Ky Lab Pediat Resp, Natl Ctr Childrens Hlth,Key Lab Major Dis Childre, Natl Clin Res Ctr Resp Dis,Beijing Pediat Res Ins, Beijing, Peoples R China.; Zhao, W (corresponding author), Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China."	"shenad16@hotmail.com; zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81703603]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015M582102, 2017M620831]; National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002, 2017ZX09304029-005]; Young Taishan Scholars Program; Fundamental Research Fund [2016GN029]; Capital's Funds for Health Improvement and Research [2016-1-2092]; Young Scholars Program of Shandong University [2015WLJH49]"	"This work is supported by the National Science Foundation of China (81703603), China Postdoctoral Science Foundation (2015M582102, 2017M620831), National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002 and 2017ZX09304029-005), Young Taishan Scholars Program, Fundamental Research Fund (2016GN029), Capital's Funds for Health Improvement and Research (2016-1-2092), and Young Scholars Program of Shandong University (2015WLJH49)."	28	4	4	0	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"SEP"	2018	62	9	"NA"	"NA"	"e00686-18"	"10.1128/AAC.00686-18"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"GR6NN"	"WOS:000442771200037"	29941652	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Djerada, Z; Feliu, C; Cazaubon, Y; Smati, F; Gomis, P; Guerrot, D; Charbit, B; Fernandes, O; Malinovsky, JM"	"Djerada, Zoubir; Feliu, Catherine; Cazaubon, Yoann; Smati, Faouzi; Gomis, Philippe; Guerrot, Dominique; Charbit, Beny; Fernandes, Olivier; Malinovsky, Jean-Marc"	"NA"	"A"	"Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"CEREBROSPINAL-FLUID VOLUME; HYPERBARIC BUPIVACAINE; NEURAL BLOCKADE; HUMAN PLASMA; NERVE BLOCK; AGE; VOLUNTEERS; PARAMETERS; ANALGESIA; ADOLESCENTS"	"Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping. Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two-compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E (max) model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics. This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight. This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de S,curit, du M,dicament et des Produits de Sant, ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France)."	"[Djerada, Zoubir; Feliu, Catherine; Cazaubon, Yoann; Malinovsky, Jean-Marc] Reims Univ Hosp, EA3801, Dept Pharmacol, SFR CAP Sante, 51 Rue Cognacq Jay, F-51095 Reims, France; [Smati, Faouzi; Gomis, Philippe; Charbit, Beny; Fernandes, Olivier; Malinovsky, Jean-Marc] Reims Univ Hosp, Dept Anaesthesia & Intens Care Pole URAD, 45 Rue Cognacq Jay, F-51092 Reims, France; [Guerrot, Dominique] Dept Nephrol & Transplantat, Rouen, France"	"Djerada, Z (corresponding author), Reims Univ Hosp, EA3801, Dept Pharmacol, SFR CAP Sante, 51 Rue Cognacq Jay, F-51095 Reims, France."	"zoubir.djerada@univ-reims.fr"	"Guerrot, Dominique/N-7769-2019; Cazaubon, Yoann/J-5628-2019"	"Guerrot, Dominique/0000-0002-5953-5785; Cazaubon, Yoann/0000-0003-1032-0879; Feliu, Catherine/0000-0002-3928-8908; djerada, zoubir/0000-0002-4022-7889"	"Regional Clinical Research Program of Reims University Hospital, in 2004 (PHRC 2005)"	"This study was funded by the Regional Clinical Research Program of Reims University Hospital, in 2004 (PHRC 2005)."	53	12	12	1	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"SEP"	2018	57	9	1135	1147	"NA"	"10.1007/s40262-017-0617-2"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GO6XX"	"WOS:000440199100005"	29236228	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Schalkwijk, S; ter Heine, R; Colbers, AC; Huitema, ADR; Denti, P; Dooley, KE; Capparelli, E; Best, BM; Cressey, TR; Greupink, R; Russel, FGM; Mirochnick, M; Burger, DM"	"Schalkwijk, Stein; ter Heine, Rob; Colbers, Angela C.; Huitema, Alwin D. R.; Denti, Paolo; Dooley, Kelly E.; Capparelli, Edmund; Best, Brookie M.; Cressey, Tim R.; Greupink, Rick; Russel, Frans G. M.; Mirochnick, Mark; Burger, David M."	"NA"	"A"	"A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400mg in Pregnant Women"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"1ST-LINE ANTIRETROVIRAL THERAPY; FREE DRUG CONCENTRATION; MIXED-EFFECTS MODELS; PLASMA-CONCENTRATIONS; CYP2B6; NEVIRAPINE; INDIVIDUALS; PREDICTION; HIV-1; 2NN"	"BackgroundReducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400mg daily dose is adequate during pregnancy.MethodsWe developed a mechanistic population pharmacokinetic model using pooled data from women included in seven studies (1968 samples, 774 collected during pregnancy). Total and free efavirenz exposure (AUC(24) and C-12) were predicted for 400 (reduced) and 600mg (standard) doses in both pregnant and non-pregnant women.ResultsUsing a 400mg dose, the median efavirenz total AUC(24) and C-12 during the third trimester of pregnancy were 91 and 87% of values among non-pregnant women, respectively. Furthermore, the median free efavirenz C-12 and AUC(24) were predicted to increase during pregnancy by 11 and 15%, respectively.ConclusionsIt was predicted that reduced-dose efavirenz provides adequate exposure during pregnancy. These findings warrant prospective confirmation."	"[Schalkwijk, Stein; ter Heine, Rob; Colbers, Angela C.; Burger, David M.] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, RIHS, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands; [Schalkwijk, Stein; Greupink, Rick; Russel, Frans G. M.] Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, RIMLS, Nijmegen, Netherlands; [Huitema, Alwin D. R.] Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands; [Huitema, Alwin D. R.] Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands; [Denti, Paolo] Univ Cape Town, Div Clin Pharmacol, Dept Med, Cape Town, South Africa; [Dooley, Kelly E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA; [Capparelli, Edmund; Best, Brookie M.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA; [Capparelli, Edmund; Best, Brookie M.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA; [Cressey, Tim R.] Chiang Mai Univ, Fac Associated Med Sci, Chiang Mai, Thailand; [Cressey, Tim R.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA; [Cressey, Tim R.] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England; [Mirochnick, Mark] Boston Univ, Boston, MA 02215 USA"	"Schalkwijk, S (corresponding author), Radboud Univ Nijmegen, Med Ctr, Dept Pharm, RIHS, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands.; Schalkwijk, S (corresponding author), Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, RIMLS, Nijmegen, Netherlands."	"stein.j.schalkwijk@radboudumc.nl"	"Denti, Paolo/AAF-3484-2020; Heine, Rob ter/A-1757-2016; Greupink, Rick/G-8525-2013; Schalkwijk, Stein/D-1055-2015; Russel, Frans G.M./B-3184-2014; Cressey, Tim/U-6428-2019; Colbers, Angela/L-4248-2015; Denti, Paolo/H-6393-2015"	"Greupink, Rick/0000-0003-2599-7540; Russel, Frans G.M./0000-0002-7959-2314; Cressey, Tim/0000-0002-8106-0974; Denti, Paolo/0000-0001-7494-079X"	"NEAT/PENTA; BMSBristol-Myers Squibb; MerckMerck & Company; ViiV Healthcare; Janssen PharmaceuticaJohnson & Johnson USAJanssen Biotech Inc; Boehringer IngelheimBoehringer Ingelheim; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [R01HD064354]; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver NICHDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); National Institute of Mental Health (NIMH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH)"	"Funding was received for some of the individual clinical trials from which data were used in this project (listed below); however, the current study did not receive any specific funding. The PANNA network is funded by NEAT/PENTA, BMS, Merck, ViiV Healthcare, and Janssen Pharmaceutica; the 2NN study was sponsored by Boehringer Ingelheim; and the Tshepiso study was funded by a Grant (R01HD064354) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; Principal Investigator, Richard Chaisson). Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver NICHD and the National Institute of Mental Health (NIMH). The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the NIH."	51	3	3	0	2	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NOV"	2018	57	11	1421	1433	"NA"	"10.1007/s40262-018-0642-9"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GX7RH"	"WOS:000447972300006"	29520730	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Hu, C; Yin, WJ; Li, DY; Ding, JJ; Zhou, LY; Wan, JL; Ma, RR; Liu, K; Zhou, G; Zuo, XC"	"Hu, Can; Yin, Wen-jun; Li, Dai-yang; Ding, Jun-jie; Zhou, Ling-yun; Wan, Jiang-lin; Ma, Rong-rong; Liu, Kun; Zhou, Ge; Zuo, Xiao-cong"	"NA"	"A"	"Evaluating tacrolimus pharmacokinetic models in adult renal transplant recipients with different CYP3A5 genotypes"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Population pharmacokinetics; Tacrolimus; Evaluation; Renal transplant"	"POPULATION PHARMACOKINETICS; CLINICAL PHARMACOKINETICS; BAYESIAN-ESTIMATION; EXTERNAL EVALUATION; CYTOCHROME-P450 3A; KIDNEY; POLYMORPHISMS; PREDICTION; CLEARANCE; EXPOSURE"	"Purpose Numerous studies have been conducted on the population pharmacokinetics of tacrolimus in adult renal transplant recipients. It has been reported that the cytochrome P450 (CYP) 3A5 genotype is an important cause of variability in tacrolimus pharmacokinetics. However, the predictive performance of population pharmacokinetic (PK) models of tacrolimus should be evaluated prior to their implementation in clinical practice. The aim of the study reported here was to test the predictive performance of these published PK models of tacrolimus. Methods A literature search of the PubMed and Web of Science databases ultimately led to the inclusion of eight one-compartment models in our analysis. We collected a total of 1715 trough concentrations from 174 patients. Predictive performance was assessed based on visual and numerical comparison bias and imprecision and by the use of simulation-based diagnostics and Bayesian forecasting. Results Of the eight one-compartment models assessed, seven showed better predictive performance in CYP3A5 extensive metabolizers in terms of bias and imprecision. Results of the simulation-based diagnostics also supported the findings. The model based on a Chinese population in 2013 (model 3) showed the best and most stable predictive performance in all the tests and was more informative in CYP3A5 extensive metabolizers. As expected, Bayesian forecasting improved model predictability. Diversity among models and between different CYP3A5 genotypes of the same model was also narrowed by Bayesian forecasting. Conclusions Based on our results, we recommend using model 3 in CYP3A5 extensive metabolizers in clinical practice. All models had a poor predictive performance in CYP3A5 poor metabolizers, and they should be used with caution in this patient population. However, Bayesian forecasting improved the predictability and reduced differences, and thus the models could be applied in this latter patient population for the design of maintenance dose."	"[Hu, Can; Yin, Wen-jun; Li, Dai-yang; Zhou, Ling-yun; Wan, Jiang-lin; Liu, Kun; Zhou, Ge; Zuo, Xiao-cong] Cent S Univ, Xiangya Hosp 3, Dept Pharm, Changsha 410013, Hunan, Peoples R China; [Ding, Jun-jie] Fudan Univ, Childrens Hosp, Dept Pharm, Shanghai 100029, Peoples R China; [Ma, Rong-rong] Xinjiang Med Univ, Affiliated Hosp 1, Dept Pharm, 137 Liyushan South Rd, Urumqi 830054, Xinjiang, Peoples R China; [Zuo, Xiao-cong] Cent S Univ, Xiangya Hosp 3, Ctr Clin Pharmacol, Changsha 410013, Hunan, Peoples R China"	"Zuo, XC (corresponding author), Cent S Univ, Xiangya Hosp 3, Dept Pharm, Changsha 410013, Hunan, Peoples R China."	"zuoxc08@126.com"	"NA"	"NA"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81773822]; New Xiangya Talent Project of the Third Xiangya Hospital of Central South University [20150218]"	"This study was funded by the National Natural Science Foundation of China (81773822) and the New Xiangya Talent Project of the Third Xiangya Hospital of Central South University (No. 20150218)."	50	6	7	1	4	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"NOV"	2018	74	11	1437	1447	"NA"	"10.1007/s00228-018-2521-6"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HH0BU"	"WOS:000455378000008"	30019212	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Lui, G; Treluyer, JM; Fresneau, B; Piperno-Neumann, S; Gaspar, N; Corradini, N; Gentet, JC; Berard, PM; Laurence, V; Schneider, P; Entz-Werle, N; Pacquement, H; Millot, F; Taque, S; Freycon, C; Lervat, C; Le Deley, MC; Oukhatar, CMA; Brugieres, L; Le Teuff, G; Bouazza, N"	"Lui, Gabrielle; Treluyer, Jean-Marc; Fresneau, Brice; Piperno-Neumann, Sophie; Gaspar, Nathalie; Corradini, Nadege; Gentet, Jean-Claude; Berard, Perrine Marec; Laurence, Valerie; Schneider, Pascale; Entz-Werle, Natacha; Pacquement, Helene; Millot, Frederic; Taque, Sophie; Freycon, Claire; Lervat, Cyril; Le Deley, Marie Cecile; Oukhatar, Celine Mahier Ait; Brugieres, Laurence; Le Teuff, Gwenael; Bouazza, Naim"	"Sarcoma Grp UNICANCER"	"A"	"A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High-Dose Methotrexate: Data From the OS2006/Sarcoma-09 Trial"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"methotrexate; osteosarcoma; pharmacogenetics; population pharmacokinetics"	"CANCER RESISTANCE PROTEIN; POPULATION PHARMACOKINETICS; ABCC2 POLYMORPHISMS; IMPACT; ABCG2; TRANSPORTERS; PREDICTION; CLEARANCE; TOXICITY; CHILDREN"	"Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed-effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK-pharmacogenetic analysis. A 2-compartment model adequately described the data. Although high-dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between-subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers."	"[Lui, Gabrielle; Treluyer, Jean-Marc; Bouazza, Naim] Univ Paris 05, EA 7323, Sorbonne Paris Cite, Paris, France; [Lui, Gabrielle; Treluyer, Jean-Marc] Cochin Hosp, Clin Pharmacol Det, Paris, France; [Lui, Gabrielle; Treluyer, Jean-Marc; Bouazza, Naim] Cochin Necker, Inserm, CIC 1419, Paris, France; [Treluyer, Jean-Marc; Bouazza, Naim] Tarnier Hosp, URC, Paris, France; [Fresneau, Brice; Gaspar, Nathalie; Brugieres, Laurence] Gustave Roussy, Dept Children & Adolescents Oncol, Villejuif, France; [Fresneau, Brice; Le Deley, Marie Cecile; Le Teuff, Gwenael] Paris Saclay Univ, CESP, INSERM, Villejuif, France; [Piperno-Neumann, Sophie; Laurence, Valerie; Pacquement, Helene] Inst Curie, Med Oncol Dept, Paris, France; [Corradini, Nadege] Mother Children Hosp, Pediat Oncol Dept, Nantes, France; [Gentet, Jean-Claude] La Timone Childrens Hosp, Pediat Oncol Dept, Marseille, France; [Berard, Perrine Marec] Leon Berard Anticanc Ctr, Inst Pediat Hematol & Oncol, Pediat Oncol Dept, Lyon, France; [Berard, Perrine Marec] Inst Curie, Oncol Dept, Paris, France; [Schneider, Pascale] Univ Hosp, Pediat Hematooncol Dept, Rouen, France; [Entz-Werle, Natacha] CHU Hautepierre, Pediat Oncol Dept, Strasbourg, France; [Millot, Frederic] INSERM, CIC 1402, Poitiers, France; [Taque, Sophie] Univ Hosp, Dept Pediat Hematooncol, Rennes, France; [Freycon, Claire] Univ Hosp, Child & Family Hosp, Pediat Dept, Grenoble, France; [Lervat, Cyril] Ctr Oscar Lambret, Pediat Oncol Unit, Lille, France; [Le Deley, Marie Cecile; Le Teuff, Gwenael] Gustave Roussy, Biostat Unit, Villejuif, France; [Oukhatar, Celine Mahier Ait] UNICANC Sarcoma Grp, Paris, France"	"Bouazza, N (corresponding author), Unite Rech Clin Paris Descartes Necker Cochin, 89 Rue Assas, F-75006 Paris, France."	"naim.bouazza@aphp.fr"	"NA"	"Le Deley, Marie-Cecile/0000-0002-2946-4592"	"Fondation pour la Recherche MedicaleFondation pour la Recherche Medicale; French National Cancer Institute (INCa)Institut National du Cancer (INCA) France; Ligue Nationale contre le CancerLigue nationale contre le cancer; Federation Enfants et Sante; Societe Francaise des Cancers et Leucemies de l'Enfant"	"This study was sponsored by the Fondation pour la Recherche Medicale, French National Cancer Institute (INCa), Ligue Nationale contre le Cancer, Federation Enfants et Sante, Societe Francaise des Cancers et Leucemies de l'Enfant."	43	4	4	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"DEC"	2018	58	12	1541	1549	"NA"	"10.1002/jcph.1252"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GZ9LO"	"WOS:000449821100002"	29791011	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Russo, FM; Mian, P; Krekels, EH; Van Calsteren, K; Tibboel, D; Deprest, J; Allegaert, K"	"Russo, Francesca M.; Mian, Paola; Krekels, Elke H.; Van Calsteren, Kristel; Tibboel, Dick; Deprest, Jan; Allegaert, Karel"	"NA"	"A"	"Pregnancy affects the pharmacokinetics of sildenafil and its metabolite in the rabbit"	"XENOBIOTICA"	"English"	"Article"	"Pharmacokinetics; population pharmacokinetics modeling; pregnancy; sildenafil"	"CITRATE THERAPY; MODEL"	"1.There is growing interest in the use of sildenafil during pregnancy for various maternal and fetal conditions. This study aims to investigate the effect of pregnancy on the maternal pharmacokinetics (PK) of sildenafil and its main metabolite desmethylsildenafil in rabbits. Using NONMEM, population PK modeling was performed based on plasma samples from 31 rabbits of whom 15 were pregnant and 16 were not. All received a single subcutaneous sildenafil dose of 10 mg/kg. One sample was obtained per rabbit at either 30, 60, 120, 360, 720 or 1320 min after sildenafil administration. 2.A two- and one-compartment PK-model best described the data for sildenafil and desmethylsildenafil, respectively. Compared to non-pregnant rabbits, the central and peripheral volume of distribution and inter-compartmental clearance of sildenafil were lower in pregnant rabbits [32.1 versus 12.2 L, 110 versus 44.4 L and 25.5 versus 12.1 L/h; all p < 0.05]. The formation clearance from sildenafil to desmethylsildenafil was also reduced during pregnancy [13.3 versus 7.8 L/h; p < 0.05]. 3.In contrast, the elimination clearance of desmethylsildenafil, was higher in pregnancy [73.5 versus 116. 9; p < 0.05]. In rabbits, pregnancy impacts PK parameters of sildenafil and its metabolite, leading to an increased peak concentration and 24 h exposure for sildenafil and a decreased 24 h exposure for desmethylsildenafil."	"[Russo, Francesca M.; Van Calsteren, Kristel; Deprest, Jan; Allegaert, Karel] Katholieke Univ Leuven, Cluster Woman & Child, Dept Dev & Regenerat, Biomed Sci, Leuven, Belgium; [Russo, Francesca M.; Van Calsteren, Kristel; Deprest, Jan] Univ Hosp Leuven, Dept Obstet & Gynecol, Leuven, Belgium; [Mian, Paola; Tibboel, Dick; Allegaert, Karel] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [Mian, Paola; Tibboel, Dick; Allegaert, Karel] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Rotterdam, Netherlands; [Krekels, Elke H.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Deprest, Jan] UCL, Inst Womens Hlth, Dept Obstet & Gynecol, London, England"	"Allegaert, K (corresponding author), Katholieke Univ Leuven, Cluster Woman & Child, Dept Dev & Regenerat, Biomed Sci, Leuven, Belgium."	"karel.allegaert@uzleuven.be"	"allegaert, karel/C-3611-2016; Mian, Paola/Y-1481-2019"	"allegaert, karel/0000-0001-9921-5105; Russo, Francesca/0000-0002-5029-7899; Deprest, Jan/0000-0002-4920-945X"	"Fund for Scientific Research, FlandersFWO [1800214 N]; agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG projectInstitute for the Promotion of Innovation by Science and Technology in Flanders (IWT) [IWT/SBO 130033]; Brianna Memorial Research Fund; KU LeuvenKU Leuven [C3/17/054, C3/15/353]; Great Ormond Street Hospital Charity Fund"	"Karel Allegaert has been supported by the Fund for Scientific Research, Flanders (fundamental clinical investigatorship 1800214 N), and his research activities are further facilitated by the agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project (IWT/SBO 130033). The Leuven program on medical therapy of CDH is funded by the Brianna Memorial Research Fund and the KU Leuven (C3/17/054, and C3/15/353). JDP is supported by the Great Ormond Street Hospital Charity Fund."	39	2	2	0	3	"TAYLOR & FRANCIS LTD"	"ABINGDON"	"2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND"	"0049-8254"	"1366-5928"	"NA"	"XENOBIOTICA"	"Xenobiotica"	"JAN 2"	2019	49	1	98	105	"NA"	"10.1080/00498254.2017.1422217"	8	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"HJ2SJ"	"WOS:000457019900010"	29278046	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"van Oud-Alblas, HJB; Brill, MJE; Peeters, MYM; Tibboel, D; Danhof, M; Knibbe, CAJ"	"van Oud-Alblas, Heleen J. Blusse; Brill, Margreke J. E.; Peeters, Mariska Y. M.; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Population pharmacokinetic-pharmacodynamic model of propofol in adolescents undergoing scoliosis surgery with intraoperative wake-up test: a study using Bispectral index and composite auditory evoked potentials as pharmacodynamic endpoints"	"BMC ANESTHESIOLOGY"	"English"	"Article"	"Propofol; Pharmacokinetics; Pharmacodynamics; Population PKPD modeling; Bispectral index; Auditory evoked potentials; Adolescents; Anesthetic depth"	"CHILDREN; REMIFENTANIL; ANESTHESIA; DETERMINANT; PERFORMANCE; INFUSION; SEDATION; INFANTS; AGE"	"Background: In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia using both Bispectral Index (BIS) and composite A-line ARX index (cAAI) as endpoints. Methods: Fourteen adolescents (9.8-20.1 years) were evaluated during standardized propofol-remifentanil anesthesia for idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia. BIS and cAAI were continuously measured and blood samples collected. A propofol PKPD model was developed using NONMEM. Results: The time courses of propofol concentrations, BIS and cAAI values during anesthesia, intra-operative wakeup and reduction of anesthesia were best described by a two-compartment PK model linked to an inhibitory sigmoidal Emax PD model. For the sigmoidal Emax model, the propofol concentration at half maximum effect (EC50) was 3.51 and 2.14 mg/L and Hill coefficient 1.43 and 6.85 for BIS and cAAI, respectively. The delay in PD effect in relation to plasma concentration was best described by a two compartment effect-site model with a ke(o) of 0.102 min(-1), ke(12) of 0. 121 min(-1) and ke(21) of 0.172 min(-1). Conclusions: A population PKPD model for propofol in adolescents was developed that successfully described the time course of propofol concentration, BIS and cAAI in individuals upon undergoing scoliosis surgery with intraoperative wake-up test and reinduction of anesthesia. Large differences were demonstrated between both monitors. This may imply that BIS and cAAI measure fundamentally different endpoints in the brain."	"[van Oud-Alblas, Heleen J. Blusse] Erasmus MC, Dept Anesthesiol, Rotterdam, Netherlands; [van Oud-Alblas, Heleen J. Blusse] St Antonius Hosp, Dept Anesthesiol, Nieuwegein, Netherlands; [Brill, Margreke J. E.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Brill, Margreke J. E.; Peeters, Mariska Y. M.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands; [Tibboel, Dick] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Intens Care, Rotterdam, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands.; Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"NA"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NA"	"NA"	33	1	1	0	1	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1471-2253"	"NA"	"NA"	"BMC ANESTHESIOL"	"BMC Anesthesiol."	"JAN 22"	2019	19	"NA"	"NA"	"NA"	15	"10.1186/s12871-019-0684-z"	12	"Anesthesiology"	"Anesthesiology"	"HP7PM"	"WOS:000461880800001"	30669968	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Stockmann, C; Olson, J; Rashid, J; Lubsch, L; Young, DC; Hersh, AL; Frymoyer, A; Ampofo, K; Liu, XX; Wang, YH; Sherwin, CMT; Zobell, JT"	"Stockmann, Chris; Olson, Jared; Rashid, Jahidur; Lubsch, Lisa; Young, David C.; Hersh, Adam L.; Frymoyer, Adam; Ampofo, Krow; Liu, Xiaoxi; Wang, Yuhuan; Sherwin, Catherine M. T.; Zobell, Jeffery T."	"NA"	"A"	"An Evaluation of Vancomycin Area Under the Curve Estimation Methods for Children Treated for Acute Pulmonary Exacerbations of Cystic Fibrosis Due to Methicillin-Resistant Staphylococcus aureus"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Vancomycin; Pediatrics; Cystic Fibrosis; MRSA"	"TROUGH CONCENTRATIONS; PHARMACOKINETICS; ASSOCIATION; INFECTION; PACKAGE; MODELS"	"The prevalence of pulmonary methicillin-resistant Staphylococcus aureus infections in patients with cystic fibrosis (CF) has increased over the last 2 decades. Two concentrations-a postdistributive and a trough-are currently used to estimate the area under the curve (AUC) of vancomycin, an antibiotic routinely used to treat these infections, to achieve the target AUC/minimum inhibitory concentration of >= 400 mg center dot h/L in ensuring optimal dosing of this drug. This study evaluated precision and bias in estimating vancomycin AUCs obtained either from a population pharmacokinetic (PK) model by using a single trough concentration or from standard PK equation-based 2-point monitoring approach. AUCs were either obtained from a single trough concentration-fitted model or derived from a model fitted by 2 concentration points. Children >= 2 years of age with CF received intravenous vancomycin at 2 centers from June 2012 to December 2014. A population PK model was developed in Pmetrics to quantify the between-subject variability in vancomycin PK parameters, define the sources of PK variability, and leverage information from the population to improve individual AUC estimates. Twenty-three children with CF received 27 courses of vancomycin. The median age was 12.3 (interquartile range [IQR] 8.5-16.6) years. From the individual vancomycin PK parameter estimates from the population PK model, median AUC was 622 (IQR 529-680) mg center dot h/L. Values were not significantly different from the AUC calculated using the standard PK equation-based approach (median 616 [IQR 540-663] mg center dot h/L) (P = .89). A standard PK equation-based approach using 2 concentrations and a population PK model-based approach using a single trough concentration yielded unbiased and precise AUC estimates. Findings suggest that options exist to implement AUC-based pediatric vancomycin dosing in patients with CF. The findings of this study reveal that several excellent options exist for centers to implement AUC-based pediatric vancomycin dosing for patients with CF."	"[Stockmann, Chris; Rashid, Jahidur; Liu, Xiaoxi; Wang, Yuhuan; Sherwin, Catherine M. T.] Univ Utah, Div Clin Pharmacol, Dept Pediat, Sch Med, Salt Lake City, UT 84108 USA; [Stockmann, Chris; Young, David C.; Sherwin, Catherine M. T.; Zobell, Jeffery T.] Univ Utah, Coll Pharm, Salt Lake City, UT 84108 USA; [Stockmann, Chris; Olson, Jared; Hersh, Adam L.; Ampofo, Krow] Univ Utah, Div Pediat Infect Dis, Dept Pediat, Sch Med, Salt Lake City, UT 84108 USA; [Olson, Jared; Zobell, Jeffery T.] Intermt Primary Childrens Hosp, Dept Pharm, Salt Lake City, UT USA; [Lubsch, Lisa] Southern Illinois Univ Edwardsville, Sch Pharm, Edwardsville, IL USA; [Young, David C.] Univ Utah, Adult Cyst Fibrosis Ctr, Salt Lake City, UT 84108 USA; [Frymoyer, Adam] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA; [Zobell, Jeffery T.] Intermt Cyst Fibrosis Pediat Ctr, Salt Lake City, UT USA"	"Sherwin, CMT (corresponding author), Univ Utah, Sch Med, Dept Pediat, 295 Chipeta Way, Salt Lake City, UT 84108 USA."	"Catherine.sherwin@hsc.utah.edu"	"Sherwin, Catherine Mary Turner/B-2888-2012"	"Sherwin, Catherine Mary Turner/0000-0002-0844-3207"	"NA"	"NA"	36	5	6	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"FEB"	2019	59	2	198	205	"NA"	"10.1002/jcph.1323"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HI3DT"	"WOS:000456327700005"	30371946	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Tang, BH; Wu, YE; Kou, C; Qi, YJ; Qi, H; Xu, HY; Leroux, S; Huang, X; Zhou, Y; Zheng, Y; Jacqz-Aigrain, E; Shen, AD; Zhao, W"	"Tang, Bo-Hao; Wu, Yue-E; Kou, Chen; Qi, Yu-Jie; Qi, Hui; Xu, Hai-Yan; Leroux, Stephanie; Huang, Xin; Zhou, Yue; Zheng, Yi; Jacqz-Aigrain, Evelyne; Shen, A-Dong; Zhao, Wei"	"NA"	"A"	"Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"amoxicillin; dosing optimization; neonates; pharmacokinetics"	"PRETERM INFANTS; SEVERE SEPSIS; PHARMACODYNAMICS; INFUSION; MODELS"	"Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics."	"[Tang, Bo-Hao; Wu, Yue-E; Zhou, Yue; Zheng, Yi; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Kou, Chen] Capital Med Univ, Beijing Obstet & Gynecol Hosp, Dept Neonatol, Beijing, Peoples R China; [Qi, Yu-Jie] Capital Med Univ, Beijing Childrens Hosp, Natl Ctr Childrens Hlth, Neonatal Intens Care Unit, Beijing, Peoples R China; [Qi, Hui; Shen, A-Dong] Capital Med Univ, Minist Educ,Key Lab Major Dis Children,Natl Ctr C, Beijing Pediat Res Inst,Beijing Childrens Hosp,Be, Natl Key Discipline Pediat,Natl Clin Res Ctr Resp, Beijing, Peoples R China; [Xu, Hai-Yan] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Neonatol, Jinan, Shandong, Peoples R China; [Leroux, Stephanie] CHU Rennes, Neonatal Intens Care Unit, Rennes, France; [Huang, Xin] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China."	"zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002]; Young Taishan Scholars Program of Shandong Province; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015M582102]; Capital's Funds for Health Improvement and Research [2018-4-1142]; Qilu Outstanding Program of Shandong University, Capital Health Research and Development of Special Grant [2016-1-2092]"	"This study was supported by National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002), the Young Taishan Scholars Program of Shandong Province and Qilu Outstanding Program of Shandong University, Capital Health Research and Development of Special Grant (2016-1-2092) and China Postdoctoral Science Foundation (2015M582102), and Capital's Funds for Health Improvement and Research (2018-4-1142)."	29	2	2	0	7	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"FEB"	2019	63	2	"NA"	"NA"	"e02336-18"	"10.1128/AAC.02336-18"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"HJ3YN"	"WOS:000457110200057"	30509939	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Patel, K; Kirkpatrick, CM; Nieforth, KA; Chanda, S; Zhang, QL; McClure, M; Fry, J; Symons, JA; Blatt, LM; Beigelman, L; DeVincenzo, JP; Huntjens, DR; Smith, PF"	"Patel, Kashyap; Kirkpatrick, Carl M.; Nieforth, Keith A.; Chanda, Sushmita; Zhang, Qingling; McClure, Matthew; Fry, John; Symons, Julian A.; Blatt, Lawrence M.; Beigelman, Leo; DeVincenzo, John P.; Huntjens, Dymphy R.; Smith, Patrick F."	"NA"	"A"	"Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"YOUNG-CHILDREN; PALIVIZUMAB PROPHYLAXIS; EUROPEAN-SOCIETY; UPDATED GUIDANCE; INCREASED RISK; INFLUENZA; MODEL; INFANTS; HOSPITALIZATION; QUANTIFICATION"	"Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This pro drug converts to plasma-circulating ALS-8112, and then to the 5`-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods: Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicita bine treatment (EC50 - 1.79 mu M), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients."	"[Patel, Kashyap; Nieforth, Keith A.; Smith, Patrick F.] D3 Med, Parsippany, NJ 07054 USA; [Patel, Kashyap; Kirkpatrick, Carl M.] Monash Univ, Ctr Med Use & Safety, Melbourne, Vic, Australia; [Chanda, Sushmita; Zhang, Qingling; McClure, Matthew; Fry, John; Symons, Julian A.; Blatt, Lawrence M.; Beigelman, Leo] Alios BioPharma Inc, San Francisco, CA USA; [DeVincenzo, John P.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA; [DeVincenzo, John P.] Univ Tennessee, Ctr Hlth Sci, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA; [DeVincenzo, John P.] LeBonheur Childrens Hosp, Childrens Fdn Res Inst, Memphis, TN USA; [Huntjens, Dymphy R.] Janssen Pharmaceut NV, Janssen R&D, Beerse, Belgium"	"Smith, PF (corresponding author), D3 Med, Parsippany, NJ 07054 USA."	"patrick.smith@certara.com"	"Kirkpatrick, Carl MJ/F-1222-2010"	"Kirkpatrick, Carl/0000-0002-5715-1534"	"Alios Biopharma; Johnson and Johnson Company"	"This work was supported by Alios Biopharma, a Johnson and Johnson Company."	44	3	3	5	9	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"FEB"	2019	74	2	442	452	"NA"	"10.1093/jac/dky415"	11	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"HN8UW"	"WOS:000460473100022"	30376079	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Lu, T; Zhu, X; Xu, SS; Zhao, MM; Huang, XS; Wang, ZY; Zhao, LM"	"Lu, Tong; Zhu, Xu; Xu, Shansen; Zhao, Mingming; Huang, Xueshi; Wang, Zhanyou; Zhao, Limei"	"NA"	"A"	"Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"dosage optimization; genetic polymorphisms; nephrotic syndrome; population pharmacokinetics; tacrolimus"	"SCHISANDRA-SPHENANTHERA EXTRACT; PREGNANE X-RECEPTOR; RENAL-TRANSPLANT RECIPIENTS; CYP3A5 GENOTYPE; BAYESIAN-ESTIMATION; CLINICAL FACTORS; GENE-EXPRESSION; KIDNEY; POLYMORPHISMS; PHARMACODYNAMICS"	"PurposeThe objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients.MethodsNephrotic syndrome patients (>16years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus.ResultsThe mean apparent clearance (CL/F) of tacrolimus was 13.4L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers.ConclusionsA new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration."	"[Lu, Tong; Zhu, Xu; Xu, Shansen; Zhao, Mingming; Zhao, Limei] China Med Univ, Shengjing Hosp, Dept Pharm, Shenyang 110004, Liaoning, Peoples R China; [Lu, Tong; Zhao, Limei] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang 110016, Liaoning, Peoples R China; [Huang, Xueshi] Northeastern Univ, Coll Life & Hlth Sci, Shenyang 110169, Liaoning, Peoples R China; [Wang, Zhanyou] China Med Univ, Key Lab Med Cell Biol, Minist Educ, Inst Hlth Sci, Shenyang 110122, Liaoning, Peoples R China"	"Zhao, LM (corresponding author), China Med Univ, Shengjing Hosp, Dept Pharm, Shenyang 110004, Liaoning, Peoples R China.; Zhao, LM (corresponding author), Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang 110016, Liaoning, Peoples R China."	"15840122619@163.com; zhaolm@sj-hospital.org"	"NA"	"NA"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81,673,510, 81,703,626, U1608282]; Science and Technology Research Project of Education Department of Liaoning Province [LK201611]"	"The authors would like to thank Professor Zheng Jiao from Huashan Hospital, Fudan University, China, for his invaluable advice and support. This project was supported by grants from the National Natural Science Foundation of China (Nos. 81,673,510, 81,703,626, and U1608282) and the Science and Technology Research Project of Education Department of Liaoning Province (No. LK201611). The authors declare no conflicts of interest."	49	5	5	1	11	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"MAR"	2019	36	3	"NA"	"NA"	45	"10.1007/s11095-019-2579-6"	11	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"HK3CE"	"WOS:000457789400001"	30719576	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Qi, H; Kou, C; Qi, YJ; Tang, BH; Wu, YE; Jin, F; Luo, XJ; Shen, YH; Guo, YJ; Qi, X; Wang, YC; Dong, Q; Chen, XK; Shi, HY; Zheng, Y; Zhao, W; Shen, AD"	"Qi, Hui; Kou, Chen; Qi, Yu-Jie; Tang, Bo-Hao; Wu, Yue-E; Jin, Fei; Luo, Xiao-Jing; Shen, Yan-Hua; Guo, Ya-Jie; Qi, Xue; Wang, Ya-Cui; Dong, Qian; Chen, Xing-Kai; Shi, Hai-Yan; Zheng, Yi; Zhao, Wei; Shen, A-Dong"	"NA"	"A"	"Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants"	"INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS"	"English"	"Article"	"Latamoxef; Population; Pharmacokinetics-pharmacodynamics; Neonates and young infants"	"MOXALACTAM; SEPSIS"	"Objectives: There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has recently been brought back into use for treatment of infections in newborns; however, it is still used off-label in neonatal clinical practice due to the lack of an evidence-based dosing regimen. This study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants, and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD). Methods: Opportunistic blood samples from newborns treated with latamoxef were collected to determine the latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range 28.4-46.1 weeks) were available for analysis. Results: A two-compartment model with first-order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicated that the current dosing regimen (30 mg/kg q12h) is adequate with an MIC of 1 mg/L. For an MIC of 4 mg/L, 30 mg/kg q8h was required to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval. Conclusions: Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen. (c) 2018 Published by Elsevier B.V."	"[Qi, Hui; Guo, Ya-Jie; Qi, Xue; Wang, Ya-Cui; Shen, A-Dong] Capital Med Univ, Beijing Key Lab Pediat Resp Infect Dis, Key Lab Major Dis Children,Natl Clin Res Ctr Resp, Minist Educ,Beijing Childrens Hosp,Natl Ctr Child, Beijing, Peoples R China; [Kou, Chen] Capital Med Univ, Beijing Obstet & Gynecol Hosp, Dept Neonatol, Beijing, Peoples R China; [Qi, Yu-Jie; Jin, Fei; Luo, Xiao-Jing; Shen, Yan-Hua] Capital Med Univ, Beijing Childrens Hosp, Natl Ctr Childrens Hlth, Neonatal Intens Care Unit, Beijing, Peoples R China; [Tang, Bo-Hao; Wu, Yue-E; Dong, Qian; Chen, Xing-Kai; Zheng, Yi; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Shi, Hai-Yan; Zhao, Wei] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China"	"Shen, AD (corresponding author), Capital Med Univ, Beijing Key Lab Pediat Resp Infect Dis, Key Lab Major Dis Children,Natl Clin Res Ctr Resp, Minist Educ,Beijing Childrens Hosp,Natl Ctr Child, Beijing, Peoples R China.; Zhao, W (corresponding author), Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China."	"zhao4wei2@hotmail.com; shenad16@hotmail.com"	"Zhao, Wei/D-3322-2011; shen, chen/AAC-2458-2020"	"Zhao, Wei/0000-0002-1830-338X;"	"Capital Health Research and Development of Special Grant [2016-1-2092]; Capital's Funds for Health Improvement and Research [2018-4-1142]; National Science and Technology Major Project for Major New Drugs Innovation and Development [2017ZX09304029002, 2017ZX09304029005]; Young Taishan Scholars Program of Shandong University; Qilu Young Scholars Program of Shandong University"	"This work was supported by grants from Capital Health Research and Development of Special Grant (2016-1-2092), Capital's Funds for Health Improvement and Research (2018-4-1142), National Science and Technology Major Project for Major New Drugs Innovation and Development (2017ZX09304029002; 2017ZX09304029005), Young Taishan Scholars Program and Qilu Young Scholars Program of Shandong University. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript."	19	2	2	0	7	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0924-8579"	"1872-7913"	"NA"	"INT J ANTIMICROB AG"	"Int. J. Antimicrob. Agents"	"MAR"	2019	53	3	347	351	"NA"	"10.1016/j.ijantimicag.2018.11.017"	5	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"HM9GQ"	"WOS:000459791500019"	30472290	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Niu, WJ; Sun, T; Liu, L; Liu, XQ; Zhang, RF; Yin, L; Wang, JR; Jia, XF; Lu, HZ; Zhong, MK; Jiao, Z; Zhang, LJ"	"Niu, Wan-jie; Sun, Tao; Liu, Li; Liu, Xiao-qian; Zhang, Ren-fang; Yin, Lin; Wang, Jiang-rong; Jia, Xiao-fang; Lu, Hong-Zhou; Zhong, Ming-kang; Jiao, Zheng; Zhang, Li-jun"	"NA"	"A"	"Population pharmacokinetics and dosing regimen optimisation of lopinavir in Chinese adults infected with HIV"	"BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY"	"English"	"Article"	"Chinese patients; HIV; lopinavir; population pharmacokinetics; ritonavir; simulation"	"HUMAN-IMMUNODEFICIENCY-VIRUS; LOPINAVIR/RITONAVIR; INHIBITOR; RITONAVIR; NAIVE; COMBINATION; MODEL; POLYMORPHISMS; VARIABILITY; PARAMETERS"	"Lopinavir (LPV) is a protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infections. Current studies on LPV are mainly focused on Caucasians, and none have investigated the population pharmacokinetics (PPK) of LPV in Chinese population. The present study aimed to develop a PPK model for oral LPV in Chinese adults who are HIV-infected. A total of 460 LPV concentrations from 174 Chinese patients who received LPV/ritonavir (LPV/r) 400/100 mg orally every 12 hours (q12h) were analysed using the non-linear mixed-effects modelling approach. Simulations of the LPV concentration profile were performed with different dosing regimens. A one-compartment model with first-order absorption and elimination process described the data. The estimated apparent clearance (CL/F) and volume of distribution (V/F) (% relative standard error [RSE]) for oral LPV were 5.9 L/h (3%) and 117 L (8%), respectively. Body-weight was identified as a covariate on CL/F. In patients who weighed between 45 and 115 kg and received the standard 400/100 mg q12h regimen, the probability of achieving target trough concentration (C-trough) of 1 mg/L was >98% for PI-naive patients and the probability of achieving target C-trough of 4 mg/L was <80% for PI-pretreated patients. This is the first population pharmacokinetic study to characterise the PK of LPV in Chinese patients with HIV infection. There were no obvious ethnic differences in the PK of LPV between the Chinese population and Caucasian population. The simulations demonstrated that the standard dosing regimen of 400/100 mg q12h (LPV/r tablets) appears to be sufficient for PI-naive patients but suboptimal for PI-pretreated patients. Therefore, the regimen of 800/200 mg q12h was recommended for PI-pretreated patients. Further investigation of dosage recommendation could be helpful in optimising LPV therapy for HIV infections."	"[Sun, Tao; Liu, Li; Liu, Xiao-qian; Zhang, Ren-fang; Yin, Lin; Wang, Jiang-rong; Jia, Xiao-fang; Lu, Hong-Zhou; Zhang, Li-jun] Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China; [Niu, Wan-jie; Zhong, Ming-kang; Jiao, Zheng] Fudan Univ, Huashan Hosp, Dept Pharm, Shanghai, Peoples R China"	"Jiao, Z (corresponding author), Fudan Univ, Huashan Hosp, Dept Pharm, Shanghai, Peoples R China.; Zhang, LJ (corresponding author), Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China."	"zjiao@fudan.edu.cn; zhanglijun1221@163.com"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162"	"13th Five-Year National Major New Drug Development [2017ZX09304027]; Key Issues of Shanghai Municipal Commission of Health and Family Planning [201640005]; Weak Discipline Construction Project from Shanghai Municipal Commission of Health and Family Planning [2016ZB0301]; 2016 Key Clinical Program of Clinical Pharmacy of Shanghai Municipal Commission of Health and Family Planning"	"This work was supported by grants from the 13th Five-Year National Major New Drug Development (2017ZX09304027), the Key Issues of Shanghai Municipal Commission of Health and Family Planning (201640005). Dr. Jiao was supported by the Weak Discipline Construction Project (No. 2016ZB0301) from Shanghai Municipal Commission of Health and Family Planning. Dr. Zhong was supported by 2016 Key Clinical Program of Clinical Pharmacy of Shanghai Municipal Commission of Health and Family Planning."	44	2	2	1	9	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1742-7835"	"1742-7843"	"NA"	"BASIC CLIN PHARMACOL"	"Basic Clin. Pharmacol. Toxicol."	"APR"	2019	124	4	456	465	"NA"	"10.1111/bcpt.13154"	10	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"HP7QE"	"WOS:000461882700012"	30346663	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Zhang, HX; Sheng, CC; Liu, LS; Luo, B; Fu, Q; Zhao, Q; Li, J; Liu, YF; Deng, RH; Jiao, Z; Wang, CX"	"Zhang, Huan-Xi; Sheng, Chang-Cheng; Liu, Long-Shan; Luo, Bi; Fu, Qian; Zhao, Qun; Li, Jun; Liu, Yan-Feng; Deng, Rong-Hai; Jiao, Zheng; Wang, Chang-Xi"	"NA"	"M"	"Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"adult kidney transplant recipients; enterohepatic circulation; external evaluation; mycophenolate mofetil; population pharmacokinetics"	"ENTEROHEPATIC CIRCULATION; ACID; CYCLOSPORINE; PREDICTION; PARAMETERS; REJECTION"	"Aims Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. Methods The external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. Results Fifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within � 30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. Conclusions The published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF."	"[Zhang, Huan-Xi; Liu, Long-Shan; Fu, Qian; Li, Jun; Deng, Rong-Hai; Wang, Chang-Xi] Sun Yat Sen Univ, Affiliated Hosp 1, Organ Transplant Ctr, 58 Zhongshan Second Rd, Guangzhou 510080, Guangdong, Peoples R China; [Sheng, Chang-Cheng; Luo, Bi; Zhao, Qun; Jiao, Zheng] Fudan Univ, Huashan Hosp, Dept Pharm, 12 Middle Urumqi Rd, Shanghai 200040, Peoples R China; [Sheng, Chang-Cheng] Guizhou Prov Peoples Hosp, Dept Pharm, Guiyang, Guizhou, Peoples R China; [Liu, Yan-Feng] Shenzhen Peoples Hosp, Dept Urol, Shenzhen, Peoples R China; [Wang, Chang-Xi] Guangdong Prov Key Lab Organ Donat & Transplant I, Guangzhou, Guangdong, Peoples R China"	"Wang, CX (corresponding author), Sun Yat Sen Univ, Affiliated Hosp 1, Organ Transplant Ctr, 58 Zhongshan Second Rd, Guangzhou 510080, Guangdong, Peoples R China.; Jiao, Z (corresponding author), Fudan Univ, Huashan Hosp, Dept Pharm, 12 Middle Urumqi Rd, Shanghai 200040, Peoples R China."	"zjiao@fudan.edu.cn; wangchx@mail.sysu.edu.cn"	"Jiao, Zheng/H-7596-2014"	"Jiao, Zheng/0000-0001-7999-7162; SHENG, Chang-Cheng/0000-0001-5844-0154"	"NA"	"NA"	52	3	3	1	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"APR"	2019	85	4	746	761	"NA"	"10.1111/bcp.13850"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HP7UM"	"WOS:000461895700012"	30597603	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Li, SC; Ye, Q; Xu, H; Zhang, L; Wang, Y"	"Li, Si-Chan; Ye, Qi; Xu, Hua; Zhang, Long; Wang, Yang"	"NA"	"A"	"Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"children; dosing; linezolid; pharmacokinetics"	"DRUG; PREDICTION; SAFETY; ERRORS"	"Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of >= 2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization."	"[Li, Si-Chan; Ye, Qi; Xu, Hua; Wang, Yang] Huazhong Univ Sci & Technol, Tonji Med Coll, Wuhan Childrens Hosp, Dept Clin Pharm, Wuhan, Hubei, Peoples R China; [Zhang, Long] Huazhong Univ Sci & Technol, Tonji Med Coll, Wuhan Childrens Hosp, Dept Intens Care Unit, Wuhan, Hubei, Peoples R China"	"Wang, Y (corresponding author), Huazhong Univ Sci & Technol, Tonji Med Coll, Wuhan Childrens Hosp, Dept Clin Pharm, Wuhan, Hubei, Peoples R China."	"cattop3211@qq.com"	"NA"	"Li, Sichan/0000-0002-8526-1634"	"Youth Program of the National Natural Science Foundation of China [81600123]; Youth Foundation of the Wuhan Municipal Population and Family Planning Commission [WX17Z13]"	"This study was supported by the Youth Program of the National Natural Science Foundation of China (grant agreement number 81600123) and the Youth Foundation of the Wuhan Municipal Population and Family Planning Commission (grant agreement number WX17Z13)."	34	2	2	0	5	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2019	63	4	"NA"	"NA"	"e02387-18"	"10.1128/AAC.02387-18"	12	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"HQ5SY"	"WOS:000462474100067"	30642929	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ibrahim, MMA; Ueckert, S; Freiberga, S; Kjellsson, MC; Karlsson, MO"	"Ibrahim, Moustafa M. A.; Ueckert, Sebastian; Freiberga, Svetlana; Kjellsson, Maria C.; Karlsson, Mats O."	"NA"	"M"	"Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment"	"AAPS JOURNAL"	"English"	"Article"	"conditional weighted residuals; diagnostics; model evaluation; nonlinear mixed effects models; prediction bias; structural model"	"GLUCOSE-TOLERANCE TEST; MINIMAL MODEL; INSULIN"	"Nonlinear mixed effects models are widely used to describe longitudinal data to improve the efficiency of drug development process or increase the understanding of the studied disease. In such settings, the appropriateness of the modeling assumptions is critical in order to draw correct conclusions and must be carefully assessed for any substantial violations. Here, we propose a new method for structure model assessment, based on assessment of bias in conditional weighted residuals (CWRES). We illustrate this method by assessing prediction bias in two integrated models for glucose homeostasis, the integrated glucose-insulin (IGI) model, and the integrated minimal model (IMM). One dataset was simulated from each model then analyzed with the two models. CWRES outputted from each model fitting were modeled to capture systematic trends in CWRES as well as the magnitude of structural model misspecifications in terms of difference in objective function values (OFVBias). The estimates of CWRES bias were used to calculate the corresponding bias in conditional predictions by the inversion of first-order conditional estimation method's covariance equation. Time, glucose, and insulin concentration predictions were the investigated independent variables. The new method identified correctly the bias in glucose sub-model of the integrated minimal model (IMM), when this bias occurred, and calculated the absolute and proportional magnitude of the resulting bias. CWRES bias versus the independent variables agreed well with the true trends of misspecification. This method is fast easily automated diagnostic tool for model development/evaluation process, and it is already implemented as part of the Perl-speaks-NONMEM software."	"[Ibrahim, Moustafa M. A.; Ueckert, Sebastian; Freiberga, Svetlana; Kjellsson, Maria C.; Karlsson, Mats O.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Ibrahim, Moustafa M. A.] Helwan Univ, Dept Pharm Practice, Cairo, Egypt"	"Karlsson, MO (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden."	"mats.karlsson@farmbio.uu.se"	"Ueckert, Sebastian/AAU-8365-2020"	"Ueckert, Sebastian/0000-0002-3712-0255; Ibrahim, Moustafa/0000-0002-2084-1531"	"NA"	"NA"	24	0	0	0	3	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"MAY"	2019	21	3	"NA"	"NA"	34	"10.1208/s12248-019-0305-2"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HN4WL"	"WOS:000460184300001"	30815754	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Langenhorst, JB; Dorlo, TPC; van Maarseveen, EM; Nierkens, S; Kuball, J; Boelens, JJ; van Kesteren, C; Huitema, ADR"	"Langenhorst, Jurgen B.; Dorlo, Thomas P. C.; van Maarseveen, Erik M.; Nierkens, Stefan; Kuball, Jurgen; Boelens, Jaap Jan; van Kesteren, Charlotte; Huitema, Alwin D. R."	"NA"	"A"	"Population Pharmacokinetics of Fludarabine in Children and Adults during Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"PREPARATIVE REGIMEN; BUSULFAN; MODEL; CLEARANCE; CYCLOPHOSPHAMIDE; PREDICTION; PARAMETERS; EXPOSURE; THERAPY; PLASMA"	"BackgroundFludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used.ObjectiveWe sought to describe the population PK of fludarabine in HCT recipients of all ages.MethodsFrom 258 HCT recipients aged 0.3-74years, 2605 samples were acquired on days 1 (42%), 2 (17%), 3 (4%) and 4 (37%) of conditioning. Herein, the circulating metabolite of fludarabine was quantified, and derived concentration-time data were used to build a population PK model using non-linear mixed-effects modelling.ResultsVariability was extensive where area under the curve ranged from 10 to 66mgh/L. A three-compartment model with first-order kinetics best described the data. Actual body weight (BW) with standard allometric scaling was found to be the best body-size descriptor for all PK parameters. Estimated glomerular filtration rate (eGFR) was included as a descriptor of renal function. Thus, clearance was differentiated into a non-renal (3.2420% L/h/70kg) and renal (eGFRx0.782 � 11% L/h/70kg) component. The typical volumes of distribution of the central (V1), peripheral (V2), and second peripheral (V3) compartments were 39 � 8%, 20 � 11%, and 50 � 9% L/70kg respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 8.6 � 8% and 3.8 � 13% L/h/70kg, respectively.Conclusion p id=Par5 BW and eGFR are important predictors of fludarabine PK. Therefore, current linear BSA-based dosing leads to highly variable exposure, which may lead to variable treatment outcome."	"[Langenhorst, Jurgen B.; Boelens, Jaap Jan; van Kesteren, Charlotte] Univ Utrecht, Univ Med Ctr Utrecht, Pediat Blood & Marrow Transplant Program, Utrecht, Netherlands; [Langenhorst, Jurgen B.; Nierkens, Stefan; Kuball, Jurgen; van Kesteren, Charlotte] Univ Utrecht, Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands; [Dorlo, Thomas P. C.; Huitema, Alwin D. R.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands; [van Maarseveen, Erik M.; Huitema, Alwin D. R.] Univ Utrecht, Univ Med Ctr, Dept Clin Pharm, Heidelberglaan 100 D-00-X, NL-3584 CX Utrecht, Netherlands; [Kuball, Jurgen] Univ Utrecht, Univ Med Ctr, Dept Hematol, Utrecht, Netherlands; [Boelens, Jaap Jan] Mem Sloan Kettering Canc Ctr, Pediat, Stem Cell Transplant & Cellular Therapies, 1275 York Ave, New York, NY 10021 USA"	"Huitema, ADR (corresponding author), Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands.; Huitema, ADR (corresponding author), Univ Utrecht, Univ Med Ctr, Dept Clin Pharm, Heidelberglaan 100 D-00-X, NL-3584 CX Utrecht, Netherlands."	"a.d.r.huitema-2@umcutrecht.nl"	"Dorlo, Thomas/F-1339-2011"	"Dorlo, Thomas/0000-0003-3076-8435"	"Foundation Children Cancerfree (KiKa) [190]"	"This work was supported by Foundation Children Cancerfree (KiKa) project number 190."	36	8	8	3	4	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAY"	2019	58	5	627	637	"NA"	"10.1007/s40262-018-0715-9"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HS2CW"	"WOS:000463669700005"	30327943	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"van Beek, SW; ter Heine, R; Keizer, RJ; Magis-Escurra, C; Aarnoutse, RE; Svensson, EM"	"van Beek, Stijn W.; ter Heine, Rob; Keizer, Ron J.; Magis-Escurra, Cecile; Aarnoutse, Rob E.; Svensson, Elfin M."	"NA"	"A"	"Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"LIMITED SAMPLING STRATEGIES; POPULATION PHARMACOKINETICS; PULMONARY TUBERCULOSIS; SEMIMECHANISTIC MODEL; DRUG CONCENTRATIONS; AUTOINDUCTION; PHARMACODYNAMICS; QUANTIFICATION; LEVOFLOXACIN; CURVE"	"Background and objectiveThisstudy proposes a model-informed approach for therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB) treatment.MethodsTwo datasets from pulmonary TB patients were used: a pharmacokinetic study (34 patients, 373 samples), and TDM data (96 patients, 391 samples) collected at Radboud University Medical Center, The Netherlands. Nine suitable population pharmacokinetic models of rifampicin were identified in the literature and evaluated on the datasets. A model developed by Svensson et al. was found to be the most suitable based on graphical goodness of fit, residual diagnostics, and predictive performance. Prediction of individual area under the concentration-time curve from time zero to 24h (AUC(24)) and maximum concentration (C-max) employing various sampling strategies was compared with a previously established linear regression TDM strategy, using sampling at 2, 4, and 6h, in terms of bias and precision (mean error [ME] and root mean square error [RMSE]).ResultsA sampling strategy using 2- and 4-h blood collection was selected to be the most suitable. The bias and precision of the two strategies were comparable, except that the linear regression strategy was more biased in prediction of the AUC(24)than the model-informed approach (ME of 9.9% and 1.5%, respectively). A comparison of resulting dose advice, using predictions on a simulated dataset, showed no significant difference in sensitivity or specificity between the two methods. The model was successfully implemented in the InsightRX precision dosing platform.ConclusionBlood sampling at 2 and 4h, combined with model-based prediction, can be used instead of the currently used linear regression strategy, shortening the sampling by 2h and one sampling point without performance loss while simultaneously offering flexibility in sampling times."	"[van Beek, Stijn W.; ter Heine, Rob; Aarnoutse, Rob E.; Svensson, Elfin M.] Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands; [Keizer, Ron J.] InsightRX, San Francisco, CA USA; [Magis-Escurra, Cecile] Radboud Univ Nijmegen, Dept Resp Dis, Med Ctr Dekkerswald, Groesbeek, Netherlands; [Svensson, Elfin M.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden"	"Svensson, EM (corresponding author), Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.; Svensson, EM (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden."	"Elin.Svensson@radboudumc.nl"	"van Beek, Stijn W/V-6866-2018; Heine, Rob ter/A-1757-2016; Svensson, Elin/A-7575-2018; Ibanez, C. Magis-Escurra/L-4500-2015"	"van Beek, Stijn W/0000-0001-8020-1934; Svensson, Elin/0000-0002-0093-6445; Keizer, Ron/0000-0002-2460-7056"	"NA"	"NA"	48	3	3	0	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUN"	2019	58	6	815	826	"NA"	"10.1007/s40262-018-00732-2"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HX8AQ"	"WOS:000467628400009"	30671890	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Mian, R; Valkenburg, AJ; Allegaert, K; Koch, BCP; Breatnach, CV; Knibbe, CAJ; Tibboel, D; Krekels, EHJ"	"Mian, R.; Valkenburg, A. J.; Allegaert, K.; Koch, B. C. P.; Breatnach, C., V; Knibbe, C. A. J.; Tibboel, D.; Krekels, E. H. J."	"NA"	"A"	"Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"acetaminophen; cardiac surgery; cardiopulmonary bypass; Down syndrome; pediatrics; population pharmacokinetics"	"PARACETAMOL; DISPOSITION; PREDICTION"	"Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92-944], body weight, 6.1 kg [4.0-12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (>= 10 kg) at 8-hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher."	"[Mian, R.; Valkenburg, A. J.; Allegaert, K.; Tibboel, D.] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [Mian, R.; Valkenburg, A. J.; Allegaert, K.; Tibboel, D.] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Rotterdam, Netherlands; [Valkenburg, A. J.] Erasmus MC, Dept Anesthesiol, Rotterdam, Netherlands; [Allegaert, K.] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Koch, B. C. P.] Erasmus MC, Dept Hosp Pharm, Rotterdam, Netherlands; [Breatnach, C., V] Our Ladys Childrens Hosp, Dept Anesthesia & Crit Care Med, Dublin, Ireland; [Knibbe, C. A. J.; Krekels, E. H. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Knibbe, C. A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Mian, R (corresponding author), Erasmus MC Sophia Childrens Hosp, Wytemaweg 80,Room NA 1723, NL-3015 CN Rotterdam, Netherlands."	"p.mian@erasmusmc.nl; A.Valkenburg@erasmusmc.nl"	"allegaert, karel/C-3611-2016; Mian, Paola/Y-1481-2019"	"allegaert, karel/0000-0001-9921-5105; Breatnach, Cormac V/0000-0002-5871-3236; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Sophia Stichting Wetenschappelijk Onderzoek (SSWO) [S16-08]"	"P. Mian was supported by the Sophia Stichting Wetenschappelijk Onderzoek (SSWO) (S16-08)."	31	3	3	1	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JUN"	2019	59	6	847	855	"NA"	"10.1002/jcph.1373"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HX5NC"	"WOS:000467447200008"	30633373	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Dong, L; Zhai, XY; Yang, YL; Wang, L; Zhou, Y; Shi, HY; Tang, BH; Wu, YE; Yang, F; Wen, L; Kong, HX; Zhi, LJ; Jacqz-Aigrain, E; Zhao, W"	"Dong, Lei; Zhai, Xiao-Ying; Yang, Yi-Lei; Wang, Li; Zhou, Yue; Shi, Hai-Yan; Tang, Bo-Hao; Wu, Yue-E; Yang, Fan; Wen, Li; Kong, Hong-Xiao; Zhi, Li-Juan; Jacqz-Aigrain, Evelyne; Zhao, Wei"	"NA"	"A"	"Population Pharmacokinetics and Dosing Optimization of Imipenem in Children with Hematological Malignancies"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"children; dosing; imipenem; population pharmacokinetics"	"CRITICALLY-ILL PATIENTS; CLINICAL-EVALUATION; IMIPENEM/CILASTATIN; CILASTATIN; INFECTIONS; MEROPENEM; SURVEILLANCE; VANCOMYCIN; PNEUMONIA; PATTERNS"	"Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h."	"[Dong, Lei; Zhi, Li-Juan] Childrens Hosp Hebei Prov, Dept Pharm, Shijiazhuang, Hebei, Peoples R China; [Zhai, Xiao-Ying; Wang, Li; Wen, Li; Kong, Hong-Xiao] Childrens Hosp Hebei Prov, Dept Paediat Haematol Oncol, Shijiazhuang, Hebei, Peoples R China; [Yang, Yi-Lei; Shi, Hai-Yan] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Zhou, Yue; Tang, Bo-Hao; Wu, Yue-E; Yang, Fan; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, APHP, Dept Paediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France; [Zhao, Wei] Childrens Hosp Hebei Prov, Paediat Res Inst, Shijiazhuang, Hebei, Peoples R China"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China.; Zhao, W (corresponding author), Childrens Hosp Hebei Prov, Paediat Res Inst, Shijiazhuang, Hebei, Peoples R China."	"zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"Young Research Program of the Health and Family Planning Commission of Hebei Province [20160412]; National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002]; Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security) [CG2016030001]; Hundred-Talent Program (The People's Government of Hebei Province) [E2015100010]"	"This study was supported by the Young Research Program of the Health and Family Planning Commission of Hebei Province (grant agreement number 20160412), the National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002), the Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security, grant agreement number CG2016030001), and the Hundred-Talent Program (The People's Government of Hebei Province, grant agreement number E2015100010)."	33	2	2	0	5	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JUN"	2019	63	6	"NA"	"NA"	"e00006-19"	"10.1128/AAC.00006-19"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"HZ6AV"	"WOS:000468935100003"	30962334	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Yang, XM; Leroux, S; Storme, T; Zhang, DL; de Beaumais, TA; Shi, HY; Yang, YL; Wang, XL; Zhao, W; Jacqz-Aigrain, E"	"Yang, Xin-Mei; Leroux, Stephanie; Storme, Thomas; Zhang, Dao-Lun; de Beaumais, Tiphaine Adam; Shi, Hai-Yan; Yang, Yi-Lei; Wang, Xiao-Ling; Zhao, Wei; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Body Surface Area-Based Dosing Regimen of Caspofungin in Children: a Population Pharmacokinetics Confirmatory Study"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"caspofungin; children; developmental pharmacokinetics; dose"	"LIQUID-CHROMATOGRAPHY; INFANTS; SAFETY; PLASMA"	"We evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics, compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin dosage based on body surface area is most appropriate for pediatric use."	"[Yang, Xin-Mei; Shi, Hai-Yan; Yang, Yi-Lei; Zhao, Wei] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Leroux, Stephanie; Storme, Thomas; Zhang, Dao-Lun; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Leroux, Stephanie] CHU Rennes, Neonatal Intens Care Unit, Rennes, France; [de Beaumais, Tiphaine Adam] Inst Gustave Roussy, Precis Canc Med Team, Villejuif, France; [Wang, Xiao-Ling] Capital Med Univ, Beijing Childrens Hosp, Natl Ctr Childrens Hlth, Clin Res Ctr, Beijing, Peoples R China; [Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China.; Jacqz-Aigrain, E (corresponding author), Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France.; Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China.; Jacqz-Aigrain, E (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite, Paris, France."	"zhao4wei2@hotmail.com; evelyne.jacqzaigrain@gmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"National Science and Technology Major Project for Major New Drugs Innovation and Development [2017ZX09304029-001, 2017ZX09304029-002]; Shandong University"	"Funding was provided by the National Science and Technology Major Project for Major New Drugs Innovation and Development (grants 2017ZX09304029-001 and 2017ZX09304029-002) and the Young Taishan Scholars Program and Qilu Young Scholars Program of Shandong University. The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript."	20	3	3	0	4	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JUL"	2019	63	7	"NA"	"NA"	"e00248-19"	"10.1128/AAC.00248-19"	5	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"IE8KP"	"WOS:000472622600018"	30988148	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Jacqz-Aigrain, E; Leroux, S; Thomson, AH; Allegaert, K; Capparelli, EV; Biran, V; Simon, N; Meibohm, B; Lo, YL; Marques, R; Peris, JE; Lutsar, I; Saito, J; Nakamura, H; van den Anker, JN; Sharland, M; Zhao, W"	"Jacqz-Aigrain, Evelyne; Leroux, Stephanie; Thomson, Alison H.; Allegaert, Karel; Capparelli, Edmund V.; Biran, Valerie; Simon, Nicolas; Meibohm, Bernd; Lo, Yoke-Lin; Marques, Remedios; Peris, Jose-Esteban; Lutsar, Irja; Saito, Jumpei; Nakamura, Hidefumi; van den Anker, Johannes N.; Sharland, Mike; Zhao, Wei"	"NA"	"A"	"Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"CONTINUOUS-INFUSION; DOSING REGIMENS; DRUG; NEPHROTOXICITY; CHILDREN; PHARMACODYNAMICS; INTEGRATION; GENTAMICIN; MATURATION; PREDICTION"	"Objectives: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC(0-24) of 400mg.h/L at steady-state in at least 80% of neonates. Results: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if >= 35 weeks PMA) achieved the AUC(0-24) target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. Conclusions: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc."	"[Jacqz-Aigrain, Evelyne; Leroux, Stephanie] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne; Leroux, Stephanie] Hop Robert Debre, Clin Invest Ctr CIC1426, Paris, France; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France; [Leroux, Stephanie] CHU Rennes, Dept Child & Adolescent Med, Div Neonatol, Rennes, France; [Thomson, Alison H.] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark, Scotland; [Thomson, Alison H.; van den Anker, Johannes N.] Glasgow Royal Infirm, Pharm Dept, Glasgow, Lanark, Scotland; [Allegaert, Karel] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Allegaert, Karel] Erasmus MC, Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [Capparelli, Edmund V.] Univ Calif San Diego, Pediat Pharmacol & Drug Discovery, San Diego, CA 92103 USA; [Biran, Valerie] Hop Robert Debre, Neonatal Intens Care Unit, Paris, France; [Simon, Nicolas] Univ Mediterranee, Hop Timone, AP HM, Dept Pharmacol, Marseille, France; [Simon, Nicolas] Hop Sainte marguerite, Serv Pharmacol Clin, CAP TV, F-13274 Marseille, France; [Simon, Nicolas] Aix Marseille Univ, INSERM, SESSTIM, IRD, Marseille, France; [Meibohm, Bernd] Univ Tennessee, Ctr Hlth Sci, Dept Pharmaceut Sci, Memphis, TN 38163 USA; [Lo, Yoke-Lin] Univ Malaya, Fac Med, Dept Pharm, Kuala Lumpur, Malaysia; [Lo, Yoke-Lin] Int Med Univ, Sch Pharm, Kuala Lumpur, Malaysia; [Marques, Remedios] La Fe Hosp, Dept Pharm Serv, Valencia, Spain; [Peris, Jose-Esteban] Univ Valencia, Dept Pharm & Pharmaceut Technol, Valencia, Spain; [Lutsar, Irja] Univ Tartu, Inst Med Microbiol, Tartu, Estonia; [Saito, Jumpei] Natl Childrens Hosp, Natl Ctr Child Hlth & Dev, Dept Pharm, Tokyo, Japan; [Nakamura, Hidefumi] Natl Ctr Child Hlth & Dev, Ctr Clin Res & Dev, Dept Dev Strategy, Tokyo, Japan; [van den Anker, Johannes N.] Childrens Natl Med Ctr, Div Clin Pharmacol, Washington, DC 20010 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA; [van den Anker, Johannes N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pharmacol & Physiol, Washington, DC 20052 USA; [van den Anker, Johannes N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol & Pharmacometr, Basel, Switzerland; [Sharland, Mike] St George Hosp, Paediat Infect Dis Unit, London, England; [Zhao, Wei] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China"	"Zhao, W (corresponding author), Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pediat Pharm, Jinan 250014, Shandong, Peoples R China."	"zhao4wei2@hotmail.com"	"Lo, Lin/B-1477-2010; Zhao, Wei/D-3322-2011; Simon, nicolas/B-1235-2016; allegaert, karel/C-3611-2016"	"Lo, Lin/0000-0001-5521-2543; Zhao, Wei/0000-0002-1830-338X; Simon, nicolas/0000-0003-4393-2257; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067; Meibohm, Bernd/0000-0003-3923-3648; allegaert, karel/0000-0001-9921-5105"	"European Seven Framework programme - Health [2013.4.2-1, 602041]; China National Science and Technology Major Projects for 'Major New Drugs Innovation and Development' [2017ZX09304029-002]"	"This study was supported by The European Seven Framework programme - Health. 2013.4.2-1. Project acronym: NeoVanc -Grant Agreement number: 602041. W. Z. received additional funding from China National Science and Technology Major Projects for 'Major New Drugs Innovation and Development' (2017ZX09304029-002)."	56	3	3	3	6	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"AUG"	2019	74	8	2128	2138	"NA"	"10.1093/jac/dkz158"	11	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"IU2VE"	"WOS:000483437300003"	31049551	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Bauer, RJ"	"Bauer, Robert J."	"NA"	"M"	"NONMEM Tutorial Part II: Estimation Methods and Advanced Examples"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"MODELS"	"In this second tutorial on NONMEM, the examples of typical pharmacokinetic/pharmacodynamic modeling problems that occur in the pharmaceutical field will be presented, which the reader can use as a template for his or her own modeling endeavors. Each of the problems presented is challenging in some way, and the logic behind setting up each problem is discussed. Logical concepts of the problem itself as well as the technical aspect of how to set it up in NONMEM are described and demonstrated. The concepts behind the various estimation algorithms will first be described to allow the user a better understanding of how to use them."	"[Bauer, Robert J.] ICON Clin Res LLC, Gaithersburg, MD 21043 USA"	"Bauer, RJ (corresponding author), ICON Clin Res LLC, Gaithersburg, MD 21043 USA."	"robert.bauer@iconplc.com"	"NA"	"NA"	"NA"	"NA"	14	6	6	0	5	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"AUG"	2019	8	8	538	556	"NA"	"10.1002/psp4.12422"	19	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IV6LA"	"WOS:000484378700002"	31044558	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Traisathit, P; Urien, S; Le Coeur, S; Srirojana, S; Akarathum, N; Kanjanavanit, S; Ngampiyaskul, C; Krikajornkitti, S; Ngo-Giang-Huong, N; Lallemant, M; Jourdain, G"	"Traisathit, Patrinee; Urien, Saik; Le Coeur, Sophie; Srirojana, Sakulrat; Akarathum, Noppadon; Kanjanavanit, Suparat; Ngampiyaskul, Chaiwat; Krikajornkitti, Sawitree; Ngo-Giang-Huong, Nicole; Lallemant, Marc; Jourdain, Gonzague"	"NA"	"A"	"Impact of antiretroviral treatment on height evolution of HIV infected children"	"BMC PEDIATRICS"	"English"	"Article"	"Asia; antiretroviral therapy; catch-up growth; height-growth velocity; HIV-infected children; Thailand"	"1ST 24 MONTHS; HIV-1-INFECTED CHILDREN; 1-INFECTED CHILDREN; PROTEASE INHIBITOR; GROWTH-RESPONSE; WEIGHT GROWTH; OPEN-LABEL; THERAPY; AGE; MULTICENTER"	"Background Antiretroviral treatment (ART) has been shown to have a beneficial effect on the weight evolution but its effect on height remains unclear. We described patterns of height evolution and identified predictors of catch-up growth in HIV-infected children on ART. Methods To describe the height evolution from birth to adulthood, we developed a nonlinear mixed effect model using data from perinatally HIV-infected children who initiated ART from 1999 to 2013 in a prospective cohort study in Thailand. The main covariates of interest were: sex, ART regimen (dual nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based), baseline CD4 percentage, HIV-RNA load and CDC HIV Classification stage and occurrence of AIDS-defining events. Results A total 477 children (43% boys) contributed 18,596 height measurements over a median duration of 6.3 years on ART (interquartile range, 3.0 to 8.3). At ART initiation, median age was 6.2 years (1.8 to 9.6), 16% of children were underweight (weight-for-age z-score < - 2), 49% presented stunting (height-for-age z-score < - 2), and 7% wasting (weight-for-height z-score < - 2). The most frequent regimen at ART initiation was NNRTI-based (79%). A model with 4 components, birth length and 3 exponential functions of age accounting for the 3 growth phases was developed and show that the height-growth velocity was inversely associated with the age at ART initiation, the adult height was significantly lower in those who had experienced at least one AIDS-defining event while, as expected, the model found that adult height in females was lower than in males. Age at ART initiation, type of ART regimen, CDC stage, CD4 percentages, and HIV-RNA load were not associated with the final height. Conclusions The younger the children at ART initiation, the greater the effect on height-growth velocity, supporting the World Health Organization's recommendation to start ART as early as possible. However, final adult height was not linked to the age at ART initiation."	"[Traisathit, Patrinee] Chiang Mai Univ, Dept Stat, Fac Sci, Chiang Mai, Thailand; [Urien, Saik] Univ Paris, Pediat & Perinatal Pharmacol, Paris, France; [Urien, Saik] Hop Tarnier, AP HP, Unite Rech Clin Necker Cochin, Paris, France; [Urien, Saik] INSERM, Cochin Necker, CIC1419, Paris, France; [Le Coeur, Sophie; Ngo-Giang-Huong, Nicole; Jourdain, Gonzague] PHPT, UMI 174, IRD, Marseille, France; [Le Coeur, Sophie; Ngo-Giang-Huong, Nicole; Lallemant, Marc; Jourdain, Gonzague] Chiang Mai Univ, Fac Associated Med Sci, Chiang Mai, Thailand; [Le Coeur, Sophie] Inst Etud Demograph, Paris, France; [Srirojana, Sakulrat] Kalasin Hosp, Kalasin, Thailand; [Akarathum, Noppadon] Sanpatong Hosp, Chiang Mai, Thailand; [Kanjanavanit, Suparat] Nakornping Hosp, Chiang Mai, Thailand; [Ngampiyaskul, Chaiwat] Prapokklao Hosp, Chanthaburi, Thailand; [Krikajornkitti, Sawitree] Samutsakhon Hosp, Samutsakhon, Thailand; [Ngo-Giang-Huong, Nicole; Jourdain, Gonzague] Harvard TH Chan Sch Publ Hlth, Boston, MA USA"	"Jourdain, G (corresponding author), PHPT, UMI 174, IRD, Marseille, France.; Jourdain, G (corresponding author), Chiang Mai Univ, Fac Associated Med Sci, Chiang Mai, Thailand."	"gonzague.jourdain@ird.fr"	"Jourdain, Gonzague/F-9117-2017"	"Jourdain, Gonzague/0000-0002-3365-7020"	"Global Fund to AIDS, Tuberculosis and Malaria, Thailand [PR-A-N-008]; Oxfam Great Britain, Thailand [THAA51]; Ministry of Public Health, Thailand; Institut de Recherche pour le Developpement (IRD), France"	"The cohort study was funded by the Global Fund to AIDS, Tuberculosis and Malaria, Thailand (PR-A-N-008); Oxfam Great Britain, Thailand (THAA51); Ministry of Public Health, Thailand; and Institut de Recherche pour le Developpement (IRD), France. The funding bodies did not have any role in study design, data collection, analysis, and interpretation of data, decision to publish, or preparation of the manuscript."	61	1	1	0	1	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"NA"	"1471-2431"	"NA"	"BMC PEDIATR"	"BMC Pediatr."	"AUG 17"	2019	19	1	"NA"	"NA"	287	"10.1186/s12887-019-1663-8"	9	"Pediatrics"	"Pediatrics"	"IR9NA"	"WOS:000481770500001"	31421667	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Jing, L; Liu, TT; Guo, Q; Chen, M; Lu, JJ; Lv, CL"	"Jing, Li; Liu, Tao-tao; Guo, Qing; Chen, Ming; Lu, Jie-Jiu; Lv, Chun-le"	"NA"	"A"	"Development and comparison of population pharmacokinetic models of vancomycin in neurosurgical patients based on two different renal function markers"	"JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS"	"English"	"Article"	"glomerular rate filtering; neurosurgical patients; population pharmacokinetics; serum creatinine; serum cystatin C; vancomycin"	"SERUM CYSTATIN-C; ADULT; CREATININE; DOSAGE; CLEARANCE; FORMULA"	"What is known and objectives Some previous studies have indicated that serum cystatin C (Cys C) is a better marker than serum creatinine (SCR) for assessing the glomerular filtering rate (GFR). However, in almost all population pharmacokinetic models of vancomycin, the GFR is usually estimated from SCR. Therefore, the aim of this study was to compare the GFR estimated from SCR (sGFR) with the GFR estimated from Cys C (cGFR) and investigate which one can describe the characteristics of vancomycin population pharmacokinetics better in Chinese neurosurgical adult patients. Methods Patients from the Neurosurgery Department aged >= 18 years were enrolled retrospectively. Among these patients, the data from 222 patients were used to establish two population pharmacokinetic models based on sGFR and cGFR, separately. The data from another 95 patients were used for the external validation of these two models. Non-linear mixed-effect modelling (NONMEM) 7.4.3 was used for the population pharmacokinetic analysis. Results We developed two one-compartment models with first-order absorption based on Cys C and SCR, separately. In the Cys C model, age, body weight and cGFR were significant covariates on the clearance rate (CL) of vancomycin (typical value, 6.4 L/hour). In the SCR model, age and sGFR were significant covariates on the CL (typical value, 6.46 L/hour). The external validation results showed that the predictive performance of the two models was similar. What is new and conclusion In this study, the predictive performance of two models was similar in neurosurgical patients. We did not find a significant improvement in the predictive performance of the model when GFR was estimated from Cys C."	"[Jing, Li; Liu, Tao-tao; Guo, Qing; Chen, Ming; Lu, Jie-Jiu; Lv, Chun-le] Guangxi Med Univ, Affiliated Hosp 1, Nanning, Guangxi, Peoples R China"	"Liu, TT (corresponding author), Guangxi Med Univ, Affiliated Hosp 1, Dept Pharm, 6 Shuangyong Rd, Nanning 530021, Guangxi, Peoples R China."	"liutaotao@gxmu.edu.cn"	"NA"	"NA"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81460569]"	"This study was funded by the National Natural Science Foundation of China (81460569)."	40	2	2	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0269-4727"	"1365-2710"	"NA"	"J CLIN PHARM THER"	"J. Clin. Pharm. Ther."	"FEB"	2020	45	1	88	96	"NA"	"10.1111/jcpt.13029"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JZ7OX"	"WOS:000484366200001"	31463971	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Ohuma, EO; Altman, DG"	"Ohuma, Eric O.; Altman, Douglas G."	"Int Fetal Newborn Growth Consortiu"	"M"	"Statistical methodology for constructing gestational age-related charts using cross-sectional and longitudinal data: The INTERGROWTH-21(st) project as a case study"	"STATISTICS IN MEDICINE"	"English"	"Article"	"cross-sectional; human growth; longitudinal; statistical methodology"	"NEWBORN GROWTH STANDARDS; FETAL-GROWTH; FRACTIONAL POLYNOMIALS; QUANTILE REGRESSION; REFERENCE INTERVALS; CENTILE CURVES; INTERNATIONAL STANDARDS; T-DISTRIBUTION; NORMAL RANGES; LMS METHOD"	"Most studies aiming to construct reference or standard charts use a cross-sectional design, collecting one measurement per participant. Reference or standard charts can also be constructed using a longitudinal design, collecting multiple measurements per participant. The choice of appropriate statistical methodology is important as inaccurate centiles resulting from inferior methods can lead to incorrect judgements about fetal or newborn size, resulting in suboptimal clinical care. Reference or standard centiles should ideally provide the best fit to the data, change smoothly with age (eg, gestational age), use as simple a statistical model as possible without compromising model fit, and allow the computation of Z-scores from centiles to simplify assessment of individuals and enable comparison with different populations. Significance testing and goodness-of-fit statistics are usually used to discriminate between models. However, these methods tend not to be useful when examining large data sets as very small differences are statistically significant even if the models are indistinguishable on actual centile plots. Choosing the best model from amongst many is therefore not trivial. Model choice should not be based on statistical considerations (or tests) alone as sometimes the best model may not necessarily offer the best fit to the raw data across gestational age. In this paper, we describe the most commonly applied methodologies available for the construction of age-specific reference or standard centiles for cross-sectional and longitudinal data: Fractional polynomial regression, LMS, LMST, LMSP, and multilevel regression methods. For illustration, we used data from the INTERGROWTH-21(st) Project, ie, newborn weight (cross-sectional) and fetal head circumference (longitudinal) data as examples."	"[Ohuma, Eric O.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Womens & Reprod Hlth, Oxford OX3 9DU, England; [Ohuma, Eric O.; Altman, Douglas G.] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Botnar Res Ctr, Ctr Stat Med, Windmill Rd, Oxford OX3 7LD, England; [Ohuma, Eric O.] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Old Rd Campus, Oxford OX3 7BN, England"	"Ohuma, EO (corresponding author), Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Old Rd Campus, Oxford OX3 7BN, England."	"eric.ohuma@csm.ox.ac.uk"	"NA"	"NA"	"Bill and Melinda Gates FoundationBill & Melinda Gates Foundation [49038]; Cancer Research UKCancer Research UK"	"Bill and Melinda Gates Foundation, Grant/Award Number: 49038; Cancer Research UK"	71	7	7	1	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0277-6715"	"1097-0258"	"NA"	"STAT MED"	"Stat. Med."	"AUG 30"	2019	38	19	3507	3526	"NA"	"10.1002/sim.8018"	20	"Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability"	"Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics"	"IJ1KK"	"WOS:000475657100002"	30488491	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Brussee, JM; Krekels, EHJ; Calvier, EAM; Palic, S; Rostami-Hodjegan, A; Danhof, M; Barrett, JS; de Wildt, SN; Knibbe, CAJ"	"Brussee, Janneke M.; Krekels, Elke H. J.; Calvier, Elisa A. M.; Palic, Semra; Rostami-Hodjegan, Amin; Danhof, Meindert; Barrett, Jeffrey S.; de Wildt, Saskia N.; Knibbe, Catherijne A. J."	"NA"	"A"	"A Pediatric Covariate Function for CYP3A-Mediated Midazolam Clearance Can Scale Clearance of Selected CYP3A Substrates in Children"	"AAPS JOURNAL"	"English"	"Article"	"Clearance; CYP3A ontogeny; Scaling function; Pediatrics; Population pharmacokinetics"	"PLASMA-PROTEIN BINDING; IN-VITRO METABOLISM; POPULATION PHARMACOKINETICS; CLINICAL PHARMACOKINETICS; CYTOCHROME-P450 3A; TAMSULOSIN HYDROCHLORIDE; GLOMERULAR-FILTRATION; DRUG-INTERACTIONS; LIVER; SUFENTANIL"	"Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1-17years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) <30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding <10% in adults, between 0.05 and 0.55 when binding >90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE <50%). Scaling of sildenafil clearance was accurate (PE <30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information."	"[Brussee, Janneke M.; Krekels, Elke H. J.; Calvier, Elisa A. M.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Palic, Semra] Dutch Canc Inst NKI, Amsterdam, Netherlands; [Rostami-Hodjegan, Amin] Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England; [Rostami-Hodjegan, Amin] Simcyp Ltd, Sheffield, S Yorkshire, England; [Barrett, Jeffrey S.] Bill & Melinda Gates Med Res Inst, Cambridge, MA USA; [Barrett, Jeffrey S.] Childrens Hosp Philadelphia, Dept Pediat, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA; [de Wildt, Saskia N.] Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, Nijmegen, Netherlands; [de Wildt, Saskia N.] Erasmus MC, Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [de Wildt, Saskia N.] Erasmus MC, Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.; Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647; Rostami-Hodjegan, Amin/0000-0003-3917-844X; Brussee, Janneke/0000-0002-0813-4463; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"NIH/NICHD, Pediatric Pharmacology Research UnitUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HD037255-06]; NWO Vidi grantNetherlands Organization for Scientific Research (NWO)"	"The authors would like to thank Pfizer Inc. for kindly sharing their data on sildenafil PK in children of 1-16years of age. Drs. Jeff Galinken and Peter Adamson were the PIs on the original midazolam PK study conducted at CHOP, and the study was supported by NIH/NICHD, Pediatric Pharmacology Research Unit, grant no. HD037255-06. The authors would like to thank Sebastiaan C. Goulooze (LACDR, Leiden University) for reviewing all scripts involved in this analysis. CAJ Knibbe is supported by a NWO Vidi grant (Vidi Knibbe, June 2013)."	80	3	3	0	1	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"SEP"	2019	21	5	"NA"	"NA"	81	"10.1208/s12248-019-0351-9"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IF6QI"	"WOS:000473204800003"	31250333	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Fidler, M; Wilkins, JJ; Hooijmaijers, R; Post, TM; Schoemaker, R; Trame, MN; Xiong, Y; Wang, WP"	"Fidler, Matthew; Wilkins, Justin J.; Hooijmaijers, Richard; Post, Teun M.; Schoemaker, Rik; Trame, Mirjam N.; Xiong, Yuan; Wang, Wenping"	"NA"	"M"	"Nonlinear Mixed-Effects Model Development and Simulation Using nlmixr and Related R Open-Source Packages"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; DRUG DEVELOPMENT; PHARMACOMETRICS; TUBERCULOSIS"	"nlmixr is a free and open-source R package for fitting nonlinear pharmacokinetic (PK), pharmacodynamic (PD), joint PK-PD, and quantitative systems pharmacology mixed-effects models. Currently, nlmixr is capable of fitting both traditional compartmental PK models as well as more complex models implemented using ordinary differential equations. We believe that, over time, it will become a capable, credible alternative to commercial software tools, such as NONMEM, Monolix, and Phoenix NLME."	"[Fidler, Matthew] Novartis Pharmaceut, Ft Worth, TX 76134 USA; [Wilkins, Justin J.; Schoemaker, Rik] Occams Cooperatie UA, Amstelveen, Netherlands; [Hooijmaijers, Richard; Post, Teun M.] LAP&P Consultants BV, Leiden, Netherlands; [Trame, Mirjam N.] Novartis Inst BioMed Res, Cambridge, MA USA; [Xiong, Yuan] Certara, Princeton, NJ USA; [Wang, Wenping] Novartis Pharmaceut, E Hanover, NJ USA"	"Fidler, M (corresponding author), Novartis Pharmaceut, Ft Worth, TX 76134 USA."	"matt.fidler@novartis.com"	"NA"	"Fidler, Matthew/0000-0001-8538-6691; Wilkins, Justin/0000-0002-7099-9396"	"NA"	"NA"	46	1	1	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"SEP"	2019	8	9	621	633	"NA"	"10.1002/psp4.12445"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JA5ZO"	"WOS:000487921500001"	31207186	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Voller, S; Flint, RB; Beggah, F; Reiss, I; Andriessen, P; Zimmermann, LJI; van den Anker, JN; Liem, KD; Koch, BCP; de Wildt, S; Knibbe, CAJ; Simons, SHP"	"Voller, Swantje; Flint, Robert B.; Beggah, Fouzi; Reiss, Irwin; Andriessen, Peter; Zimmermann, Luc J., I; van den Anker, John N.; Liem, Kian D.; Koch, Birgit C. P.; de Wildt, Saskia; Knibbe, Catherijne A. J.; Simons, Sinno H. P."	"NA"	"A"	"Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"drug metabolism; fetal medicine; neonatology; pharmacokinetics; pharmacometrics; population pharmacokinetics"	"ORAL MIDAZOLAM; METABOLISM; SEDATION; INFANTS; LIVER"	"Although midazolam is a frequently used sedative in neonatal intensive care units, its use in preterm neonates has been off-label. Recently, a new dosing advice for midazolam for sedation on intensive care units has been included in the label (0.03 mg/[kg center dot h] for preterm neonates 32 weeks). Concentration-time data of a prospective multicenter study (29 patients, median gestational age 26.7 [range 24.0-31.1 weeks]) were combined with previously published data (26 patients, median gestational age 28.1 [range 26.3-33.6 weeks]), and a population pharmacokinetic model describing the maturation of midazolam pharmacokinetics was developed in NONMEM 7.3. Clearance was 73.7 mL/h for a neonate weighing 1.1 kg and changed nonlinearly with body weight (exponent 1.69). Volume of distribution increased linearly with body weight and was 1.03 L for a neonate weighing 1.1 kg. Simulations of the newly registered dosing show considerable differences in steady-state concentrations in preterm neonates. To reach similar steady-state concentrations of 400 mu g/mL (� 100 mu g/mL), a dose of 0.03 mg/(kg center dot h) is adequate for neonates >= 1 kg and <= 2 kg but would have to be reduced to 0.02 mg/(kg center dot h) (-33%) in neonates <1 kg and increased to 0.04 mg/(kg center dot h) (�%) in neonates weighing >2 kg and <= 2.5 kg. The impact of the observed differences in exposure is difficult to assess because no target concentrations have yet been defined for midazolam, but the current analysis shows that one should be cautious in giving dosage advice based on historical data with a lack of reliable pharmacokinetic and effect data."	"[Voller, Swantje; Beggah, Fouzi; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands; [Voller, Swantje; Flint, Robert B.; Reiss, Irwin; Simons, Sinno H. P.] Univ Med Ctr Rotterdam, Erasmus MC Sophia Childrens Hosp, Dept Pediat, Div Neonatol, Rotterdam, Netherlands; [Flint, Robert B.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands; [Flint, Robert B.; Koch, Birgit C. P.] Erasmus MC, Univ Med Ctr Rotterdam, Dept Pharm, Rotterdam, Netherlands; [Beggah, Fouzi] Univ Montpellier, Montpellier, France; [Andriessen, Peter] Maxima Med Ctr, Dept Pediat, Div Neonatol, Veldhoven, France; [Zimmermann, Luc J., I] Maastricht Univ, Sch Oncol & Dev Biol, Sch Mental Hlth & Neurosci, Dept Pediat, Maastricht, Netherlands; [van den Anker, John N.; de Wildt, Saskia] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [van den Anker, John N.; de Wildt, Saskia] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, John N.] Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA; [van den Anker, John N.] Univ Basel, Childrens Hosp, Div Pediat Pharmacol & Pharmacometr, Basel, Switzerland; [Liem, Kian D.] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, Div Neonatol, Nijmegen, Netherlands; [de Wildt, Saskia] Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, Nijmegen, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Voller, S (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands."	"s.voller@lacdr.leidenuniv.nl"	"Flint, Robert B/A-1862-2016; de Wildt, Saskia/A-9589-2008; simons, sinno/AAC-7442-2019"	"Flint, Robert B/0000-0002-3658-594X; de Wildt, Saskia/0000-0002-0502-0647; Simons, Sinno/0000-0001-5219-5696; Andriessen, Peter/0000-0002-5159-6874; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Netherlands Organisation for Health Research and Development ZonMwNetherlands Organization for Health Research and Development [836011022]"	"The DINO study and all accompanying research were funded by the Netherlands Organisation for Health Research and Development ZonMw (Grant 836011022)."	29	3	3	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"OCT"	2019	59	10	1300	1308	"NA"	"10.1002/jcph.1429"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IU5YX"	"WOS:000483664700002"	31093992	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Lin, WW; Wang, CL; Jiao, Z; Yu, XL; Zhang, J; Zhang, WB; Lin, RF; Lin, S; Lin, XH"	"Lin, Wei-Wei; Wang, Chang-Lian; Jiao, Zheng; Yu, Xiao-Li; Zhang, Jin; Zhang, Wen-Bin; Lin, Rong-Fang; Lin, Shen; Lin, Xin-Hua"	"NA"	"A"	"Glomerular Filtration Rate Is a Major Predictor of Clearance of Oxcarbazepine Active Metabolite in Adult Chinese Epileptic Patients: A Population Pharmacokinetic Analysis"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"glomerular filtration rate; individualized dosing; oxcarbazepine; population pharmacokinetics; adult patients"	"CLINICAL PHARMACOKINETICS; GENE POLYMORPHISMS; DRUG-INTERACTIONS; CARBAMAZEPINE; RESISTANCE; PHARMACORESISTANCE; LAMOTRIGINE; ASSOCIATION; COMBINATION; EQUATION"	"Background: Oxcarbazepine (OXC) is almost completely metabolized to its10-monohydroxy derivative (MHD), which is responsible for the pharmacological effects of the drug. Several studies have described the population pharmacokinetics (PPK) of MHD in pediatric patients, but little is known about its pharmacokinetics in adult patients. In addition, no study to date has proposed a model to investigate the influence of genetic polymorphisms on MHD pharmacokinetics. The aim of this study was to establish a PPK model of MHD to investigate the effects of genetic polymorphisms in UGT2B7, UGT1A9, ABCB1, and ABCB2 in adult Chinese patients with epilepsy and to develop a new dosage guideline for OXC. Methods: Data were prospectively collected from 187 adult patients with epilepsy who were taking OXC. MHD trough concentrations were detected by enzyme-multiplied immunoassay. Patients were genotyped for 4 single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 1399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Other covariates included sex, age, body weight (BW), hepato-renal function, and concomitant medications. Data were analyzed using the nonlinear mixed effects modelling software. Results: The apparent clearance (CL) of MHD was significantly influenced by glomerular filtration rate and BW, and was unrelated to other covariates such as genetic polymorphisms and coadministration with levetiracetam, lamotrigine, and topiramate. Moreover, a new dosage guideline was proposed based on the final model to individualize OXC regimens for adult patients with varying BW and renal function. Conclusions: Glomerular filtration rate was first found as an important covariate influencing MHD CL. A PPK model was established to estimate the individual MHD CL for adult patients taking OXC and may be applied for individualizing doses in the target population."	"[Lin, Wei-Wei; Wang, Chang-Lian; Yu, Xiao-Li; Zhang, Wen-Bin; Lin, Rong-Fang; Lin, Shen] Fujian Med Univ, Affiliated Hosp 1, Dept Pharm, Fuzhou, Peoples R China; [Jiao, Zheng] Fudan Univ, Huashan Hosp, Dept Pharm, Shanghai, Peoples R China; [Zhang, Jin] Fujian Med Univ, Union Hosp, Dept Pharm, Fuzhou, Peoples R China; [Lin, Xin-Hua] Fujian Med Univ, Sch Pharm, Xueyuan Rd, Fuzhou 350122, Peoples R China"	"Lin, XH (corresponding author), Fujian Med Univ, Sch Pharm, Xueyuan Rd, Fuzhou 350122, Peoples R China."	"lxh13906909638@163.com"	"NA"	"NA"	"Guidance Project of Fujian Science and Technology Department [2017Y0033]; Young and Middle-aged Backbone Personnel Training Project of Fujian Province Health and Family Planning Commission, China [2018-ZQN-53]; Weak Discipline Construction Project of Shanghai Municipal Health and Family Planning Commission [2016ZB0301-01]"	"Supported by the Guidance Project of Fujian Science and Technology Department (2017Y0033) and the Young and Middle-aged Backbone Personnel Training Project of Fujian Province Health and Family Planning Commission, China (2018-ZQN-53). Z. Jiao was supported by the Weak Discipline Construction Project of Shanghai Municipal Health and Family Planning Commission (2016ZB0301-01)."	55	0	0	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"OCT"	2019	41	5	665	673	"NA"	"10.1097/FTD.0000000000000644"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"KG0YF"	"WOS:000509667600017"	31033858	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Voller, S; Flint, RB; Andriessen, P; Allegaert, K; Zimmermann, LJI; Liem, KD; Koch, BCP; Simons, SHP; Knibbe, CAJ"	"Voller, Swantje; Flint, Robert B.; Andriessen, Peter; Allegaert, Karel; Zimmermann, Luc J. I.; Liem, Kian D.; Koch, Birgit C. P.; Simons, Sinno H. P.; Knibbe, Catherijne A. J."	"DINO Study Grp"	"A"	"Rapidly maturing fentanyl clearance in preterm neonates"	"ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION"	"English"	"Article"	"NA"	"HUMAN LIVER; DRUG-TREATMENT; PHARMACOKINETICS; PAIN; 3A4; METABOLISM; CHILDREN; NEWBORNS; EFFICACY; WEIGHT"	"Background Fentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation. Methods 442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9-31.9) weeks, postnatal age: 3 (range 0-68) days, bodyweight 1.00 (range 0.39-2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations. Results Fentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (mu g/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0-4 days and 5-9 days in comparison to 10 days and older. Conclusion Because of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing."	"[Voller, Swantje; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Pharmacol & Biomed, Div Pharmacol, NL-2300 RA Leiden, Netherlands; [Flint, Robert B.; Simons, Sinno H. P.] Univ Med Ctr Rotterdam, Erasmus MC Sophia Childrens Hosp, Dept Pediat, Div Neonatol, Rotterdam, Netherlands; [Flint, Robert B.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands; [Flint, Robert B.; Koch, Birgit C. P.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pharm, Rotterdam, Netherlands; [Andriessen, Peter] Maxima Med Ctr, Dept Pediat, Div Neonatol, Veldhoven, Netherlands; [Allegaert, Karel] Erasmus MC Sophia Childrens Hosp, Dept Pediat, Div Neonatol, Rotterdam, Netherlands; [Zimmermann, Luc J. I.] Maastricht Univ, Med Ctr, Sch Mental Hlth & Neurosci, Dept Pediat,Sch Oncol & Dev Biol, Maastricht, Netherlands; [Liem, Kian D.] Radboudumc, Dept Pediat, Div Neonatol, Nijmegen, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Voller, S (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Pharmacol & Biomed, Div Pharmacol, NL-2300 RA Leiden, Netherlands."	"s.voller@lacdr.leidenuniv.nl"	"allegaert, karel/C-3611-2016; Flint, Robert B/A-1862-2016"	"allegaert, karel/0000-0001-9921-5105; Flint, Robert B/0000-0002-3658-594X; Andriessen, Peter/0000-0002-5159-6874; Simons, Sinno/0000-0001-5219-5696; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Netherlands Organisation for Health Research and Development ZonMwNetherlands Organization for Health Research and Development [836011022]"	"The DINO study and all accompanying research were funded by the Netherlands Organisation for Health Research and Development ZonMw (grant number: 836011022)."	40	5	5	0	1	"BMJ PUBLISHING GROUP"	"LONDON"	"BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND"	"1359-2998"	"1468-2052"	"NA"	"ARCH DIS CHILD-FETAL"	"Arch. Dis. Child.-Fetal Neonatal Ed."	"NOV"	2019	104	6	"F598"	"F603"	"NA"	"10.1136/archdischild-2018-315920"	6	"Pediatrics"	"Pediatrics"	"JU5YG"	"WOS:000501751500006"	31498775	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Admiraal, R; Jol-van der Zijde, CM; Silva, JMF; Knibbe, CAJ; Lankester, AC; Boelens, JJ; Hale, G; Etuk, A; Wilson, M; Adams, S; Veys, P; van Kesteren, C; Bredius, RGM"	"Admiraal, Rick; Jol-van der Zijde, Cornelia M.; Furtado Silva, Juliana M.; Knibbe, Catherijne A. J.; Lankester, Arjan C.; Boelens, Jaap Jan; Hale, Goeff; Etuk, Aniekan; Wilson, Melanie; Adams, Stuart; Veys, Paul; van Kesteren, Charlotte; Bredius, Robbert G. M."	"NA"	"A"	"Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"IMMUNE RECONSTITUTION; IN-VIVO; CHRONIC GVHD; CHILDREN; IMPACT; SURVIVAL; MODEL; PHARMACODYNAMICS; SEROTHERAPY; MATURATION"	"Background and Objective Alemtuzumab (Campath) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. Methods A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers. Results Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. Conclusion The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab."	"[Admiraal, Rick; Jol-van der Zijde, Cornelia M.; Lankester, Arjan C.; Bredius, Robbert G. M.] Leiden Univ, Med Ctr, Dept Pediat, Div Stem Cell Transplantat, Leiden, Netherlands; [Admiraal, Rick; Knibbe, Catherijne A. J.; van Kesteren, Charlotte] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Admiraal, Rick; Boelens, Jaap Jan; van Kesteren, Charlotte] Prinses Maxima Ctr, Pediat Blood & Marrow Transplantat Program, Utrecht, Netherlands; [Boelens, Jaap Jan] Mem Sloane Kettering Canc Ctr, Stem Cell Transplant & Cellular Therapies, New York, NY USA; [Furtado Silva, Juliana M.; Veys, Paul] Great Ormond St Hosp Sick Children, Bone Marrow Transplantat Dept, London, England; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands; [Hale, Goeff] GH Dev, Oxford, England; [Etuk, Aniekan; Wilson, Melanie; Adams, Stuart] Great Ormond St Hosp Sick Children, Camelia Botnar Labs, Dept Haematol, London, England"	"Bredius, RGM (corresponding author), Leiden Univ, Med Ctr, Dept Pediat, Div Stem Cell Transplantat, Leiden, Netherlands."	"r.g.m.bredius@lumc.nl"	"NA"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Netherlands Organisation for Health Research and Development (ZonMW)Netherlands Organization for Health Research and Development [40-41500-98-11044]; Dutch Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO)"	"This study was funded by the Netherlands Organisation for Health Research and Development (ZonMW; Grant Number 40-41500-98-11044). The work of CAJK is supported by the Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Dutch Organization for Scientific Research (NWO). This work was performed independently of all funders."	47	2	2	0	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2019	58	12	1609	1620	"NA"	"10.1007/s40262-019-00782-0"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JR6KK"	"WOS:000499731700008"	31131436	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Rodriguez, CA; Zuluaga, AF; Neely, MN; Sierra, Y; Morales-Gutierrez, J; Zapata, J; Zapata, JD; Naranjo, TW; Agudelo, Y"	"Rodriguez, Carlos A.; Zuluaga, Andres F.; Neely, Michael N.; Sierra, Yamile; Morales-Gutierrez, Jessica; Zapata, Julian; Zapata, Juan D.; Naranjo, Tonny W.; Agudelo, Yuli"	"NA"	"A"	"Nonparametric Population Pharmacokinetic Modeling of Isoniazid in Colombian Patients With Tuberculosis"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"antitubercular drugs; INH; TB; pharmacokinetics"	"ANTITUBERCULOSIS PHARMACODYNAMICS; SIMULATION; DISTRIBUTIONS; BREAKPOINTS; RIFAMPIN; PACKAGE; PREDICT; TRIAL"	"Background: Isoniazid (INH) is a first-line antituberculosis (TB) agent with a pharmacokinetic profile characterized by high interindividual variation; however, population pharmacokinetic studies in patients with TB are scarce. The aim was to develop a population model for INH in Colombian patients with TB suitable for predicting drug exposure and assessing the probability of target attainment of pharmacodynamic goals. Methods: Ten hospitalized adult patients with TB undergoing INH treatment were recruited. After an 8-hour fasting, subjects took 300 mg of INH, and 10 samples were taken from 0 to 12 hours. INH was quantified by high-performance liquid chromatography-UV, and data were analyzed with the Pmetrics R package software. A Monte Carlo simulation with the model parameters was run to determine the probability of target attainment for optimal efficacy. Results: The best model included 2 compartments, first-order absorption (K-a), delayed absorption (T-lag), and linear clearance (CL). Median T-lag was 0.25 hours, 5.54 hour(-1) for K-a, 5.56 L/hx (WT/60)( 0.75)( )for CL, 70.2 L x (WT/60) (1) for the volume of the central compartment (V-c), 1.04 L/h for intercompartmental clearance (Q), and 788 L for the volume of the peripheral compartment (V-p). CL and V-c were allometrically scaled on basis of the normalized body weight. Conclusions: The Monte Carlo simulation indicated that 300 mg of INH per day is appropriate for Mycobacterium tuberculosis strains with minimal inhibitory concentration (MIC) up to 0.03 mg/L (target: area under the concentration-time curve/MIC >597); however, to cover strains with MIC up to 0.125 mg/L (80% of clinical isolates), a dose of 900 mg per day would be required."	"[Rodriguez, Carlos A.; Zuluaga, Andres F.; Sierra, Yamile; Morales-Gutierrez, Jessica; Zapata, Julian] Univ Antioquia, Fac Med, CIEMTO Ctr Informac & Estudio Medicamentos & Tox, Dept Farmacol & Toxicol, Medellin, Colombia; [Neely, Michael N.] Childrens Hosp Los Angeles, Lab Appl Pharmacokinet & Bioinformat LAPKB, Los Angeles, CA 90027 USA; [Zapata, Juan D.; Naranjo, Tonny W.] Univ Pontificia Bolivariana, Corporac Invest Biol CIB, Medellin, Colombia; [Zapata, Juan D.; Naranjo, Tonny W.] Univ Pontificia Bolivariana, Fac Ciencias Salud, Medellin, Colombia; [Agudelo, Yuli] Hosp Univ San Vicente Fdn, Medellin, Colombia"	"Rodriguez, CA (corresponding author), Univ Antioquia, Fac Med, Dept Farmacol & Toxicol, Ctr Informac & Estudio Medicamentos & Tox, Carrera 51D 62-42,Room 210, Medellin, Colombia."	"andres.rodriguez@udea.edu.co"	"Zuluaga, Andres F./K-7366-2016"	"Zuluaga, Andres F./0000-0001-5656-4153"	"University of Antioquia; Hospital Universitario San Vicente Fundacion; Sistema general de Regalias de Colombia, Ruta N, Gobernacion de Antioquia [BPIN 2013000100183]"	"Supported by the University of Antioquia, Hospital Universitario San Vicente Fundacion and Sistema general de Regalias de Colombia, Ruta N, Gobernacion de Antioquia (BPIN 2013000100183)."	21	0	0	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"DEC"	2019	41	6	719	725	"NA"	"10.1097/FTD.0000000000000661"	7	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"KG0YU"	"WOS:000509669100005"	31725693	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gonzalez, D; Laughon, MM; Smith, PB; Ge, SF; Ambalavanan, N; Atz, A; Sokol, GM; Hornik, CD; Stewart, D; Mundakel, G; Poindexter, BB; Gaedigk, R; Mills, M; Cohen-Wolkowiez, M; Martz, K; Hornik, CP; Furda, G; Benjamin, DK; Capparelli, E; Kearns, GL; Paul, IM; Sullivan, J; Hornik, CP; Wade, K"	"Gonzalez, Daniel; Laughon, Matthew M.; Smith, P. Brian; Ge, Shufan; Ambalavanan, Namasivayam; Atz, Andrew; Sokol, Gregory M.; Hornik, Chi D.; Stewart, Dan; Mundakel, Gratias; Poindexter, Brenda B.; Gaedigk, Roger; Mills, Mary; Cohen-Wolkowiez, Michael; Martz, Karen; Hornik, Christoph P.; Furda, Gary; Benjamin, Daniel K., Jr.; Capparelli, Edmund; Kearns, Gregory L.; Paul, Ian M.; Sullivan, Jan; Hornik, Christoph P.; Wade, Kelly"	"Best Pharmaceuticals Children"	"A"	"Population pharmacokinetics of sildenafil in extremely premature infants"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"sildenafil; premature infants; pharmacokinetics"	"PULMONARY-HYPERTENSION; BRONCHOPULMONARY DYSPLASIA; INTRAVENOUS SILDENAFIL; N-DEMETHYLATION; ORAL SILDENAFIL; CYP3A; METABOLISM; EXPRESSION; INHIBITORS; CHILDREN"	"Aims To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. Methods We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants <= 28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM (R). Results We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. Conclusions We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study."	"[Gonzalez, Daniel; Ge, Shufan] Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Campus Box 7569, Chapel Hill, NC 27599 USA; [Laughon, Matthew M.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27515 USA; [Smith, P. Brian; Hornik, Chi D.; Cohen-Wolkowiez, Michael; Hornik, Christoph P.] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27706 USA; [Smith, P. Brian; Hornik, Chi D.; Mills, Mary; Cohen-Wolkowiez, Michael; Hornik, Christoph P.; Furda, Gary; Benjamin, Daniel K., Jr.; Hornik, Christoph P.] Duke Clin Res Inst, Durham, NC USA; [Ambalavanan, Namasivayam] Univ Alabama Birmingham, Sch Med, Div Neonatol, Birmingham, AL USA; [Atz, Andrew] Med Univ South Carolina, Childrens Hosp, Dept Pediat, Charleston, SC 29425 USA; [Sokol, Gregory M.] Indiana Univ Sch Med, Sect Neonatal Perinatal Med, Indianapolis, IN 46202 USA; [Hornik, Chi D.] Duke Univ, Med Ctr, Dept Pharm, Durham, NC USA; [Stewart, Dan] Univ Louisville, Norton Childrens Hosp, Louisville, KY 40292 USA; [Mundakel, Gratias] Suny Downstate Med Ctr, Kings Cty Hosp Ctr, Brooklyn, NY 11203 USA; [Poindexter, Brenda B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA; [Gaedigk, Roger] Univ Missouri, Sch Med, Childrens Mercy Kansas City, Dept Clin Pharmacol Toxicol & Therapeut Innovat, Kansas City, MO 64108 USA; [Martz, Karen] Emmes Corp, Rockville, MD USA; [Capparelli, Edmund] Univ Calif San Diego, San Diego, CA 92103 USA; [Kearns, Gregory L.] Arkansas Childrens Hosp, Res Inst, 800 Marshall St, Little Rock, AR 72202 USA; [Paul, Ian M.] Penn State Coll Med, Hershey, PA USA; [Sullivan, Jan] Univ Louisville, Louisville, KY 40292 USA; [Wade, Kelly] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA"	"Gonzalez, D (corresponding author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Campus Box 7569, Chapel Hill, NC 27599 USA."	"daniel.gonzalez@unc.edu"	"Ambalavanan, Namasivayam/AAL-3832-2020; Paul, Ian/AAD-9813-2020; Ambalavanan, Namasivayam/AAI-4088-2020; Atz, Andrew/J-9196-2015"	"Ambalavanan, Namasivayam/0000-0003-0731-9092; Atz, Andrew/0000-0002-4744-3832; Gonzalez, Daniel/0000-0001-5522-5686"	"Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [HHSN275201000003I]"	"Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/Award Number: HHSN275201000003I"	43	2	2	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"DEC"	2019	85	12	2824	2837	"NA"	"10.1111/bcp.14111"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KB7LT"	"WOS:000502537000001"	31475367	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Chu, Y; Luo, YF; Ji, SM; Jiang, MY; Zhou, BS"	"Chu, Yang; Luo, Yifan; Ji, Shuangmin; Jiang, Mingyan; Zhou, Baosen"	"NA"	"A"	"Population pharmacokinetics of vancomycin in Chinese patients with augmented renal clearance"	"JOURNAL OF INFECTION AND PUBLIC HEALTH"	"English"	"Article"	"Vancomycin; Population pharmacokinetics; Augmented renal clearance; Chinese patients; NONMEM"	"OBESE-PATIENTS; PREDICTION; PHARMACODYNAMICS; ANTIBIOTICS; INFECTIONS; CHILDREN; MODELS; ADULT"	"Background: Augmented renal clearance (ARC) refers to enhanced renal elimination of circulating solute has attracted attention widely and in recent years increasing attention has been paid to patients with ARC. A population pharmacokinetic (PPK) analysis was performed to provide a reference for clinical individual therapy of vancomycin in in ARC patients. Methods: Patients hospitalized in the First Affiliated Hospital of China Medical University from July 2013 to December 2015 and suspected or confirmed infection caused by gram-positive bacteria were enrolled in this study. The serum concentrations were determined by enzyme multiplied immunoassay technique. A nonlinear mixed effects model (NONMEM) was used to evaluate the influence of covariates on vancomycin pharmacokinetics and obtain the PPK model. Bootstrap, visual predictive checks and normalized prediction distribution errors were used to evaluate the estabolishe model. Results: A total of 186 vancomycin serum samples from 95 patients, including 24 females and 71 males were studied. The final model was as follows: Cl-i = 8.515 x (1 - 0.01175 x (Age 45)) x(eta i) and V-i = 155.4 x e(eta i) =. The final PPK model in ARC patients was proved to be robust and reliable. Age was identified as the most significant covariate in the final model. Conclusions: In this study, a simple population pharmacokinetic (PPK) model of vancomycin in Chinese patients with ARC was established using a nonlinear mixed-effects model (NONMEM). The final PPK model could achieve a good predictive effect, which provides a reference for clinical individual therapy. (C) 2019 The Authors. Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences."	"[Chu, Yang; Zhou, Baosen] China Med Univ, Affiliated Hosp 1, Dept Clin Epidemiol, Shenyang 110001, Liaoning, Peoples R China; [Chu, Yang; Zhou, Baosen] China Med Univ, Affiliated Hosp 1, Ctr Evidence Based Med, Shenyang 110001, Liaoning, Peoples R China; [Chu, Yang; Luo, Yifan; Jiang, Mingyan] China Med Univ, Affiliated Hosp 1, Dept Pharm, Shenyang 110001, Liaoning, Peoples R China; [Ji, Shuangmin] Peking Univ, Sch Pharmaceut Sci, Beijing 100000, Peoples R China"	"Zhou, BS (corresponding author), China Med Univ, Affiliated Hosp 1, Dept Clin Epidemiol, Shenyang 110001, Liaoning, Peoples R China.; Zhou, BS (corresponding author), China Med Univ, Affiliated Hosp 1, Ctr Evidence Based Med, Shenyang 110001, Liaoning, Peoples R China."	"15002422786@163.com; 13998102689@163.com; 1249965731@qq.com; ydyyyxb@163.com; bszhou@cmu.edu.cn"	"NA"	"NA"	"China Medical Hand in Hand Engineering Committee; Beijing Medical Award Foundation [YXJL2018-0616-0060]"	"This work was supported by China Medical Hand in Hand Engineering Committee and Beijing Medical Award Foundation (Grant YXJL2018-0616-0060). The authors extremely grate to Wei Lu professor, who provided the valuable comments and thank all the investigators for their participation and help in this study."	41	1	1	2	5	"ELSEVIER SCIENCE LONDON"	"LONDON"	"84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND"	"1876-0341"	"1876-035X"	"NA"	"J INFECT PUBLIC HEAL"	"J. Infect. Public Health"	"JAN"	2020	13	1	68	74	"NA"	"10.1016/j.jiph.2019.06.016"	7	"Public, Environmental & Occupational Health; Infectious Diseases"	"Public, Environmental & Occupational Health; Infectious Diseases"	"JY8FL"	"WOS:000504643900010"	31277936	"DOAJ Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Michalickova, D; Jansa, P; Bursova, M; Hlozek, T; Cabala, R; Hartinger, JM; Ambroz, D; Aschermann, M; Lindner, J; Linhart, A; Slanar, O; Krekels, EHJ"	"Michalickova, Danica; Jansa, Pavel; Bursova, Miroslava; Hlozek, Tomas; Cabala, Radomir; Hartinger, Jan Miroslav; Ambroz, David; Aschermann, Michael; Lindner, Jaroslav; Linhart, Ales; Slanar, Ondrej; Krekels, Elke H. J."	"NA"	"A"	"Population pharmacokinetics of riociguat and its metabolite in patients with chronic thromboembolic pulmonary hypertension from routine clinical practice"	"PULMONARY CIRCULATION"	"English"	"Article"	"desmethylriociguat; NONMEM; creatinine clearance; total bilirubin"	"ARTERIAL-HYPERTENSION"	"Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials."	"[Michalickova, Danica; Hartinger, Jan Miroslav; Slanar, Ondrej] Charles Univ Prague, Inst Pharmacol, Fac Med 1, Albertov 4, Prague 12800, Czech Republic; [Michalickova, Danica; Hartinger, Jan Miroslav; Slanar, Ondrej] Charles Univ Prague, Gen Univ Hosp, Albertov 4, Prague 12800, Czech Republic; [Jansa, Pavel; Ambroz, David; Aschermann, Michael; Linhart, Ales] Charles Univ Prague, Fac Med 1, Dept Cardiovasc Med, Dept Med 2, Prague, Czech Republic; [Jansa, Pavel; Bursova, Miroslava; Hlozek, Tomas; Cabala, Radomir; Ambroz, David; Aschermann, Michael; Lindner, Jaroslav; Linhart, Ales] Gen Univ Hosp, Prague, Czech Republic; [Bursova, Miroslava; Hlozek, Tomas; Cabala, Radomir] Charles Univ Prague, Fac Med 1, Inst Forens Med & Toxicol, Prague, Czech Republic; [Hlozek, Tomas; Cabala, Radomir] Charles Univ Prague, Fac Sci, Dept Analyt Chem, Prague, Czech Republic; [Lindner, Jaroslav] Charles Univ Prague, Fac Med 1, Dept Cardiovasc Surg, Dept Surg 2, Prague, Czech Republic; [Krekels, Elke H. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands"	"Slanar, O (corresponding author), Charles Univ Prague, Inst Pharmacol, Fac Med 1, Albertov 4, Prague 12800, Czech Republic.; Slanar, O (corresponding author), Charles Univ Prague, Gen Univ Hosp, Albertov 4, Prague 12800, Czech Republic."	"Ondrej.Slanar@lf1.cuni.cz"	"Michalickova, Danica/K-2824-2017"	"Michalickova, Danica/0000-0002-9690-9846"	"Charles University [Progres Q25, Progres Q38]; project International Mobility of Researchers at Charles University' [CZ.02.2.69/0.0/0.0/16_027/0008495]"	"This study was supported by the Charles University projects Progres Q25 and Q38 and by the project International Mobility of Researchers at Charles University'' CZ.02.2.69/0.0/0.0/16_027/0008495."	18	0	0	4	4	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"2045-8932"	"2045-8940"	"NA"	"PULM CIRC"	"Pulm. Circ."	"JAN"	2020	10	1	"NA"	"NA"	2045894019898031	"10.1177/2045894019898031"	11	"Cardiac & Cardiovascular Systems; Respiratory System"	"Cardiovascular System & Cardiology; Respiratory System"	"KM8EC"	"WOS:000514371800001"	32095231	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Avedissian, SN; Rhodes, NJ; Kim, Y; Bradley, J; Valdez, JL; Le, J"	"Avedissian, Sean N.; Rhodes, Nathaniel J.; Kim, Yuna; Bradley, John; Valdez, Joshua L.; Le, Jennifer"	"NA"	"A"	"Augmented renal clearance of aminoglycosides using population-based pharmacokinetic modelling with Bayesian estimation in the paediatric ICU"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"CRITICALLY-ILL PATIENTS; ANTIMICROBIAL THERAPY; ANTIBACTERIAL; PREDICTION; DURATION; OUTCOMES; PACKAGE"	"Objective: To evaluate augmented renaL cLearance (ARC) using aminoglycoside clearance (CLAMINO24h) derived from pharmacokinetic (PK) modelling. Methods: A retrospective study at two paediatric hospitals of patients who received tobramycin or gentamicin from 1999 to 2016 was conducted. Compartmental PK models were constructed using the Pmetrics package, and Bayesian posteriors were used to estimate CLAMINO24h .ARC was defined as a CLAMINO24h of >= 130 mL/min/ 1.73 m(2). Risk factors for ARC were identified using multivariate Logistic regression. Results: The final popuLation model was fitted to 275 aminoglycoside serum concentrations. Overall cLearance (L/h) was=CL(0)x (TBW/70)(0.75)xAGE(H)/(TMH AGE(H))  CL1 (0.5/SCr), where TBW is total body weight, H is the Hill coefficient, TM is a maturation term and SCr is serum creatinine. Median CLAMINO24h in those with versus without ARC was 157.36 and 93.42 mL/min/1.73 m(2), respectively (P<0.001). ARC was identified in 19.5% of 118 patients. For patients with ARC, median baseline SCr was Lower than for those without ARC (0.38 versus 0.41 mg/dL, P=0.073). Risk factors for ARC included sepsis [adjusted OR (a0R) 3.77, 95% CI 1.01-14.07, P=0.048], increasing age (aOR 1.11, 95% CI 1-1.23, P=0.04) and Low Log-transformed SCr (aOR 0.16, 95% CI 0.05-0.52, P=0.002). Median 24 h AUC (AUC(24h)) was significantly Lower in patients with ARC at 45.27 versus 56.95 mg center dot h/L, P <0.01. Conclusions: ARC was observed in one of every five patients. Sepsis, increasing age and Low SCr were associated with ARC. Increased cLearance was associated with an attenuation of AUC 24h in this popuLation. Future studies are needed to define optimal dosing in paediatric patients with ARC."	"[Avedissian, Sean N.; Rhodes, Nathaniel J.] Midwestern Univ, Chicago Coll Pharm, Downers Grove, IL 60515 USA; [Avedissian, Sean N.; Rhodes, Nathaniel J.] Midwestern Univ, Chicago Coll Pharm, Ctr Pharmacometr Excellence, Downers Grove, IL 60515 USA; [Avedissian, Sean N.] UNMC, Ctr Drug Discovery, Antiviral Pharmacol Lab, Omaha, NE USA; [Avedissian, Sean N.] Univ Nebraska Med Ctr, Coll Pharm, Omaha, NE USA; [Kim, Yuna; Le, Jennifer] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA; [Bradley, John] Univ Calif San Diego, Sch Med, Div Infect Dis, San Diego, CA 92103 USA; [Bradley, John] Rady Childrens Hosp, San Diego, CA USA; [Valdez, Joshua L.] Kaiser Permanente, San Diego Med Ctr, San Diego, CA USA; [Le, Jennifer] Miller Childrens & Womens Hosp, Long Beach, CA 90806 USA"	"Le, J (corresponding author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA.; Le, J (corresponding author), Miller Childrens & Womens Hosp, Long Beach, CA 90806 USA."	"jenle@ucsd.edu"	"Avedissian, Sean/L-3172-2018"	"Avedissian, Sean/0000-0002-0935-6455; Rhodes, Nathaniel/0000-0002-0018-5434"	"NA"	"NA"	43	1	1	0	0	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JAN"	2020	75	1	162	169	"NA"	"10.1093/jac/dkz408"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"KY5TM"	"WOS:000522635100022"	31648297	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wu, XM; Venkataramanan, R; Rivosecchi, RM; Tang, CX; Marini, RV; Shields, RK; Clancy, CJ; Nguyen, MH"	"Wu, Xuemei; Venkataramanan, Raman; Rivosecchi, Ryan M.; Tang, Chenxiao; Marini, Rachel, V; Shields, Ryan K.; Clancy, Cornelius J.; Nguyen, M. Hong"	"NA"	"A"	"Population Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"isavuconazole; population pharmacokinetics; probability of PK-PD target attainment; nonlinear mixed-effects model; solid-organ transplantation"	"ANTIFUNGAL TRIAZOLE BAL4815; INVASIVE FUNGAL-INFECTIONS; DOSE PHARMACOKINETICS; PHARMACODYNAMICS; ASPERGILLUS; SOCIETY; SAFETY; PROPHYLAXIS; GUIDELINES; BAL8557"	"Isavuconazole (ISA) is a triazole antifungal with activity against yeasts and molds. We established a population pharmacokinetic (pop PK) model of intravenous (i.v.) ISA to identify covariates that affect pharmacokinetics, using plasma samples from solid-organ transplant (SOT) recipients receiving peritransplant prophylaxis. Samples (n = 471) from 79 SOT recipients were utilized for pop PK analysis using nonlinear mixed-effect modeling NONMEM software. ISA (i.v.) PK parameters were best described by a two-compartment model. Significant covariates were sex on clearance (similar to 53% higher in women than men) and body mass index on peripheral volume of distribution. Incorporating drug exposure into Monte Carlo simulations, we demonstrated that standard ISA dosing is likely to attain the PK-pharmacodynamic (PD) target (area under the concentration curve/MIC ratio [AUC/MIC]) for treatment effectiveness against almost all infections caused by Aspergillus fumigatus isolates exhibiting MICs of <0.5 mu g/ml (modal MIC). In contrast, standard dosing is predicted to attain PK-PD targets against <20% of infections caused by Candida albicans and Candida glabrata isolates exhibiting MICs of >0.016 and >0.5 mu g/ml, respectively (modal MICs). These data are consistent with our SOT program's experience with ISA breakthrough infections, where 3 of 4 were caused by C. glabrata for which probabilities of PK-PD target attainment (PTA) were only 70% and 0% for isolates with MICs of 0.25 mu g/ml and 1 mu g/ml. Our findings provide important new insights into how ISA use might be optimized following SOT."	"[Wu, Xuemei; Venkataramanan, Raman; Tang, Chenxiao] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA; [Wu, Xuemei] Fujian Med Univ, Dept Pharm, Union Hosp, Fuzhou, Fujian, Peoples R China; [Venkataramanan, Raman] Thomas Starzl Transplantat Inst, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA; [Venkataramanan, Raman] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA; [Rivosecchi, Ryan M.; Marini, Rachel, V] Univ Pittsburgh, Med Ctr, Dept Pharm & Therapeut, Pittsburgh, PA USA; [Shields, Ryan K.; Clancy, Cornelius J.; Nguyen, M. Hong] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA; [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA"	"Venkataramanan, R (corresponding author), Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA.; Venkataramanan, R (corresponding author), Thomas Starzl Transplantat Inst, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA.; Venkataramanan, R (corresponding author), Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA."	"rv@pitt.edu"	"NA"	"NA"	"NIAID NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [K08 AI114883, R03 AI144636] Funding Source: Medline"	"NA"	43	1	1	3	4	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"FEB"	2020	64	2	"NA"	"NA"	"e01728-19"	"10.1128/AAC.01728-19"	13	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"KG2CG"	"WOS:000509748200023"	31767725	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Cochius-den Otter, SCM; Kipfmueller, F; de Winter, BCM; Allegaert, K; Tibboel, D; Mueller, A; Koch, BCP"	"Cochius-den Otter, Suzan C. M.; Kipfmueller, Florian; de Winter, Brenda C. M.; Allegaert, Karel; Tibboel, Dick; Mueller, Andreas; Koch, Birgit C. P."	"NA"	"A"	"Pharmacokinetic modeling of intravenous sildenafil in newborns with congenital diaphragmatic hernia"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Sildenafil; Pharmacokinetics; Modeling; Congenital diaphragmatic hernia; Cardiovascular tolerance"	"PERSISTENT PULMONARY-HYPERTENSION; STANDARDIZED POSTNATAL MANAGEMENT; INFANTS; MATURATION; CLEARANCE; MIDAZOLAM; EUROPE"	"Purpose We developed a pharmacokinetic model of intravenous sildenafil in newborns with congenital diaphragmatic hernia (CDH) to achieve a target plasma concentration of over 50 mu g/l. Methods Twenty-three CDH newborns with pulmonary hypertension (64 blood samples) received intravenous sildenafil. Patients received a loading dose of 0.35 mg/kg (IQR 0.16 mg/kg) for 3 h, followed by a continuous infusion of 1.5 mg/kg/day (IQR 0.1 mg/kg/day). For model development, non-linear mixed modeling was used. Inter-individual variability (IIV) and inter-occasion variability were tested. Demographic and laboratory parameters were evaluated as covariates. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were used for model validation. Results A two-compartment disposition model of sildenafil and a one-compartment disposition model of desmethyl sildenafil (DMS) was observed with IIV in sildenafil and DMS clearance and volume of distribution of sildenafil. NPDE and VPC revealed adequate predictability. Only postnatal age increased sildenafil clearance. This was partly compensated by a higher DMS concentration, which also has a therapeutic effect. In this small group of patients, sildenafil was tolerated well. Conclusions This model for sildenafil in CDH patients shows that concentration-targeted sildenafil dosing of 0.4 mg/kg in 3 h, followed by 1.6 mg/kg/day continuous infusion achieves appropriate sildenafil plasma levels."	"[Cochius-den Otter, Suzan C. M.; Allegaert, Karel; Tibboel, Dick] Erasmus MC Univ Med Ctr, Dept Pediat Intens Care & Pediat Surg, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands; [Kipfmueller, Florian; Mueller, Andreas] Univ Childrens Hosp, Dept Neonatol & Pediat Crit Care Med, Bonn, Germany; [de Winter, Brenda C. M.; Koch, Birgit C. P.] Erasmus MC Univ Med Ctr, Dept Pharm, Rotterdam, Netherlands; [Allegaert, Karel] KU, Dept Dev & Regenerat, Leuven, Belgium"	"Cochius-den Otter, SCM (corresponding author), Erasmus MC Univ Med Ctr, Dept Pediat Intens Care & Pediat Surg, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands."	"s.denotter@erasmusmc.nl"	"allegaert, karel/C-3611-2016"	"allegaert, karel/0000-0001-9921-5105"	"NA"	"NA"	39	0	0	0	0	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"FEB"	2020	76	2	219	227	"NA"	"10.1007/s00228-019-02767-1"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KI6YH"	"WOS:000511496200005"	31740991	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Benitez-Cano, A; Luque, S; Sorli, L; Carazo, J; Ramos, I; Campillo, N; Curull, V; Sanchez-Font, A; Vilaplana, C; Horcajada, JP; Adalia, R; Bermejo, S; Samso, E; Hope, W; Grau, S"	"Benitez-Cano, Adela; Luque, Sonia; Sorli, Luisa; Carazo, Jesus; Ramos, Isabel; Campillo, Nuria; Curull, Victor; Sanchez-Font, Albert; Vilaplana, Carles; Horcajada, Juan P.; Adalia, Ramon; Bermejo, Silvia; Samso, Enric; Hope, William; Grau, Santiago"	"NA"	"A"	"Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial"	"CRITICAL CARE"	"English"	"Article"	"Meropenem; Population pharmacokinetics; Pharmacodynamics; Critically ill patients; Nosocomial pneumonia; Lung penetration; Dose selection"	"VENTILATOR-ASSOCIATED PNEUMONIA; DEFINING ANTIBIOTIC LEVELS; EPITHELIAL LINING FLUID; BETA-LACTAM INFUSION; CARE-UNIT PATIENTS; CLINICAL-PRACTICE; BRONCHOALVEOLAR LAVAGE; PHARMACODYNAMICS; EXPOSURE; SEPSIS"	"Background Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. Methods Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results The median (IQR) of meropenem AUC(0-24 h) in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. Conclusions An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC <= 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected."	"[Benitez-Cano, Adela; Carazo, Jesus; Ramos, Isabel; Adalia, Ramon; Bermejo, Silvia; Samso, Enric] Hosp del Mar, Dept Anaesthesiol & Surg Intens Care, Parc Salut Mar, Barcelona, Spain; [Benitez-Cano, Adela; Luque, Sonia; Sorli, Luisa; Campillo, Nuria; Horcajada, Juan P.; Grau, Santiago] Inst Hosp del Mar Invest Med IMIM, Infect Pathol & Antimicrobials Res Grp IPAR, Barcelona, Spain; [Luque, Sonia; Campillo, Nuria; Grau, Santiago] Hosp del Mar, Pharm Dept, Parc Salut Mar, Barcelona, Spain; [Luque, Sonia; Hope, William] Univ Liverpool, Dept Mol & Clin Pharmacol Antimicrobial Pharmacod, Liverpool, Merseyside, England; [Luque, Sonia; Hope, William] Royal Liverpool Broadgreen Univ Hosp Trust, Liverpool, Merseyside, England; [Sorli, Luisa; Horcajada, Juan P.] Hosp del Mar, Infect Dis Dept, Parc Salut Mar, Barcelona, Spain; [Sorli, Luisa; Horcajada, Juan P.] Univ Pompeu Fabra, CEXS, Barcelona, Spain; [Sorli, Luisa; Curull, Victor; Sanchez-Font, Albert; Horcajada, Juan P.; Adalia, Ramon; Bermejo, Silvia; Grau, Santiago] Univ Barcelona, Barcelona, Spain; [Curull, Victor; Sanchez-Font, Albert] Hosp del Mar Res Inst, Hosp del Mar IMIM, Resp Med Dept, Barcelona, Spain; [Curull, Victor; Sanchez-Font, Albert] ISCIII, CIBER Enfermedades Resp CIBERES, Barcelona, Spain; [Vilaplana, Carles] Lab Referencia Catalunya, Lab Dept, Barcelona, Spain; [Samso, Enric] Univ Pompeu Fabra, Barcelona, Spain"	"Benitez-Cano, A (corresponding author), Hosp del Mar, Dept Anaesthesiol & Surg Intens Care, Parc Salut Mar, Barcelona, Spain.; Benitez-Cano, A; Luque, S (corresponding author), Inst Hosp del Mar Invest Med IMIM, Infect Pathol & Antimicrobials Res Grp IPAR, Barcelona, Spain."	"ABenitez-cano@parcdesalutmar.cat; sluque@parcdesalutmar.cat"	"NA"	"Hope, William/0000-0001-6187-878X"	"Instituto de Salud Carlos III (ISCIII)Instituto de Salud Carlos III [BA18/00005]; Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC); Spanish Society of Hospital Pharmacy (SEFH)"	"We gratefully received support from the Instituto de Salud Carlos III (ISCIII) (grant number BA18/00005), the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), and the Spanish Society of Hospital Pharmacy (SEFH) to do this work thanks to the research travel grant received by SL."	50	2	2	1	1	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1466-609X"	"1364-8535"	"NA"	"CRIT CARE"	"Crit. Care"	"FEB 17"	2020	24	1	"NA"	"NA"	55	"10.1186/s13054-020-2763-4"	14	"Critical Care Medicine"	"General & Internal Medicine"	"KS9SA"	"WOS:000518649100002"	32066497	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Jeong, SH; Jang, JH; Cho, HY; Lee, YB"	"Jeong, Seung-Hyun; Jang, Ji-Hun; Cho, Hea-Young; Lee, Yong-Bok"	"NA"	"A"	"Population Pharmacokinetic Analysis of Tiropramide in Healthy Korean Subjects"	"PHARMACEUTICS"	"English"	"Article"	"tiropramide; healthy Korean subjects; modeling; population pharmacokinetic"	"HUMAN PLASMA; QUANTITATIVE-ANALYSIS; GAS-CHROMATOGRAPHY; PREDICTION; BIOEQUIVALENCE; METABOLITES; BLOOD"	"The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related diseases as an antispasmodic, PPK reporting and factors affecting PKs are not clearly reported. Thus, this study for healthy subjects is very significant because it could find new covariates in patients that had not been reported before or predict PPK for patients in the clinic by establishing PPK in healthy adults. By using Phoenix NLME, PK, demographic, and genetic data (collected to explain PK diversity of tiropramide in population) analyses were performed. As a basic model, a one-compartment with first-order absorption and lag-time was established and extended to include covariates that influenced the inter-subject variability. The total protein significantly influenced the distribution volume and systemic clearance of tiropramide, but genetic factors such as ABCB1 (1236C>T, 2677G>T/A, and 3435C>T), CYP2D6 (*1 and *10), OCT2 (808G>T), and PEPT1 (1287G>C) genes did not show any significant association with PK parameters of tiropramide. The final PPK model of tiropramide was validated, and suggested that some of the PK diversity in the population could be explained. Herein, we first describe the establishment of the PPK model of tiropramide for healthy Korean subjects, which may be useful as a dosing algorithm for the diseased population."	"[Jeong, Seung-Hyun; Jang, Ji-Hun; Lee, Yong-Bok] Chonnam Natl Univ, Coll Pharm, 77 Yongbong Ro, Gwangju 61186, South Korea; [Cho, Hea-Young] CHA Univ, Coll Pharm, 335 Pangyo Ro, Seongnam Si 13488, Gyeonggi Do, South Korea"	"Lee, YB (corresponding author), Chonnam Natl Univ, Coll Pharm, 77 Yongbong Ro, Gwangju 61186, South Korea."	"rhdqn95@naver.com; jangji0121@naver.com; hycho@cha.ac.kr; leeyb@chonnam.ac.kr"	"Lee, Yong-Bok/AAR-8501-2020"	"Lee, Yong-Bok/0000-0002-0797-5324"	"NA"	"NA"	22	0	0	0	0	"MDPI"	"BASEL"	"ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND"	"NA"	"1999-4923"	"NA"	"PHARMACEUTICS"	"Pharmaceutics"	"APR"	2020	12	4	"NA"	"NA"	374	"10.3390/pharmaceutics12040374"	20	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LR3DV"	"WOS:000535575000079"	32325672	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Abdulla, A; Rogouti, O; Hunfeld, NGM; Endeman, H; Dijkstra, A; van Gelder, T; Muller, AE; de Winter, BCM; Koch, BCP"	"Abdulla, Alan; Rogouti, Omar; Hunfeld, Nicole G. M.; Endeman, Henrik; Dijkstra, Annemieke; van Gelder, Teun; Muller, Anouk E.; de Winter, Brenda C. M.; Koch, Birgit C. P."	"NA"	"A"	"Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Population pharmacokinetics; Ciprofloxacin; Critically ill patients; Target attainment; NONMEM"	"CARE-UNIT PATIENTS; INTRAVENOUS CIPROFLOXACIN; SEVERE SEPSIS; IMPACT; MODEL; PHARMACODYNAMICS; INFECTIONS"	"Purpose To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. Methods Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an integral AUC(0-24)/MIC >= 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. Results A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m(2), and eGFR of 58.5 mL/min/1.73 m(2). The median integral AUC(0-24) and integral C-max were 29.9 mg center dot h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target integral AUC(0-24)/MIC >= 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of >= 1200 mg/day is needed to achieve sufficient integral AUC(0-24)/MIC ratios. Conclusions The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure."	"[Abdulla, Alan; Rogouti, Omar; Hunfeld, Nicole G. M.; van Gelder, Teun; de Winter, Brenda C. M.; Koch, Birgit C. P.] Erasmus MC, Dept Hosp Pharm, POB 2040, NL-3000 CA Rotterdam, Netherlands; [Hunfeld, Nicole G. M.; Endeman, Henrik] Erasmus MC, Dept Intens Care, Rotterdam, Netherlands; [Dijkstra, Annemieke] Maasstad Hosp, Dept Intens Care, Rotterdam, Netherlands; [van Gelder, Teun] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands; [Muller, Anouk E.] Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands; [Muller, Anouk E.] Haaglanden Med Ctr, Dept Med Microbiol, The Hague, Netherlands"	"Abdulla, A (corresponding author), Erasmus MC, Dept Hosp Pharm, POB 2040, NL-3000 CA Rotterdam, Netherlands."	"a.abdulla@erasmusmc.nl"	"NA"	"Muller, Anouk/0000-0001-5042-6251"	"Erasmus Medical Center"	"The EXPAT study was supported by the Erasmus Medical Center; no specific funding was received."	50	0	0	1	1	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JUL"	2020	76	7	957	967	"NA"	"10.1007/s00228-020-02873-5"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LZ6NL"	"WOS:000527461700001"	32307575	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Engbers, AGJ; Flint, RB; Voller, S; de Klerk, JCA; Reiss, IKM; Andriessen, P; Liem, KD; Degraeuwe, PLJ; Croubels, S; Millecam, J; Allegaert, K; Simons, SHP; Knibbe, CAJ"	"Engbers, Aline G. J.; Flint, Robert B.; Voller, Swantje; de Klerk, Johan C. A.; Reiss, Irwin K. M.; Andriessen, Peter; Liem, Kian D.; Degraeuwe, Pieter L. J.; Croubels, Siska; Millecam, Joske; Allegaert, Karel; Simons, Sinno H. P.; Knibbe, Catherijne A. J."	"NA"	"A"	"Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"enantiomers; ibuprofen; patent ductus arteriosus; population pharmacokinetics; preterm neonates"	"BIRTH-WEIGHT; INFANTS; CLOSURE; MODEL; QUANTIFICATION; ACETAMINOPHEN"	"Aims Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model. Methods We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24-30] weeks, median body weight 0.83 [0.45-1.59] kg, median postnatal age [PNA] 3 [1-12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen. Results We found that S-ibuprofen clearance (CLS, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen. Conclusion S-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CLS during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure."	"[Engbers, Aline G. J.; Voller, Swantje; Knibbe, Catherijne A. J.] Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Engbers, Aline G. J.; Flint, Robert B.; de Klerk, Johan C. A.; Reiss, Irwin K. M.; Allegaert, Karel; Simons, Sinno H. P.; Knibbe, Catherijne A. J.] Erasmus UMC, Sophia Childrens Hosp, Dept Paediat, Div Neonatol, Rotterdam, Netherlands; [Flint, Robert B.] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands; [Flint, Robert B.] Erasmus MC, Dept Pharm, Rotterdam, Netherlands; [Voller, Swantje] Leiden Univ, LACDR, Div BioTherapeut, Leiden, Netherlands; [Andriessen, Peter] Maxima Med Ctr, Dept Neonatol, Veldhoven, Netherlands; [Liem, Kian D.] Radboud Univ Nijmegen, Med Ctr, Dept Neonatol, Nijmegen, Netherlands; [Degraeuwe, Pieter L. J.] Maastricht Univ, Med Ctr, Div Neonatol, Dept Paediat, Maastricht, Netherlands; [Croubels, Siska; Millecam, Joske] Univ Ghent, Fac Vet Med, Dept Pharmacol Toxicol & Biochem, Ghent, Belgium; [Allegaert, Karel] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Flint, RB (corresponding author), Erasmus MC, Sophia Childrens Hosp, Dept Pediat, Div Neonatol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands."	"r.flint@erasmusmc.nl"	"Flint, Robert B/A-1862-2016; allegaert, karel/C-3611-2016"	"Flint, Robert B/0000-0002-3658-594X; allegaert, karel/0000-0001-9921-5105; Andriessen, Peter/0000-0002-5159-6874; Engbers, Aline/0000-0002-7230-0091; de Klerk, Johan/0000-0001-7907-8510"	"ZonMwNetherlands Organization for Health Research and Development [836011022]"	"ZonMw, Grant/Award Number: 836011022"	36	0	0	1	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"OCT"	2020	86	10	2028	2039	"NA"	"10.1111/bcp.14298"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NP0GF"	"WOS:000527235400001"	32250464	"Green Accepted, Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Maharaj, AR; Wu, HL; Hornik, CP; Arrieta, A; James, L; Bhatt-Mehta, V; Bradley, J; Muller, WJ; Al-Uzri, A; Downes, KJ; Cohen-Wolkowiez, M"	"Maharaj, Anil R.; Wu, Huali; Hornik, Christoph P.; Arrieta, Antonio; James, Laura; Bhatt-Mehta, Varsha; Bradley, John; Muller, William J.; Al-Uzri, Amira; Downes, Kevin J.; Cohen-Wolkowiez, Michael"	"NA"	"M"	"Use of normalized prediction distribution errors for assessing population physiologically-based pharmacokinetic model adequacy"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Population physiologically-based pharmacokinetic modeling; Normalized prediction distribution errors; Pediatric subpopulations; Potential biases"	"TISSUE DISTRIBUTION; CLINDAMYCIN; VARIABILITY; DRUGS; PERFORMANCE; METRICS"	"Currently employed methods for qualifying population physiologically-based pharmacokinetic (Pop-PBPK) model predictions of continuous outcomes (e.g., concentration-time data) fail to account for within-subject correlations and the presence of residual error. In this study, we propose a new method for evaluating Pop-PBPK model predictions that account for such features. The approach focuses on deriving Pop-PBPK-specific normalized prediction distribution errors (NPDE), a metric that is commonly used for population pharmacokinetic model validation. We describe specific methodological steps for computing NPDE for Pop-PBPK models and define three measures for evaluating model performance: mean of NPDE, goodness-of-fit plots, and the magnitude of residual error. Utility of the proposed evaluation approach was demonstrated using two simulation-based study designs (positive and negative control studies) as well as pharmacokinetic data from a real-world clinical trial. For the positive-control simulation study, where observations and model simulations were generated under the same Pop-PBPK model, the NPDE-based approach denoted a congruency between model predictions and observed data (mean of NPDE = - 0.01). In contrast, for the negative-control simulation study, where model simulations and observed data were generated under different Pop-PBPK models, the NPDE-based method asserted that model simulations and observed data were incongruent (mean of NPDE = - 0.29). When employed to evaluate a previously developed clindamycin PBPK model against prospectively collected plasma concentration data from 29 children, the NPDE-based method qualified the model predictions as successful (mean of NPDE = 0). However, when pediatric subpopulations (e.g., infants) were evaluated, the approach revealed potential biases that should be explored."	"[Maharaj, Anil R.; Wu, Huali; Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27708 USA; [Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Dept Pediat, Sch Med, Durham, NC 27708 USA; [Arrieta, Antonio] Orange Cty Res Inst, Childrens Hosp, Orange, CA USA; [James, Laura] Arkansas Childrens Hosp, Res Ctr, 800 Marshall St, Little Rock, AR 72202 USA; [James, Laura] Univ Arkansas Med Sci, Little Rock, AR 72205 USA; [Bhatt-Mehta, Varsha] Univ Michigan, Coll Pharm, 428 Church St, Ann Arbor, MI 48109 USA; [Bhatt-Mehta, Varsha] Michigan Med, Ann Arbor, MI USA; [Bradley, John] Rady Childrens Hosp & Hlth Ctr, San Diego, CA USA; [Muller, William J.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA; [Al-Uzri, Amira] Oregon Hlth & Sci Univ, Portland, OR 97201 USA; [Downes, Kevin J.] Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA; [Downes, Kevin J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA"	"Cohen-Wolkowiez, M (corresponding author), Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27708 USA.; Cohen-Wolkowiez, M (corresponding author), Duke Univ, Dept Pediat, Sch Med, Durham, NC 27708 USA."	"michael.cohenwolkowiez@duke.edu"	"NA"	"Muller, William J/0000-0001-7690-0695"	"National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01-HD076676-01A1]"	"This study was funded by the National Institutes of Health (1R01-HD076676-01A1; M.C.W.)."	39	0	0	2	2	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2020	47	3	199	218	"NA"	"10.1007/s10928-020-09684-2"	20	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LY0GN"	"WOS:000528162300001"	32323049	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Methaneethorn, J; Lohitnavy, M"	"Methaneethorn, Janthima; Lohitnavy, Manupat"	"NA"	"A"	"External evaluation of a published population pharmacokinetic model of valproic acid in Thai manic patients"	"EUROPEAN JOURNAL OF HOSPITAL PHARMACY-SCIENCE AND PRACTICE"	"English"	"Article"	"valproic acid; population pharmacokinetics; external validation; nonlinear mixed effect modeling; therapeutic drug monitoring"	"CLINICAL-DATA; CHILDREN; PREDICTION"	"Objective To evaluate external predictability of a population pharmacokinetic model of valproic acid in Thai patients with mania to ensure its appropriateness for use in other clinical settings. Methods The published population pharmacokinetic model was evaluated for its predictive ability (at both individual and population levels) and its precision by means of mean absolute prediction error (MAPE), root mean square error (RMSE) and normalised prediction distribution error (NPDE). Results Forty-six steady-state serum valproic acid concentration levels from 30 manic patients were retrospectively collected from routine therapeutic drug monitoring at Srithanya Hospital, Thailand. For the prediction-based diagnostics, the MAPE and RMSE were 10.44% (95% CI 8.12% to 12.76%) and 12.99% (95% CI 9.51% to 15.72%), respectively, suggesting that the proposed model was relatively predictive and had a good precision. In simulation-based diagnostics, the NPDE results also showed that the model appropriately predicted valproic acid concentration levels, as indicated by a normal distribution of NPDEs with a mean and a variance of 0 and 1, respectively. Conclusion The predictability of the population pharmacokinetic model of valproic acid in Thai patients with mania was confirmed. This model could be applied in other clinical settings."	"[Methaneethorn, Janthima; Lohitnavy, Manupat] Naresuan Univ, Fac Pharmaceut Sci, Dept Pharm Practice, Pharmacokinet Res Unit, Phitsanulok, Thailand; [Methaneethorn, Janthima; Lohitnavy, Manupat] Naresuan Univ, Ctr Excellence Environm Hlth & Toxicol, Phitsanulok, Thailand"	"Methaneethorn, J (corresponding author), Naresuan Univ, Fac Pharmaceut Sci, Phitsanulok 65000, Thailand."	"janthima.methaneethorn@gmail.com"	"Lohitnavy, Manupat/A-6621-2008"	"Lohitnavy, Manupat/0000-0002-4439-0560"	"Coordinating Center for Thai Government Science and Technology Scholarship Students (CSTS), National Science and Technology Development Agency (NSTDA)"	"This study received financial support from Coordinating Center for Thai Government Science and Technology Scholarship Students (CSTS), National Science and Technology Development Agency (NSTDA)."	23	0	0	3	3	"BMJ PUBLISHING GROUP"	"LONDON"	"BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND"	"2047-9956"	"2047-9964"	"NA"	"EUR J HOSP PHARM-S P"	"Eur. J. Hosp. Pharm.-Sci. Pract."	"MAY"	2020	27	3	168	172	"NA"	"10.1136/ejhpharm-2018-001653"	5	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LL9RQ"	"WOS:000531893200008"	32419938	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kloosterboer, SM; Egberts, KM; de Winter, BCM; van Gelder, T; Gerlach, M; Hillegers, MHJ; Dieleman, GC; Bahmany, S; Reichart, CG; van Daalen, E; Kouijzer, MEJ; Dierckx, B; Koch, BCP"	"Kloosterboer, Sanne M.; Egberts, Karin M.; de Winter, Brenda C. M.; van Gelder, Teun; Gerlach, Manfred; Hillegers, Manon H. J.; Dieleman, Gwen C.; Bahmany, Soma; Reichart, Catrien G.; van Daalen, Emma; Kouijzer, Mirjam E. J.; Dierckx, Bram; Koch, Birgit C. P."	"NA"	"A"	"Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents"	"CLINICAL PHARMACOKINETICS"	"English"	"Article; Early Access"	"NA"	"ANTIPSYCHOTICS; PERFORMANCE; MEDICATIONS; DISORDERS"	"Background Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. Objectives The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. Methods Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM(R)). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. Results In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th-75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 mu g/L [56.0-180.5 mu g/L]) than in non-responders (58.0 mu g/L [14.9-105.5 mu g/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. Conclusions Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100-400 mu g/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account."	"[Kloosterboer, Sanne M.; de Winter, Brenda C. M.; van Gelder, Teun; Bahmany, Soma; Koch, Birgit C. P.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Hosp Pharm, Dr Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands; [Kloosterboer, Sanne M.; Hillegers, Manon H. J.; Dieleman, Gwen C.; Dierckx, Bram] Univ Med Ctr Rotterdam, Erasmus MC, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands; [Egberts, Karin M.; Gerlach, Manfred] Univ Hosp Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, Ctr Mental Hlth, Wurzburg, Germany; [Reichart, Catrien G.] Leiden Univ, Med Ctr, Curium LUMC Child & Adolescent Psychiat, Leiden, Netherlands; [van Daalen, Emma] Yulius Mental Hlth, Dordrecht, Netherlands; [Kouijzer, Mirjam E. J.] GGZ Breburg, Ctr Youth, Breda, Netherlands"	"Kloosterboer, SM (corresponding author), Univ Med Ctr Rotterdam, Erasmus MC, Dept Hosp Pharm, Dr Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands.; Kloosterboer, SM (corresponding author), Univ Med Ctr Rotterdam, Erasmus MC, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands."	"s.kloosterboer@erasmusmc.nl"	"NA"	"NA"	"Netherlands Organization for Health Research and Development (ZonMW)Netherlands Organization for Health Research and Development [836041011]; Erasmus Trustfonds; German Federal Institute for Drugs and Medical Devices [73.05/3832-397285/12]; German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [BMBF-FKZ: 01EZ0937]; 'Verein zur Durchfuhrung Neurowissenschaftlicher Tagungen e.V.', Berlin"	"Sanne M. Kloosterboer, Bram Dierckx, and Birgit C.P. Koch received Grant research support from The Netherlands Organization for Health Research and Development (ZonMW), number 836041011. Sanne M. Kloosterboer received grant research support from the Erasmus Trustfonds. Karin M. Egberts and Manfred Gerlach received Grant research support from the German Federal Institute for Drugs and Medical Devices (BfArM-reference number: 73.05/3832-397285/12). The patient registry of the `Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry' was additionally supported by the German Federal Ministry of Education and Research (BMBF-FKZ: 01EZ0937) and the 'Verein zur Durchfuhrung Neurowissenschaftlicher Tagungen e.V.', Berlin."	46	0	0	0	0	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40262-020-00894-y"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LN4OK"	"WOS:000532918600001"	32394297	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ye, PP; Zheng, Y; Du, B; Liu, XT; Tang, BH; Kan, M; Zhou, Y; Hao, GX; Huang, X; Su, LQ; Wang, WQ; Yu, F; Zhao, W"	"Ye, Pan-Pan; Zheng, Yi; Du, Bin; Liu, Xi-Ting; Tang, Bo-Hao; Kan, Min; Zhou, Yue; Hao, Guo-Xiang; Huang, Xin; Su, Le-Qun; Wang, Wen-Qi; Yu, Feng; Zhao, Wei"	"NA"	"A"	"First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A"	"XENOBIOTICA"	"English"	"Article"	"Bridging study; pharmacokinetics; juvenile mice; neonates; midazolam; clindamycin"	"POPULATION PHARMACOKINETICS; INTRAMUSCULAR MIDAZOLAM; PREMATURE-INFANTS; HUMAN LIVER; CLINDAMYCIN; PREDICTION; CLEARANCE; MODEL; PHARMACODYNAMICS; CHILDREN"	"First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (V-d), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and V(d)were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and V(d)were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates."	"[Ye, Pan-Pan; Yu, Feng] China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Dept Clin Pharm, Nanjing 211100, Peoples R China; [Ye, Pan-Pan; Huang, Xin; Su, Le-Qun; Zhao, Wei] Shandong First Med Univ, Dept Clin Pharm, Affiliated Hosp 1, Jinan, Peoples R China; [Zheng, Yi; Du, Bin; Liu, Xi-Ting; Tang, Bo-Hao; Kan, Min; Zhou, Yue; Hao, Guo-Xiang; Zhao, Wei] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan 250012, Peoples R China; [Wang, Wen-Qi; Zhao, Wei] Shandong First Med Univ, Clin Res Ctr, Affiliated Hosp 1, Jinan, Peoples R China; [Zhao, Wei] Shandong First Med Univ, Dept Pediat, Affiliated Hosp 1, Jinan, Peoples R China"	"Yu, F (corresponding author), China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Dept Clin Pharm, Nanjing 211100, Peoples R China.; Zhao, W (corresponding author), Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan 250012, Peoples R China."	"yufengcpu@163.com; zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"Key Technologies R & D Program of Shandong Province [2018GSF118053]; National Science and Technology Major Project for Major New Drugs Innovation and Development [2017ZX09304029-002]; Young Taishan Scholars Program of Shandong Province; Qilu Young Scholars Program of Shandong University"	"This study was supported by the Key Technologies R & D Program of Shandong Province (Grant No.2018GSF118053), National Science and Technology Major Project for Major New Drugs Innovation and Development (2017ZX09304029-002), Young Taishan Scholars Program of Shandong Province, and Qilu Young Scholars Program of Shandong University."	59	0	0	2	2	"TAYLOR & FRANCIS LTD"	"ABINGDON"	"2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND"	"0049-8254"	"1366-5928"	"NA"	"XENOBIOTICA"	"Xenobiotica"	"NOV 1"	2020	50	11	1275	1284	"NA"	"10.1080/00498254.2020.1768454"	10	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"NO0AY"	"WOS:000540082000001"	32400275	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, HC; Long-Boyle, J; Winger, BA; Nicolaides, T; Mueller, S; Prados, M; Ivaturi, A"	"Wang, Hechuan; Long-Boyle, Janel; Winger, Beth Apsel; Nicolaides, Theodore; Mueller, Sabine; Prados, Michael; Ivaturi, Vijay"	"NA"	"A"	"Population Pharmacokinetics of Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E-Mutant Astrocytomas"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"astrocytomas; crushed tablets; pediatrics; pharmacokinetics; vemurafenib"	"MELANOMA PATIENTS IMPACT; TUMOR RESPONSE; STEM GANGLIOGLIOMA; PREDICTION; CLEARANCE; TOLERANCE; ORIGIN; ERRORS; MODEL; MASS"	"Vemurafenib (Zelboraf) is an orally available BRAF(V600E) inhibitor approved for the treatment of unresectable or metastatic BRAF(V600E)-mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAF(V600E) mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAF(V600E)-mutant astrocytomas received whole (n = 19) or crushed (n = 6) vemurafenib tablets twice daily. Plasma samples were collected on days 1, 15, and 22 in cycle 1 of vemurafenib treatment. Descriptive PK analyses demonstrated significant variability (approximately 6-fold) in drug exposure. A 1-compartment model with first-order absorption and elimination was developed by adjusting the vemurafenib PK model previously validated in adults with mutant BRAF(V600E) melanoma. After inclusion of allometric scaling on total body weight, the model adequately described the PK of vemurafenib in children between a wide age range of 3 to 19 years old. In the crushed-tablet cohort, relative bioavailability was approximately 96% (95% confidence interval, 49%-142%) compared to that seen in pediatric patients receiving whole tablets based on the preliminary comparison analysis results. Moderate intrapatient variability (48%) of vemurafenib clearance was observed. There was significant correlation (R-2 = 0.83) between area under the plasma concentration-time curve and trough concentration at steady state. These results will help increase the number of pediatric patients for whom vemurafenib is accessible and facilitate improved dosing in pediatric patients with recurrent/refractory BRAF(V600E) astrocytomas."	"[Wang, Hechuan; Ivaturi, Vijay] Univ Maryland, Sch Pharm, Ctr Translat Med, 20 N Pine St N515, Baltimore, MD 21201 USA; [Long-Boyle, Janel] Univ Calif San Francisco, Dept Pediat, Div Allergy Immunol & Bone Marrow Transplantat, San Francisco, CA USA; [Long-Boyle, Janel] Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA 94143 USA; [Winger, Beth Apsel; Mueller, Sabine; Prados, Michael] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA; [Nicolaides, Theodore] NYU Langone Hlth, Dept Pediat, New York, NY USA; [Mueller, Sabine; Prados, Michael] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA; [Mueller, Sabine] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA USA"	"Ivaturi, A (corresponding author), Univ Maryland, Sch Pharm, Ctr Translat Med, 20 N Pine St N515, Baltimore, MD 21201 USA."	"vivaturi@rx.umaryland.edu"	"NA"	"Nicolaides, Theodore/0000-0002-0637-1086; Ivaturi, Vijay/0000-0002-6433-1154"	"Genentech/RocheRoche HoldingGenentech; Pacific Pediatric Neuro-Oncology Consortium Foundation; Pediatric Brain Tumor Foundation; NIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [SPORE P50CA097257]; St. Baldrick's Foundation [527421]; Frank A. Campini Foundation"	"This trial was supported by funds from Genentech/Roche, the Pacific Pediatric Neuro-Oncology Consortium Foundation, and the Pediatric Brain Tumor Foundation. T.N. and M.P. were supported by NIH/NCI SPORE P50CA097257. B.W. was supported by St. Baldrick's Foundation Award ID: 527421 and the Frank A. Campini Foundation."	39	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"SEP"	2020	60	9	1209	1219	"NA"	"10.1002/jcph.1617"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MS6QO"	"WOS:000536478000001"	32476174	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Khan, MW; Wang, YK; Wu, YE; Tang, BH; Kan, M; Shi, HY; Zheng, Y; Xu, BP; Shen, AD; Jacqz-Aigrain, E; Tian, LY; Zhao, W"	"Khan, Muhammad Wasim; Wang, Ya-Kun; Wu, Yue-E; Tang, Bo-Hao; Kan, Min; Shi, Hai-Yan; Zheng, Yi; Xu, Bao-Ping; Shen, A-Dong; Jacqz-Aigrain, Evelyne; Tian, Li-Yuan; Zhao, Wei"	"NA"	"A"	"Population pharmacokinetics and dose optimization of ceftriaxone for children with community-acquired pneumonia"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article; Early Access"	"Community-acquired pneumonia; Ceftriaxone; Dosing regimen; Children"	"DEPENDENT PROTEIN-BINDING; PEDIATRIC-PATIENTS; ANTIBACTERIAL ACTIVITY; BACTERIAL-MENINGITIS; DISTRIBUTION TERMS; UPDATE; PLASMA; VOLUME"	"Purpose To assess ceftriaxone population pharmacokinetics in a large pediatric population and describe the proper dose for establishing an optimized antibiotic regimen. Methods From pediatric patients using ceftriaxone, blood samples were obtained and the concentration was measured using high-performance liquid chromatography ultraviolet detection. The NONMEM software program was used for population pharmacokinetic analysis, for which data from 99 pediatric patients (2 to 12 years old) was collected and 175 blood concentrations were obtained. Results The best fit with the data was shown by the one-compartment model with first-order elimination. According to covariate analysis, weight had a significant impact on the clearance of ceftriaxone. Using Monte Carlo simulation, in a pediatric population with community-acquired pneumonia, a dose regimen of 100 mg/kg every 24 h produced satisfactory target attainment rates while remaining within the required minimum inhibitory concentration (2 mg/L). Conclusion Population pharmacokinetics of ceftriaxone was evaluated in children and an optimum dosing regimen was constructed on the basis of the pharmacokinetics-pharmacodynamics model-based approach."	"[Khan, Muhammad Wasim; Wu, Yue-E; Tang, Bo-Hao; Kan, Min; Zheng, Yi; Zhao, Wei] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Clin Pharm, 44 Wenhua West Rd, Jinan, Shandong, Peoples R China; [Wang, Ya-Kun; Tian, Li-Yuan] Hebei Med Univ, Dept Resp Care, Childrens Hosp Hebei Prov, Shijiazhuang, Hebei, Peoples R China; [Shi, Hai-Yan; Zhao, Wei] Shandong First Med Univ, Shandong Prov Qianfoshan Hosp, Clin Trial Ctr, Dept Clin Pharm,Affiliated Hosp 1, Jinan, Peoples R China; [Xu, Bao-Ping] Capital Med Univ, Beijing Childrens Hosp, China Natl Clin Res Ctr Resp Dis, Natl Ctr Childrens Hlth, Beijing, Peoples R China; [Shen, A-Dong] Capital Med Univ, Beijing Key Lab Pediat Resp Infect Dis,Minist Edu, Key Lab Major Dis Children,Natl Key Discipline Pe, Natl Clin Res Ctr Resp Dis,Natl Ctr Childrens Hlt, Beijing 100045, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Clin Pharm, 44 Wenhua West Rd, Jinan, Shandong, Peoples R China.; Zhao, W (corresponding author), Shandong First Med Univ, Shandong Prov Qianfoshan Hosp, Clin Trial Ctr, Dept Clin Pharm,Affiliated Hosp 1, Jinan, Peoples R China."	"zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002, 2017ZX09304029-005]; Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security) [CG2016030001]; Hundred-Talent Program (The People's Government of Hebei Province) [E2015100010]; Young Taishan Scholars Program of Shandong Province; Qilu Young Scholar Program of Shandong University; Science and Technology Planning Project of Hebei Province [15277705D]"	"This work was supported by the National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002, 2017ZX09304029-005), Scientific Research Foundation for the High-Level Returned Overseas Chinese Scholars (Ministry of Human Resources and Social Security, CG2016030001) and Hundred-Talent Program (The People's Government of Hebei Province, E2015100010), Young Taishan Scholars Program of Shandong Province, Qilu Young Scholar Program of Shandong University, and Science and Technology Planning Project of Hebei Province (15277705D), We declare that we have no conflicts of interest relevant to this article."	47	0	0	3	3	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s00228-020-02939-4"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MC2PF"	"WOS:000543134900001"	32583354	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Shi, HY; Wang, K; Wang, RH; Wu, YE; Tang, BH; Li, X; Du, B; Kan, M; Zheng, Y; Xu, BP; Shen, AD; Su, LQ; Jacqz-Aigrain, E; Huang, X; Zhao, W"	"Shi, Hai-Yan; Wang, Kai; Wang, Rong-Hua; Wu, Yue-E; Tang, Bo-Hao; Li, Xue; Du, Bin; Kan, Min; Zheng, Yi; Xu, Bao-Ping; Shen, A-Dong; Su, Le-Qun; Jacqz-Aigrain, Evelyne; Huang, Xin; Zhao, Wei"	"NA"	"A"	"Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"NA"	"Objectives: To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment. Methods: A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). Results: A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. Conclusions: For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of <= 16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice."	"[Shi, Hai-Yan; Su, Le-Qun; Huang, Xin; Zhao, Wei] Shandong First Med Univ, Dept Pharm, Affiliated Hosp 1, Jinan, Peoples R China; [Shi, Hai-Yan; Wu, Yue-E; Tang, Bo-Hao; Li, Xue; Du, Bin; Kan, Min; Zheng, Yi; Huang, Xin; Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Peoples R China; [Wang, Kai] Shandong First Med Univ, Dept Paediat Resp Cardiol, Affiliated Hosp 1, Jinan, Peoples R China; [Wang, Rong-Hua] Qingdao Univ, Dept Pharm, Affiliated Weihai Municipal Hosp 2, Weihai, Peoples R China; [Xu, Bao-Ping] Capital Med Univ, Beijing Childrens Hosp, China Natl Clin Res Ctr Resp Dis, Natl Ctr Childrens Hlth,Resp Dept, Beijing, Peoples R China; [Shen, A-Dong] Capital Med Univ, Beijing Childrens Hosp,Natl Key Discipline Paedia, Beijing Key Lab Paediat Resp Infect Dis,Beijing P, Key Lab Major Dis Children,Minist Educ,Natl Clin, Beijing, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, Dept Paediat Pharmacol & Pharmacogenet, APHP, Paris, France"	"Zhao, W (corresponding author), Shandong First Med Univ, Dept Pharm, Affiliated Hosp 1, Jinan, Peoples R China.; Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Peoples R China."	"zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"National Science and Technology Major Projects for 'Major New Drugs Innovation and Development' [2017ZX09304029-002, 2017ZX09304029-005]; Young Taishan Scholars Program of Shandong Province; Qilu Young Scholars Program of Shandong University"	"This study was supported by the National Science and Technology Major Projects for 'Major New Drugs Innovation and Development' (2017ZX09304029-002 and 2017ZX09304029-005), the Young Taishan Scholars Program of Shandong Province and the Qilu Young Scholars Program of Shandong University."	24	0	0	2	2	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JUL"	2020	75	7	1917	1924	"NA"	"10.1093/jac/dkaa071"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"NE2EX"	"WOS:000562411300033"	32129861	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Stillemans, G; Belkhir, L; Vandercam, B; Vincent, A; Haufroid, V; Elens, L"	"Stillemans, Gabriel; Belkhir, Leila; Vandercam, Bernard; Vincent, Anne; Haufroid, Vincent; Elens, Laure"	"NA"	"A"	"Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations"	"CLINICAL PHARMACOKINETICS"	"English"	"Article; Early Access"	"NA"	"ONCE-DAILY DARUNAVIR/RITONAVIR; PROTEASE INHIBITORS; INFECTED PATIENTS; HIV-1-INFECTED PATIENTS; EFFICACY; RITONAVIR; DARUNAVIR; SAFETY; PLASMA; MONOTHERAPY"	"Background and objectives Protease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naive patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations. Methods Sparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated. Results Our model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure wereCYP3A5*3andSLCO3A1rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC(50)in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients. Conclusions These results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models."	"[Stillemans, Gabriel; Elens, Laure] Catholic Univ Louvain, Louvain Drug Res Inst, Integrated PharmacoMetr PharmacoGen & PharmacoKin, Brussels, Belgium; [Stillemans, Gabriel; Belkhir, Leila; Haufroid, Vincent; Elens, Laure] Catholic Univ Louvain, Louvain Ctr Toxicol & Appl Pharmacol, Inst Rech Expt & Clin, Brussels, Belgium; [Belkhir, Leila; Vandercam, Bernard; Vincent, Anne] Catholic Univ Louvain, Clin Univ St Luc, AIDS Reference Ctr, Dept Internal Med, Brussels, Belgium; [Haufroid, Vincent] Clin Univ St Luc, Dept Clin Chem, Brussels, Belgium; [Stillemans, Gabriel] Ave E Mounier 72,B01-72-02, Brussels, Belgium"	"Stillemans, G (corresponding author), Catholic Univ Louvain, Louvain Drug Res Inst, Integrated PharmacoMetr PharmacoGen & PharmacoKin, Brussels, Belgium.; Stillemans, G (corresponding author), Catholic Univ Louvain, Louvain Ctr Toxicol & Appl Pharmacol, Inst Rech Expt & Clin, Brussels, Belgium.; Stillemans, G (corresponding author), Ave E Mounier 72,B01-72-02, Brussels, Belgium."	"gabriel.stillemans@uclouvain.be"	"NA"	"Belkhir, Leila/0000-0002-1701-7584"	"Fonds pour la Formation a la Recherche dans l'Industrie et dans l'Agriculture (FRIA)Fonds de la Recherche Scientifique - FNRS [FC16749]"	"This work was supported by the Fonds pour la Formation a la Recherche dans l'Industrie et dans l'Agriculture (FRIA) [Grant number FC16749 to Gabriel Stillemans]."	60	0	0	0	0	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40262-020-00920-z"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MN7IQ"	"WOS:000551018200001"	32696441	"Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Flint, RB; Simons, SHP; Andriessen, P; Liem, KD; Degraeuwe, PLJ; Reiss, IKM; Ter Heine, R; Engbers, AGJ; Koch, BCP; de Groot, R; Burger, DM; Knibbe, CAJ; Voller, S"	"Flint, Robert B.; Simons, Sinno H. P.; Andriessen, Peter; Liem, Kian D.; Degraeuwe, Pieter L. J.; Reiss, Irwin K. M.; Ter Heine, Rob; Engbers, Aline G. J.; Koch, Birgit C. P.; de Groot, Ronald; Burger, David M.; Knibbe, Catherijne A. J.; Voller, Swantje"	"DINO Res Grp"	"A"	"The bioavailability and maturing clearance of doxapram in preterm infants"	"PEDIATRIC RESEARCH"	"English"	"Article; Early Access"	"NA"	"IDIOPATHIC APNEA; CAFFEINE THERAPY; PREMATURITY; PHARMACOTHERAPY; BRADYCARDIA; METABOLISM; DISABILITY; HYPOXEMIA; CHILDREN; WEIGHT"	"Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. Impact Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure."	"[Flint, Robert B.; Simons, Sinno H. P.; Reiss, Irwin K. M.] Erasmus MC, Dept Pediat, Div Neonatol, Sophia Childrens Hosp, Rotterdam, Netherlands; [Flint, Robert B.; Koch, Birgit C. P.] Erasmus MC, Dept Hosp Pharm, Rotterdam, Netherlands; [Flint, Robert B.; Ter Heine, Rob; Burger, David M.] Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands; [Andriessen, Peter] Maxima Med Ctr, Dept Pediat, Div Neonatol, Veldhoven, Netherlands; [Liem, Kian D.] Radboudumc, Div Neonatol, Dept Pediat, Nijmegen, Netherlands; [Degraeuwe, Pieter L. J.] Maastricht Univ, Sch Oncol & Dev Biol, Sch Mental Hlth & Neurosci, Dept Pediat,Med Ctr, Maastricht, Netherlands; [Engbers, Aline G. J.; Knibbe, Catherijne A. J.; Voller, Swantje] Leiden Univ, Leiden Amsterdam Ctr Drug Res LACDR, Div Pharmacol, LACDR, Leiden, Netherlands; [de Groot, Ronald] Radboud Univ Nijmegen, Lab Pediat Infect Dis, Radboud Inst Mol Life Sci, Dept Pediat,Med Ctr, Nieuwegein, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Flint, RB (corresponding author), Erasmus MC, Dept Pediat, Div Neonatol, Sophia Childrens Hosp, Rotterdam, Netherlands.; Flint, RB (corresponding author), Erasmus MC, Dept Hosp Pharm, Rotterdam, Netherlands.; Flint, RB (corresponding author), Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands."	"r.flint@erasmusmc.nl"	"NA"	"NA"	"Netherlands Organization for Health Research and Development ZonMwNetherlands Organization for Health Research and Development [80-83600-98-10190]"	"This study was enabled by funding from the Netherlands Organization for Health Research and Development ZonMw (Grant number: 80-83600-98-10190)."	46	0	0	0	0	"NATURE PUBLISHING GROUP"	"NEW YORK"	"75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA"	"0031-3998"	"1530-0447"	"NA"	"PEDIATR RES"	"Pediatr. Res."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1038/s41390-020-1037-9"	10	"Pediatrics"	"Pediatrics"	"MQ5UR"	"WOS:000552960000001"	32698193	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kloosterboer, SM; de Winter, BCM; Reichart, CG; Kouijzer, MEJ; de Kroon, MMJ; van Daalen, E; Ester, WA; Rieken, R; Dieleman, GC; van Altena, D; Bartelds, B; van Schaik, RHN; Nasserinejad, K; Hillegers, MHJ; van Gelder, T; Dierckx, B; Koch, BCP"	"Kloosterboer, Sanne Maartje; de Winter, Brenda C. M.; Reichart, Catrien G.; Kouijzer, Mirjam E. J.; de Kroon, Matthias M. J.; van Daalen, Emma; Ester, Wietske A.; Rieken, Rob; Dieleman, Gwen C.; van Altena, Daphne; Bartelds, Beatrijs; van Schaik, Ron H. N.; Nasserinejad, Kazem; Hillegers, Manon H. J.; van Gelder, Teun; Dierckx, Bram; Koch, Birgit C. P."	"NA"	"A"	"Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article; Early Access"	"adolescent; antipsychotic; autism spectrum disorder; body mass index; child; cytochrome P-450; drug monitoring; prolactin; risperidone; weight gain"	"INDUCED WEIGHT-GAIN; 9-HYDROXYRISPERIDONE CONCENTRATIONS; 2ND-GENERATION ANTIPSYCHOTICS; POPULATION PHARMACOKINETICS; SERUM CONCENTRATION; PEDIATRIC-PATIENTS; THAI CHILDREN; POLYMORPHISM; MODELS; HYPERPROLACTINEMIA"	"Aim Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI)z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence andCYP2D6,CYP3A4,CYP3A5and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM (R)) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMIz-scores during follow-up (P< .001). Higher sum trough concentrations also predicted more sedation (P< .05), higher prolactin levels (P< .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P< .01). Conclusion Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems."	"[Kloosterboer, Sanne Maartje; de Winter, Brenda C. M.; van Gelder, Teun; Koch, Birgit C. P.] Univ Med Ctr Rotterdam, Dept Hosp Pharm, Erasmus MC, Dr Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands; [Kloosterboer, Sanne Maartje; Dieleman, Gwen C.; van Altena, Daphne; Hillegers, Manon H. J.; Dierckx, Bram] Univ Med Ctr Rotterdam, Erasmus MC, Dept Child & Adolescent Psychiat Psychol, Sophia Childrens Hosp, Rotterdam, Netherlands; [Reichart, Catrien G.; Ester, Wietske A.] Leiden Univ, Med Ctr, Curium LUMC Child & Adolescent Psychiat, Oegstgeest, Netherlands; [Kouijzer, Mirjam E. J.] GGz Breburg, Ctr Youth, Breda, Netherlands; [de Kroon, Matthias M. J.] Kroon Child Psychiat, Breda, Netherlands; [van Daalen, Emma] Yulius Mental Hlth, Dordrecht, Netherlands; [Ester, Wietske A.] Sarr Expert Ctr Autism Youz Child & Adolescent Ps, Rotterdam, Netherlands; [Ester, Wietske A.] Parnassia Psychiat Inst, The Hague, Netherlands; [Rieken, Rob] GGZ Delfland, Dept Youth, Delft, Netherlands; [Bartelds, Beatrijs] Univ Med Ctr Rotterdam, Sophia Childrens Hosp, Dept Pediat, Erasmus MC, Rotterdam, Netherlands; [van Schaik, Ron H. N.] Univ Med Ctr Rotterdam, Dept Clin Chem, Erasmus MC, Rotterdam, Netherlands; [Nasserinejad, Kazem] Univ Med Ctr Rotterdam, Dept Hematol, Erasmus MC, Rotterdam, Netherlands"	"Kloosterboer, SM (corresponding author), Univ Med Ctr Rotterdam, Dept Hosp Pharm, Erasmus MC, Dr Molewaterpl 40, NL-3015 GD Rotterdam, Netherlands."	"s.kloosterboer@erasmusmc.nl"	"NA"	"NA"	"Netherlands Organization for Health Research and Development (ZonMW)Netherlands Organization for Health Research and Development [836041011]; Chiesi; AstellasAstellas Pharmaceuticals"	"We thank Soma Bahmany of the Erasmus MC Rotterdam for the quantification of the risperidone and 9-hydroxyrisperidone concentrations. S.K., B.D. and B.K. received grant research support from The Netherlands Organization for Health Research and Development (ZonMW), number 836041011. TG has received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Vitaeris, Astellas, Aurinia Pharma and Novartis."	62	0	0	1	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1111/bcp.14465"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MP5MQ"	"WOS:000552248900001"	32643213	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Gao, XB; Zheng, Y; Yang, F; Wang, CH; Jiang, ZH; Wu, YE; Jacqz-Aigrain, E; Ni, SQ; Zhao, W"	"Gao, Xiang-Bo; Zheng, Yi; Yang, Fan; Wang, Chen-Hong; Jiang, Zhou-Hong; Wu, Yue-E; Jacqz-Aigrain, Evelyne; Ni, Shao-Qing; Zhao, Wei"	"NA"	"A"	"Developmental population pharmacokinetics of caffeine in Chinese premature infants with apnoea of prematurity: A post-marketing study to support paediatric labelling in China"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article; Early Access"	"apnoea of prematurity; Chinese premature infants; pharmacokinetics-pharmacogenetics; postmarketing study"	"CHRONIC-RENAL-FAILURE; CONCISE GUIDE; HUMAN LIVER; METABOLISM; CHILDREN"	"Aims The aim of the study was to evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modelling and simulation approach. Methods Pharmacokinetic samples were collected from 99 Chinese newborns with premature apnoea. The median (range) of gestational age and postmenstrual age were 28.3 (25.0-33.4) weeks and 31.1 (26.4-38.0) weeks, respectively. Newborns were receiving caffeine citrate at a loading dose of 20 mg/kg/d and a maintenance dose of 5-10 mg/kg/d. Caffeine concentrations and CYP1A2 polymorphisms were investigated. Population pharmacokinetic modelling of caffeine in Chinese preterm newborn on a population-wide scale was conducted using NONMEM. Results A 1-compartment model with first-order elimination was used to describe population pharmacokinetic. With current weight implemented using 0.75 allometric scaling, clearance (CL) was positively related to current weight and postmenstrual age, but a negative relationship was observed with serum creatinine concentration. Eight genotypes of CYP1A2 were tested and none of them had a significant impact on caffeine pharmacokinetic parameters. Interindividual variability of CL and volume of distribution was 7.70 and 65.9%. The median (range) of 95% confidence intervals of CL were 0.0128 (0.0128-0.0131) L/h/kg. Monte Carlo simulation demonstrated that 80% (loading dose) and 98% (maintenance dose) of premature infants treated with a labelled dosing regimen attained the concentration target range of 5-20 mg/L. Conclusion A population PK model of caffeine was developed in Chinese newborns. Body weight-implemented allometric scaling, postmenstrual age and serum creatinine concentration markedly affected caffeine clearance. The labelled dosing regimen is suitable for Chinese premature infants."	"[Gao, Xiang-Bo; Jiang, Zhou-Hong] Zhejiang Univ, Childrens Hosp, Dept Pharm, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Wang, Chen-Hong] Zhejiang Univ, Childrens Hosp, Dept Neonatal Intens Care Unit, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Ni, Shao-Qing] Zhejiang Univ, Childrens Hosp, Clin Trial Inst, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Zheng, Yi; Yang, Fan; Wu, Yue-E; Zhao, Wei] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Clin Pharm, 44 Wenhua West Rd, Jinan, Shandong, Peoples R China; [Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France; [Zhao, Wei] Shandong First Med Univ, Affiliated Hosp 1, Dept Clin Pharm, Jinan, Peoples R China; [Zhao, Wei] Shandong First Med Univ, Affiliated Hosp 1, Clin Res Ctr, Jinan, Peoples R China"	"Ni, SQ (corresponding author), Zhejiang Univ, Childrens Hosp, Clin Trial Inst, Sch Med, Hangzhou, Zhejiang, Peoples R China.; Zhao, W (corresponding author), Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Clin Pharm, 44 Wenhua West Rd, Jinan, Shandong, Peoples R China."	"chnsq@zju.edu.cn; zhao4wei2@hotmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81573516, 81273607]; National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002]; Key Technologies R & D Program of Shandong Province [2018GSF118053]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2015 M582102]"	"This work was supported financially by National Natural Science Foundation of China (81573516, 81273607), National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002), the Key Technologies R & D Program of Shandong Province (2018GSF118053) and China Postdoctoral Science Foundation (2015 M582102)."	36	0	0	2	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1111/bcp.14483"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MQ0KA"	"WOS:000552584700001"	32687613	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Guk, J; Guedj, J; Burdet, C; Andremont, A; de Gunzburg, J; Ducher, A; Mentre, F"	"Guk, Jinju; Guedj, Jeremie; Burdet, Charles; Andremont, Antoine; de Gunzburg, Jean; Ducher, Annie; Mentre, France"	"NA"	"A"	"Modeling the Effect of DAV132, a Novel Colon-Targeted Adsorbent, on Fecal Concentrations of Moxifloxacin and Gut Microbiota Diversity in Healthy Volunteers"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article; Early Access"	"NA"	"ORAL ACTIVATED-CHARCOAL; DRUG ABSORPTION; PHARMACOKINETICS; IMPACT; EFFICACY"	"To prevent antibiotic-induced perturbations on gut microbiota, DAV132, a novel colon-targeted adsorbent, which sequesters antibiotic residues in the lower gastrointestinal tract, was developed. We built an integrated pharmacological model of how DAV132 reduces fecal free moxifloxacin and preserves gut microbiota. We used plasma and fecal free moxifloxacin concentrations, and Shannon diversity index from 16S ribosomal RNA gene metagenomics analysis of fecal microbiota, of 143 healthy volunteers assigned randomly to receive moxifloxacin only, or with 10 DAV132 dose regimens, or to a control group. We modeled reduced fecal moxifloxacin concentrations using a transit model for DAV132 kinetics and a Michaelis-Menten model with an effect of the amount of activated charcoal on adsorption efficacy. Changes in moxifloxacin-induced perturbations on gut microbiota diversity were then quantified through a turnover model with the Emax model. With the developed model, the efficiency of pharmacokinetic antagonism and its consequences on gut microbiota diversity were quantified."	"[Guk, Jinju; Guedj, Jeremie; Burdet, Charles; Andremont, Antoine; Mentre, France] Univ Paris, INSERM, IAME, Paris, France; [Andremont, Antoine; de Gunzburg, Jean; Ducher, Annie] Da Volterra, Paris, France"	"Mentre, F (corresponding author), Univ Paris, INSERM, IAME, Paris, France."	"france.mentre@inserm.fr"	"; guedj, Jeremie/A-6842-2017"	"Mentre, france/0000-0002-7045-1275; guedj, Jeremie/0000-0002-5534-5482"	"Da Volterra, Paris, France"	"The data come from a clinical study that was funded by Da Volterra, Paris, France."	42	0	0	1	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1002/cpt.1977"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NA8QX"	"WOS:000560084500001"	32617960	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Royer, B; Schmitt, A; Nguyen, T; Jary, M; Demarchi, M; Vernerey, D; Henriques, J; Jacquin, M; Borg, C; Kim, S; Paillard, MJ"	"Royer, Bernard; Schmitt, Antonin; Nguyen, Thierry; Jary, Marine; Demarchi, Martin; Vernerey, Dewi; Henriques, Julie; Jacquin, Marion; Borg, Christophe; Kim, Stefano; Paillard, Marie-Justine"	"NA"	"A"	"Exposure-response analysis of Raltitrexed assessing liver toxicity"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article; Early Access"	"body surface area; clearance; dosing rational; population pharmacokinetics; raltitrexed"	"BODY-SURFACE AREA; POPULATION PHARMACOKINETIC ANALYSIS; THYMIDYLATE SYNTHASE INHIBITOR; METASTATIC COLORECTAL-CANCER; FACTOR XA INHIBITOR; RANDOMIZED-TRIAL; ANTITUMOR-ACTIVITY; ANTICANCER DRUGS; 5-FLUOROURACIL; CHEMOTHERAPY"	"Aim Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m(2)every 3 weeks. However, every 2 weeks administration at 2 mg/m(2)demonstrated a favourable toxicity profile. Method We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m(2)) and every 3 weeks TOMOX (RTX 3 mg/m(2)). Results A three-compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P= 0.006, OR = 3.91, 95%CI = [1.48-10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates-based dose was calculated, leading to less variability in AUC than observed with the actual BSA-based or fixed doses. Conclusion These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA."	"[Royer, Bernard] CHU Besancon, Lab Pharmacol Clin & Toxicol, F-25000 Besancon, France; [Royer, Bernard; Jary, Marine; Vernerey, Dewi; Henriques, Julie; Borg, Christophe; Kim, Stefano] Univ Bourgogne Franche Comte, Interact Hote Greffon Tumeur Ingn Cellulaire & Ge, UMR1098, INSERM,EFS BFC, F-25000 Besancon, France; [Schmitt, Antonin] Ctr Georges Francois Leclerc, Serv Pharm, F-21000 Dijon, France; [Schmitt, Antonin] Univ Bourgogne Franche Comte, INSERM U1231, F-21000 Dijon, France; [Nguyen, Thierry; Jary, Marine; Demarchi, Martin; Borg, Christophe; Kim, Stefano; Paillard, Marie-Justine] CHU Besancon, Serv Oncol Med, F-25000 Besancon, France; [Vernerey, Dewi; Henriques, Julie; Paillard, Marie-Justine] CHU Besancon, Unite Methodol & Quake Vie Canc, F-25000 Besancon, France; [Jary, Marine; Jacquin, Marion; Borg, Christophe; Kim, Stefano] CHU Besancon, INSERM CIC 1431, F-25000 Besancon, France; [Jacquin, Marion] Canceropole Grand Est, Paris, France"	"Royer, B (corresponding author), CHU Besancon, Dept Pharmacol & Toxicol, F-25030 Besancon, France."	"broyer@chu-besancon.fr"	"Schmitt, Antonin/AAG-9397-2020"	"Schmitt, Antonin/0000-0002-3132-7730; Kim, Stefano/0000-0003-2851-7119"	"Hospira"	"We thank Ines Tizon for English writing assistance. Hospira provided raltitrexed and funded the study. Hospira provided raltitrexed and funded the study."	37	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1111/bcp.14519"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NJ0OQ"	"WOS:000565744100001"	32789966	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Zhou, SR; Zhang, R; Lv, CL; Lu, JJ; Wei, YY; Li, CX; Chen, M; Li, QC; Liu, TT"	"Zhou, Siru; Zhang, Ren; Lv, Chunle; Lu, Jiejiu; Wei, Yinyi; Li, Chengxin; Chen, Ming; Li, Qiaochuan; Liu, Taotao"	"NA"	"A"	"Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics"	"ANNALS OF PHARMACOTHERAPY"	"English"	"Article; Early Access"	"tacrolimus; thalassemia major; hematopoietic stem cell transplantation; population pharmacokinetics; initial dosage regimens"	"VERSUS-HOST-DISEASE; RECIPIENTS; MODEL; FK506; PREVALENCE; CLEARANCE; CHILDREN; BURDEN; ADULTS"	"Background: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with beta-thalassemia major (beta-TM) undergoing HSCT are insufficient. Objective: To establish a PPK model of tacrolimus in children with beta-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. Methods: Data on patients aged Results: A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. Conclusion and Relevance: A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy."	"[Zhou, Siru; Zhang, Ren; Lv, Chunle; Lu, Jiejiu; Wei, Yinyi; Li, Chengxin; Chen, Ming; Li, Qiaochuan; Liu, Taotao] Guangxi Med Univ, Affiliated Hosp 1, Nanning, Peoples R China"	"Liu, TT (corresponding author), Guangxi Med Univ, Affiliated Hosp 1, Dept Pharm, 6 Shuangyong Rd, Nanning 530021, Guangxi, Peoples R China.; Li, QC (corresponding author), Guangxi Med Univ, Affiliated Hosp 1, Dept Hematol, 6 Shuangyong Rd, Nanning 530021, Guangxi, Peoples R China."	"liqiaochuan@sohu.com; liutaotao@gxmu.edu.cn"	"NA"	"NA"	"NA"	"NA"	48	0	0	0	0	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"1060-0280"	"1542-6270"	"NA"	"ANN PHARMACOTHER"	"Ann. Pharmacother."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	1060028020959039	"10.1177/1060028020959039"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NP4UC"	"WOS:000570171700001"	32924532	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gibiansky, L; Ravva, P; Parrott, NJ; Bhardwaj, R; Zwanziger, E; Grimsey, P; Clinch, B; Sturm, S"	"Gibiansky, Leonid; Ravva, Patanjali; Parrott, Neil J.; Bhardwaj, Rajinder; Zwanziger, Elke; Grimsey, Paul; Clinch, Barry; Sturm, Stefan"	"NA"	"A"	"Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"NEURAMINIDASE INHIBITOR OSELTAMIVIR; PRODRUG OSELTAMIVIR; INFLUENZA INFECTION; CARBOXYLESTERASE 1; EXPRESSION; EFFICACY; SAFETY"	"A mechanistic population-pharmacokinetic model was developed to predict oseltamivir exposures in neonates and infants accounting for physiological changes during the first 2 years of life. The model included data from 13 studies, comprising 436 subjects with normal renal function (317 pediatric subjects (>= 38 weeks postmenstrual age (PMA), >= 13 days old) and 119 adult subjects < 40 years). Concentration-time profiles of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were characterized by a four-compartment model, with absorption described by three additional compartments. Renal maturational changes were implemented by description of OC clearance with allometric function of weight and Hill function of PMA. Clearance of OC increased with weight up to 43 kg (allometric coefficient 0.75). Half the adult OC clearance was reached at a PMA of 45.6 weeks (95% confidence interval (CI) 41.6-49.6) with a Hill coefficient of 2.35 (95% CI 1.67-3.04). The model supports the European Union/United States-approved 3 mg/kg twice-daily oseltamivir dose for infants < 1 year (PMA >= 38 weeks) and allows prediction of exposures in preterm neonates."	"[Gibiansky, Leonid] QuantPharm LLC, North Potomac, MD 20878 USA; [Ravva, Patanjali] Roche Innovat Ctr New York, Roche Pharmaceut Res & Early Dev, New York, NY USA; [Parrott, Neil J.; Zwanziger, Elke; Sturm, Stefan] Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Basel, Switzerland; [Bhardwaj, Rajinder] Certara Strateg Consulting, Integrated Drug Dev, Parsippany, NJ USA; [Grimsey, Paul] Roche Innovat Ctr Welwyn, Roche Pharmaceut Res & Early Dev, Welwyn Garden City, Herts, England; [Clinch, Barry] Roche Prod Ltd, Prod Dev, Welwyn Garden City, Herts, England; [Ravva, Patanjali] Pfizer Inc, Global Clin Pharmacol, New York, NY USA"	"Gibiansky, L (corresponding author), QuantPharm LLC, North Potomac, MD 20878 USA."	"lgibiansky@quantpharm.com"	"NA"	"NA"	"F. Hoffmann-La Roche LtdHoffmann-La Roche Funding Source: Medline; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [N01-AI-30025, N01-AI-15113, N01-AI-62554, N01-AI-65306] Funding Source: Medline; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA Funding Source: Medline; NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA Funding Source: Medline"	"NA"	32	0	0	2	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"JUL"	2020	108	1	126	135	"NA"	"10.1002/cpt.1791"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LZ5HG"	"WOS:000541254400017"	31957010	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Kanji, S; Roberts, JA; Xie, J; Zelenitsky, S; Hiremath, S; Zhang, GJ; Watpool, I; Porteous, R; Patel, R"	"Kanji, Salmaan; Roberts, Jason A.; Xie, Jiao; Zelenitsky, Sheryl; Hiremath, Swapnil; Zhang, Guijun; Watpool, Irene; Porteous, Rebecca; Patel, Rakesh"	"NA"	"A"	"Vancomycin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"RENAL REPLACEMENT THERAPY; ACUTE KIDNEY INJURY; INTENSIVE-CARE-UNIT; MEROPENEM; PATTERNS; FAILURE; IMPACT"	"Background Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking. Objective The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies. Methods Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses. Results From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46) L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration-time curve from time zero to 24 h [AUC(24)]/minimum inhibitory concentration [MIC] >= 400) and safety (AUC(24) >= 700), a loading dose of 2400 mg followed by daily doses of 1600 mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels. Conclusions In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels."	"[Kanji, Salmaan; Hiremath, Swapnil; Watpool, Irene; Porteous, Rebecca; Patel, Rakesh] Ottawa Hosp, Ottawa Hosp Res Inst, 501 Smyth Rd, Ottawa, ON, Canada; [Roberts, Jason A.; Xie, Jiao] Univ Queensland, Fac Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med & Pharm, Brisbane, Qld, Australia; [Zelenitsky, Sheryl] Univ Manitoba, Coll Pharm, Rady Fac Hlth Sci, Winnipeg, MB, Canada; [Zhang, Guijun] Ottawa Hosp Res Inst, Clin Invest Unit, Ottawa, ON, Canada"	"Kanji, S (corresponding author), Ottawa Hosp, Ottawa Hosp Res Inst, 501 Smyth Rd, Ottawa, ON, Canada."	"skanji@toh.ca"	"Roberts, Jason A/F-6272-2010"	"Roberts, Jason A/0000-0001-6218-435X; Hiremath, Swapnil/0000-0003-0010-3416"	"NA"	"NA"	29	1	1	1	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAR"	2020	59	3	327	334	"NA"	"10.1007/s40262-019-00817-6"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KU1HE"	"WOS:000519460000004"	31471789	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Lu, D; Lu, T; Gibiansky, L; Li, XB; Li, CZ; Agarwal, P; Shemesh, CS; Shi, R; Dere, RC; Hirata, J; Miles, D; Chanu, P; Girish, S; Jin, JY"	"Lu, Dan; Lu, Tong; Gibiansky, Leonid; Li, Xiaobin; Li, Chunze; Agarwal, Priya; Shemesh, Colby S.; Shi, Rong; Dere, Randall C.; Hirata, Jamie; Miles, Dale; Chanu, Pascal; Girish, Sandhya; Jin, Jin Yan"	"NA"	"A"	"Integrated Two-Analyte Population Pharmacokinetic Model of Polatuzumab Vedotin in Patients With Non-Hodgkin Lymphoma"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"ANTIBODY-DRUG CONJUGATE; QUANTIFICATION"	"A two-analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non-Hodgkin lymphoma. A two-compartment model with a nonspecific, time-dependent linear clearance, a linear time-dependent exponentially declining clearance, and a Michaelis-Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two-compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims."	"[Lu, Dan; Lu, Tong; Li, Xiaobin; Li, Chunze; Agarwal, Priya; Shemesh, Colby S.; Shi, Rong; Dere, Randall C.; Hirata, Jamie; Miles, Dale; Girish, Sandhya; Jin, Jin Yan] Genentech Inc, San Francisco, CA 94080 USA; [Gibiansky, Leonid] QuantPharm LLC, North Potomac, MD USA; [Chanu, Pascal] Genentech Roche, Lyon, France"	"Lu, D; Lu, T (corresponding author), Genentech Inc, San Francisco, CA 94080 USA."	"lu.dan@gene.com; lu.tong@gene.com"	"li, chunze/AAC-8730-2020"	"NA"	"F. Hoffmann-La Roche Ltd.Hoffmann-La Roche"	"This study was funded by F. Hoffmann-La Roche Ltd."	34	5	5	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"JAN"	2020	9	1	48	59	"NA"	"10.1002/psp4.12482"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KD0LJ"	"WOS:000503894400001"	31749251	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Heffernan, AJ; Germano, A; Sime, FB; Roberts, JA; Kimura, E"	"Heffernan, A. J.; Germano, A.; Sime, F. B.; Roberts, Jason A.; Kimura, E."	"NA"	"A"	"Vancomycin population pharmacokinetics for adult patients with sepsis or septic shock: are current dosing regimens sufficient?"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Vancomycin; Pharmacokinetics; Therapeutic drug monitoring; Sepsis; Septic shock"	"CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; PREDICTION; SURVIVAL; MODEL"	"Purpose Vancomycin is commonly used for the management of severe infections; however, vancomycin dosing may be challenging in critically ill patients. This observational study aims to describe the population pharmacokinetics of vancomycin in adult patients with sepsis or septic shock. Methods A single-centre retrospective review of adult patients with sepsis or septic shock receiving vancomycin with therapeutic drug monitoring was undertaken. Blood samples taken 1 h after the vancomycin infusion cessation and 30 min prior to the next dose were assayed using the Vitros Crea Slide method. Vancomycin concentrations determined on different days were included. A pharmacokinetic model was developed using Pmetrics for R. Monte Carlo dosing simulations were performed using the final model. Results Vancomycin concentrations were available for 27 adult patients admitted to the intensive care unit with sepsis or septic shock. A one-compartment pharmacokinetic model with inter-occasion variability of clearance and volume of distribution before and after 72 h adequately described the data. Creatinine clearance normalized to body surface area was included as a covariate on vancomycin clearance. The clearance and volume of distribution within 72 h of admission were 7.29 L/h and 54.20 L, respectively. Monte Carlo simulations suggested that for patients with a creatinine clearance of >= 80 mL/min/1.73 m(2), vancomycin doses of >= 2 g every 8 h are required to consistently achieve key therapeutic targets. Conclusions Vancomycin doses >= 2 g every 8 h in adult patients with sepsis or septic shock with a creatinine clearance >= 80 mL/min/1.73 m(2) are likely needed to achieve an optimal therapeutic exposure."	"[Heffernan, A. J.; Sime, F. B.; Roberts, Jason A.] Univ Queensland, Ctr Translat Antiinfect Pharmacodynam, Sch Pharm, Brisbane, Qld, Australia; [Heffernan, A. J.] Griffith Univ, Sch Med, Gold Coast, Qld, Australia; [Germano, A.; Kimura, E.] Univ Estadual Maringa Hosp, Dept Intens Care Med, Maringa, Parana, Brazil; [Sime, F. B.; Roberts, Jason A.] Univ Queensland, Ctr Clin Res, Fac Med, Herston, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Pharm Dept, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia"	"Roberts, JA (corresponding author), Univ Queensland, Ctr Translat Antiinfect Pharmacodynam, Sch Pharm, Brisbane, Qld, Australia.; Roberts, JA (corresponding author), Univ Queensland, Ctr Clin Res, Fac Med, Herston, Qld, Australia.; Roberts, JA (corresponding author), Royal Brisbane & Womens Hosp, Pharm Dept, Brisbane, Qld, Australia.; Roberts, JA (corresponding author), Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia."	"j.roberts2@uq.edu.au"	"Roberts, Jason A/F-6272-2010; Sime, Fekade Bruck/I-3643-2019; Heffernan, Aaron/U-8703-2017"	"Roberts, Jason A/0000-0001-6218-435X; Sime, Fekade Bruck/0000-0003-4061-2063; Heffernan, Aaron/0000-0002-7929-9812"	"Science and Technology Secretariat of Parana State, Brazil"	"E. K. and A. G. would like to acknowledge funding from the Science and Technology Secretariat of Parana State, Brazil for this project."	26	1	1	1	6	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"SEP"	2019	75	9	1219	1226	"NA"	"10.1007/s00228-019-02694-1"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IR9QB"	"WOS:000481779100005"	31154476	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gibiansky, E; Gibiansky, L; Buchheit, V; Frey, N; Brewster, M; Fingerle-Rowson, G; Jamois, C"	"Gibiansky, Ekaterina; Gibiansky, Leonid; Buchheit, Vincent; Frey, Nicolas; Brewster, Michael; Fingerle-Rowson, Gunter; Jamois, Candice"	"NA"	"A"	"Pharmacokinetics, exposure, efficacy and safety of obinutuzumab in rituximab-refractory follicular lymphoma patients in the GADOLIN phase III study"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"drug exposure; follicular lymphoma; obinutuzumab; pharmacokinetics"	"NON-HODGKIN-LYMPHOMA; ANTI-CD20 MONOCLONAL-ANTIBODY; B-CELL LYMPHOMA; POPULATION PHARMACOKINETICS; PLUS BENDAMUSTINE; MAINTENANCE PROLONGS; FINAL ANALYSIS; GA101; SURVIVAL; FC"	"Aims Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL. Methods Using a previously described population pharmacokinetic (PK) model of obinutuzumab in patients with non-Hodgkin lymphoma and CLL, we conducted an exposure-response analysis using data from 6 clinical trials in patients with CD20 B-cell malignancies (CLL11, GADOLIN, GATHER, GAUDI, GAUGUIN and GAUSS) to describe the PK properties of obinutuzumab, identify covariates influencing exposure, and explore how exposure affects safety, efficacy and pharmacodynamics. Results A 2-compartment model with linear and time-dependent clearance described obinutuzumab PK. Disease type and subtype, body weight, baseline tumour size, and sex had the largest effects on PK. Obinutuzumab exposure was not associated with occurrence or severity of adverse events, but higher exposure appeared to be associated with greater efficacy, particularly longer progression-free survival. However, in multivariate Cox regression analysis, progression-free survival benefit in the obinutuzumab plus bendamustine arm was independent of exposure. Conclusion The updated population PK model reported here accurately describes the PK of obinutuzumab patients with non-Hodgkin lymphoma and CLL. The selected obinutuzumab dosing regimen offers clinical benefit in a majority of rituximab-refractory FL patients treated with bendamustine, irrespective of variability in exposure, whilst minimising adverse events."	"[Gibiansky, Ekaterina; Gibiansky, Leonid] QuantPharm LLC, North Potomac, MD USA; [Buchheit, Vincent; Frey, Nicolas; Jamois, Candice] Roche Innovat Ctr Basel, Pharma Res & Early Dev, Hochstr 4, CH-4053 Basel, Switzerland; [Brewster, Michael] Roche Innovat Ctr Welwyn, Clin Dev, Welwyn Garden City, Herts, England; [Fingerle-Rowson, Gunter] F Hoffmann La Roche Ltd, Pharma Dev Clin Oncol, Basel, Switzerland"	"Jamois, C (corresponding author), Roche Innovat Ctr Basel, Pharma Res & Early Dev, Hochstr 4, CH-4053 Basel, Switzerland."	"candice.jamois@roche.com"	"NA"	"Jamois, Candice/0000-0001-7018-9687"	"F. Hoffmann-La Roche Ltd.Hoffmann-La Roche"	"Support for third-party writing assistance under the directions of the lead authors was provided by Helen Cathro at Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd.r This work was supported by F. Hoffmann-La Roche Ltd."	49	0	0	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2019	85	9	1935	1945	"NA"	"10.1111/bcp.13974"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IT6PS"	"WOS:000476145400001"	31050355	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Roberts, JA; Alobaid, AS; Wallis, SC; Perner, A; Lipman, J; Sjovall, F"	"Roberts, Jason A.; Alobaid, Abdulaziz S.; Wallis, Steven C.; Perner, Anders; Lipman, Jeffrey; Sjovall, Fredrik"	"NA"	"A"	"Defining optimal dosing of ciprofloxacin in patients with septic shock"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"CRITICALLY-ILL PATIENTS; DEFINITIONS; SEPSIS"	"Background: Patients with septic shock may undergo extensive physiological alterations that can alter antibiotic pharmacokinetics. Objectives: To describe the population pharmacokinetics of ciprofloxacin in septic shock and to define recommendations for effective ciprofloxacin dosing in these patients. Methods: Adult patients with septic shock treated with ciprofloxacin were eligible for inclusion. Concentrations were measured by HPLC-MS/MS. Population pharmacokinetic modelling was performed with Monte Carlo simulations then used to define dosing regimens that optimize the PTA of an AUC/MIC ratio>125 for different MICs and fractional target attainment (FTA) of empirical and targeted therapy against Pseudomonas aeruginosa. Results: We included 48 patients with median Simplified Acute Physiology Score (SAPS) II of 49 and 90 day mortality of 33%. Ciprofloxacin pharmacokinetics was best described by a two-compartment linear model including CLCR and body weight as covariates on CL and central volume respectively. With a dose of 400 mg q8h and CLCR of 80 mL/min, >= 95% PTA was achieved for bacteria with MICs <= 0.25 mg/L. For empirical treatment of P. aeruginosa, 600mg q8h only reached a maximum of 68% FTA. For directed therapy against P. aeruginosa, a dose of 600mg q8h was needed to achieve sufficient AUC/MIC ratios. Conclusions: In patients with septic shock, standard ciprofloxacin dosing achieved concentrations to successfully treat bacteria with MICs <= 0.25 mg/L and then only in patients with normal or reduced CLCR. To cover pathogens with higher MICs or in patients with augmented renal CL, doses may have to be increased."	"[Roberts, Jason A.; Alobaid, Abdulaziz S.; Wallis, Steven C.; Lipman, Jeffrey] Univ Queensland, Ctr Clin Res, Fac Med, Brisbane, Qld, Australia; [Roberts, Jason A.; Lipman, Jeffrey] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Ctr Translat Antiinfect Pharmacodynam, Brisbane, Qld, Australia; [Alobaid, Abdulaziz S.] King Saud Med City, Dept Pharm, Riyadh, Saudi Arabia; [Perner, Anders] Univ Copenhagen, Copenhagen, Denmark; [Perner, Anders; Sjovall, Fredrik] Copenhagen Univ Hosp, Dept Intens Care, Rigshosp, Copenhagen, Denmark; [Lipman, Jeffrey] Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia; [Sjovall, Fredrik] Skane Univ Hosp, Dept Intens Care & Perioperat Med, Inga Marie Nilssons Gata 47,Pl 3, S-20502 Malmo, Sweden; [Sjovall, Fredrik] Lund Univ, Mitochondrial Med, Lund, Sweden"	"Sjovall, F (corresponding author), Skane Univ Hosp, Dept Intens Care & Perioperat Med, Inga Marie Nilssons Gata 47,Pl 3, S-20502 Malmo, Sweden."	"fredrik.sjovall@med.lu.se"	"Roberts, Jason A/F-6272-2010; Wallis, Steven/F-2046-2010"	"Roberts, Jason A/0000-0001-6218-435X; Wallis, Steven/0000-0002-2392-9854; Sjovall, Fredrik/0000-0001-5612-0325"	"Skane Region Research Funds; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [APP1099452, APP1117065]"	"This work was funded by Skane Region Research Funds for F. S.. J.A. Rwould like to acknowledge funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and Practitioner Fellowship (APP1117065)."	16	3	3	0	5	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JUN"	2019	74	6	1662	1669	"NA"	"10.1093/jac/dkz069"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"IS3TR"	"WOS:000482076800030"	30809648	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Tenorio-Canamas, T; Grau, S; Luque, S; Fortun, J; Liano, F; Roberts, JA"	"Tenorio-Canamas, Teresa; Grau, Santiago; Luque, Sonia; Fortun, Jesus; Liano, Fernando; Roberts, Jason A."	"NA"	"A"	"Pharmacokinetics of Micafungin in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis With High Cutoff Membranes"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"micafungin; pharmacokinetics; continuous venovenous hemodialysis with high cutoff membranes; critically ill; antifungals"	"INVASIVE CANDIDIASIS; SEPTIC SHOCK; CANDIDEMIA; MANAGEMENT; SEPSIS; INFECTIONS; GUIDELINE; OUTCOMES; REMOVAL; THERAPY"	"Background: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO). Methods: Prospective observational study performed in critically ill patients treated with 100 mg/d of micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyaryle-thersulfone of 1.1-m(2) surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and micafungin concentrations were determined using HPLC-UV. Results: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of micafungin concentrations in the effluent were <0.2 (<0.2- 0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model. Conclusions: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of micafungin, and that standard doses of this antifungal can be used."	"[Tenorio-Canamas, Teresa] Hosp Univ Ramon Y Cajal, Dept Nephrol, Madrid, Spain; [Tenorio-Canamas, Teresa] Univ Alcala De Henares, Sch Med, Dept Med, Alcala De Henares, Spain; [Grau, Santiago; Luque, Sonia] UAB, Inst Hosp Mar Invest Med IMIM, Infect Pathol & Antimicrobial Res Grp IPAR, Pharm Dept,Hosp Mar,CEXS Univ Pompeu Fabra, Barcelona, Spain; [Grau, Santiago; Luque, Sonia] Inst Salud Carlos III, Spanish Network Res Infect Dis REIPI RD 16 0016 0, Barcelona, Spain; [Fortun, Jesus] Hosp Univ Ramon Y Cajal, Dept Infect Dis, Madrid, Spain; [Liano, Fernando] Hosp Univ Ramon Y Cajal, Inst Invest Sanitaria Ramon Y Cajal IRYCIS, Dept Nephrol, Madrid, Spain; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Fac Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia"	"Luque, S (corresponding author), Hosp del Mar, Pharm Dept, Parc Salut Mar,Passeig Maritim 25, Barcelona 08003, Spain."	"sluque@parcdesalutmar.cat"	"Roberts, Jason A/F-6272-2010; Fortun, Jesus/H-1816-2017"	"Roberts, Jason A/0000-0001-6218-435X; Fortun, Jesus/0000-0002-6959-5263"	"Astellas, Spain"	"This study was funded by a research grant from Astellas, Spain."	35	1	1	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"JUN"	2019	41	3	376	382	"NA"	"10.1097/FTD.0000000000000595"	7	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"IQ4HA"	"WOS:000480710500011"	30633087	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Lanke, S; Shoaf, SE"	"Lanke, Shankar; Shoaf, Susan E."	"NA"	"A"	"Population Pharmacokinetic Analyses and Model Validation of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"ADPKD; tolvaptan; population pharmacokinetics; model development; validation; prediction"	"NONPEPTIDE AVP ANTAGONIST; PHARMACODYNAMICS; SAFETY"	"Tolvaptan is the first approved drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The objective is to develop (1091 subjects, 7335 observations) and validate (678 subjects, 3012 observations) a population pharmacokinetic model to describe tolvaptan pharmacokinetics in ADPKD subjects. The final model was evaluated with a bootstrapping method. The final model was internally and externally evaluated using visual predictive checks (VPC). Pharmacokinetics was best described by a 1-compartmental model with 0-order absorption, nonlinear relative bioavailability (F1), and first-order elimination. Accounting for changes in F1 significantly improved the model: as the dose increased from 15 mg to 120 mg, F1 decreased by 36%. Population estimates for clearance/F (CL/F), volume of distribution/F (Vd/F), duration of absorption (D1), the highest dose at which F1 is lowest, and the amount of dose at which F1 is 50% were 12.6 L center dot h(-1), 110 L, 0.58 hour, 182 mg, and 166 mg, respectively. The interindividual variability was 64% in CL/F, 70% in Vd/F, and 238% in D1. Residual variability was described by a combined-error model. The VPC (500 data sets simulated) showed that 76% to 92% of the observed data fell within the 90% prediction intervals. The model stability assessed by a 1000-run bootstrap analysis showed that the mean parameter estimates of data were within 10% of those obtained with the final model. The developed model is robust and stable. Internal and external validation confirmed the model ability to describe the data optimally."	"[Lanke, Shankar; Shoaf, Susan E.] Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ 08540 USA"	"Lanke, S (corresponding author), Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ 08540 USA."	"shankar.lanke@otsuka-us.com"	"NA"	"NA"	"Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJOtsuka Pharmaceutical"	"Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ. provided all funding for the analysis."	25	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"MAY"	2019	59	5	763	770	"NA"	"10.1002/jcph.1370"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HX0JC"	"WOS:000467074500013"	30618157	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Tangden, T; Cojutti, PG; Roberts, JA; Pea, F"	"Tangden, Thomas; Cojutti, Pier Giorgio; Roberts, Jason A.; Pea, Federico"	"NA"	"A"	"Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; GANCICLOVIR; RECIPIENTS; PREVENTION; CLEARANCE; DISEASE; PLASMA"	"Background and ObjectivesValganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations.MethodsTherapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration-time curve (AUC) target of 40-50mg<bold>h</bold>/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics package for R.ResultsThis study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir)=TVCLx(CLCR/51)(0.75), where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CLCR) according to the Cockcroft-Gaultt equation and 51 is the mean CLCR determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CLCR<50mL/min.ConclusionsHigher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures."	"[Tangden, Thomas] Uppsala Univ, Dept Med Sci, Uppsala, Sweden; [Cojutti, Pier Giorgio; Pea, Federico] Santa Maria della Misericordia Univ, Inst Clin Pharmacol, ASUIUD, Udine, Italy; [Cojutti, Pier Giorgio; Pea, Federico] Univ Udine, Dept Med, Udine, Italy; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Ctr Clin Res, Fac Med, Level 3,Ned Hanlon Bldg, Herston, Qld 4029, Australia; [Roberts, Jason A.] Univ Queensland, Ctr Antiinfect Translat Pharmacodynam, Sch Pharm, Level 3,Ned Hanlon Bldg, Herston, Qld 4029, Australia"	"Roberts, JA (corresponding author), Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia.; Roberts, JA (corresponding author), Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia.; Roberts, JA (corresponding author), Univ Queensland, Ctr Clin Res, Fac Med, Level 3,Ned Hanlon Bldg, Herston, Qld 4029, Australia.; Roberts, JA (corresponding author), Univ Queensland, Ctr Antiinfect Translat Pharmacodynam, Sch Pharm, Level 3,Ned Hanlon Bldg, Herston, Qld 4029, Australia."	"j.roberts2@uq.edu.au"	"Pea, Federico/O-3636-2019; Roberts, Jason A/F-6272-2010"	"Pea, Federico/0000-0002-6966-7167; Roberts, Jason A/0000-0001-6218-435X"	"Australian National Health and Medical Research Council for a Centre of Research ExcellenceNational Health and Medical Research Council of Australia [APP1099452]; National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [APP1117065]"	"This work was supported by internal funding. We wish to recognise funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452). JAR is funded in part by a Practitioner Fellowship (APP1117065) from the National Health and Medical Research Council of Australia."	17	5	5	0	6	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NOV"	2018	57	11	1399	1405	"NA"	"10.1007/s40262-018-0638-5"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GX7RH"	"WOS:000447972300004"	29546589	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Simeoni, M; Chen, C"	"Simeoni, Monica; Chen, Chao"	"NA"	"A"	"Population Pharmacokinetic Modelling for Estimation of Remifentanil Metabolic-Ratio Using Non-steady-State Concentrations under Rapidly Adaptive Dosing"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"metabolic ratio; model evaluation; population pharmacokinetics; remifentanil"	"VISUAL PREDICTIVE CHECK; MAJOR METABOLITE; PHARMACODYNAMICS"	"PurposeTo predict steady-state metabolite-to-drug concentration ratio (metabolic ratio) for analgesic drug remifentanil, using sparse non-steady-state data from patients with normal or impaired renal function during individualised, highly variable and rapidly adaptive intravenous infusion.MethodsA three-compartment joint parent-metabolite population pharmacokinetic model was developed using concentrations of remifentanil and its metabolite remifentanil acid from two trials. Renal function was included as an important mechanistic covariate. To address the large covariate effect and highly individualised and rapidly adaptive dosing, standardised visual predictive check was conducted on the observations and individualised visual predictive check was conducted on metabolic ratio estimates. The model was used to simulate metabolic ratio distribution in patients with various renal functions.ResultsThe model, including its covariate structure, adequately described the data. The predictive checks allowed informative model evaluation. The predictedmedian (10th - 90th percentile) of remifentanil metabolic ratio was 12.5 (2.4-58.2) for patients with normal or mildly impaired renal function, or 54.3 (12.8-218.4) for patients with moderately or severely impaired renal function.ConclusionsThe methodologies applied here allowed robust estimation of steady-state parameters using non-steady-state sparse data under highly variable adaptive dosing."	"[Simeoni, Monica; Chen, Chao] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, 1 Ironbridge Rd, Uxbridge UB11 1BT, Middx, England"	"Chen, C (corresponding author), GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, 1 Ironbridge Rd, Uxbridge UB11 1BT, Middx, England."	"chao.c.chen@gsk.com"	"NA"	"NA"	"GlaxoSmithKlineGlaxoSmithKline"	"We thank Jonathan Bullman and remifentanil project team for their support, and Dr. Martin Bergstrand for discussion on prediction-corrected visual predictive check. Funding for this analysis was provided by GlaxoSmithKline. All authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors are employed by GlaxoSmithKline and declare no conflict of interest."	20	0	0	0	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"NOV"	2018	35	11	"NA"	"NA"	216	"10.1007/s11095-018-2508-0"	11	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"GU9HJ"	"WOS:000445655600005"	30255401	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kanji, S; Roberts, JA; Xie, J; Alobaid, A; Zelenitsky, S; Hiremath, S; Zhang, GJ; Watpool, I; Porteous, R; Patel, R"	"Kanji, Salmaan; Roberts, Jason A.; Xie, Jiao; Alobaid, Abdulaziz; Zelenitsky, Sheryl; Hiremath, Swapnil; Zhang, Guijun; Watpool, Irene; Porteous, Rebecca; Patel, Rakesh"	"NA"	"A"	"Piperacillin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis"	"ANNALS OF PHARMACOTHERAPY"	"English"	"Article"	"renal replacement therapy; dialysis; piperacillin; piperacillin-tazobactam; pharmacokinetics; drug dosing"	"RENAL REPLACEMENT THERAPY; ACUTE KIDNEY INJURY; INTENSIVE-CARE-UNIT; CONTINUOUS VENOVENOUS HEMODIAFILTRATION; BETA-LACTAM ANTIBIOTICS; EXTENDED DAILY DIALYSIS; CONTINUOUS-INFUSION; SEPTIC SHOCK; FAILURE; TAZOBACTAM"	"Background: Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking. Objective: To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations. Methods: This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses. Results: From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC 16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC 32 mg/L. Conclusions and Relevance: In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen."	"[Kanji, Salmaan; Hiremath, Swapnil; Patel, Rakesh] Ottawa Hosp, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada; [Kanji, Salmaan; Hiremath, Swapnil; Zhang, Guijun; Watpool, Irene; Porteous, Rebecca] Ottawa Hosp, Res Inst, Ottawa, ON, Canada; [Roberts, Jason A.; Xie, Jiao; Alobaid, Abdulaziz] Univ Queensland, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia; [Zelenitsky, Sheryl] Univ Manitoba, Winnipeg, MB, Canada"	"Kanji, S (corresponding author), Ottawa Hosp, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada."	"skanji@toh.ca"	"Hiremath, Swapnil/H-3492-2019; Roberts, Jason A/F-6272-2010"	"Hiremath, Swapnil/0000-0003-0010-3416; Roberts, Jason A/0000-0001-6218-435X; Zelenitsky, Sheryl/0000-0003-1891-1999; Xie, Jiao/0000-0002-7115-829X"	"Kidney Foundation of Canada [KFOC140003]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [APP1099452, APP1044941, APP1117065]"	"The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Kidney Foundation of Canada (KFOC140003). Jason Roberts would like to recognize funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and Project Grant (APP1044941) and a Practitioner Fellowship (APP1117065)."	40	5	5	0	7	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"1060-0280"	"1542-6270"	"NA"	"ANN PHARMACOTHER"	"Ann. Pharmacother."	"OCT"	2018	52	10	965	973	"NA"	"10.1177/1060028018773771"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GT3JZ"	"WOS:000444400400003"	29730948	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Economou, CJP; Kielstein, JT; Czock, D; Xie, J; Field, J; Richards, B; Tallott, M; Visser, A; Koenig, C; Hafer, C; Schmidt, JJ; Lipman, J; Roberts, JA"	"Economou, Caleb J. P.; Kielstein, Jan T.; Czock, David; Xie, Jiao; Field, Jonathan; Richards, Brent; Tallott, Mandy; Visser, Adam; Koenig, Christina; Hafer, Carsten; Schmidt, Julius J.; Lipman, Jeffrey; Roberts, Jason A."	"NA"	"A"	"Population pharmacokinetics of vancomycin in critically ill patients receiving prolonged intermittent renal replacement therapy"	"INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS"	"English"	"Article"	"Antibiotics; Dosing; Pharmacokinetics; Pharmacodynamics; Renal replacement therapy; Prolonged intermittent renal replacement therapy"	"ACUTE KIDNEY INJURY; CONTINUOUS-INFUSION; HEMODIAFILTRATION; GUIDELINES; SIMULATION; DIALYSIS; SEPSIS"	"Objectives: The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury. Methods: Critically ill patients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics (R). The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC(0-24))/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC(0-24) 700 for toxicity. Results: Eleven critically ill patients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean � standard deviation (SD) age, weight and body mass index (BMI) were 57 � 13 years, 98 � 43 kg and 31 � 9 kg/m(2), respectively. A two-compartment linear model adequately described the data. The mean � SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 � 1.99 L/h, non-PIRRT CL 2.15 � 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 � 24.33 L, distribution rate constant from central to peripheral compartment 5.97 � 7.93 per h and from peripheral to central compartment 5.29 � 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. Conclusions: This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring. (c) 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved."	"[Economou, Caleb J. P.; Xie, Jiao; Lipman, Jeffrey; Roberts, Jason A.] Univ Queensland, Clin Res Ctr, Fac Med, Brisbane, Qld, Australia; [Economou, Caleb J. P.] ICON Canc Fdn, Dept Res, Brisbane, Qld, Australia; [Kielstein, Jan T.; Hafer, Carsten] Acad Teaching Hosp Braunschweig, Med Clin Nephrol Rheumatol & Blood Purificat 5, Braunschweig, Germany; [Czock, David] Univ Hosp Heidelberg, Dept Clin Pharmacol & Pharmacoepidemiol, Heidelberg, Germany; [Field, Jonathan; Richards, Brent; Tallott, Mandy; Visser, Adam] Gold Coast Univ Hosp, Dept Intens Care Med, Gold Coast, Qld, Australia; [Koenig, Christina] Univ Med Ctr Hamburg Eppendorf, Dept Intens Care Med, Hamburg, Germany; [Koenig, Christina] Univ Med Ctr Hamburg Eppendorf, Hosp Pharm, Hamburg, Germany; [Schmidt, Julius J.] Hannover Med Sch, Dept Nephrol, Hannover, Germany; [Lipman, Jeffrey; Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Ctr Translat Antiinfect Pharmacodynam, Brisbane, Qld, Australia"	"Roberts, JA (corresponding author), Univ Queensland, Ctr Clin Res, Level 8, Herston, Qld, Australia."	"j.roberts2@uq.edu.au"	"Kielstein, Jan T./I-2956-2019; Roberts, Jason A/F-6272-2010; Lipman, Jeffrey/G-2211-2010"	"Kielstein, Jan T./0000-0001-8110-9064; Roberts, Jason A/0000-0001-6218-435X; Lipman, Jeffrey/0000-0002-5965-9876; , Caleb/0000-0001-9916-0343; Xie, Jiao/0000-0002-7115-829X; Richards, Brent/0000-0003-2613-0308"	"Royal Brisbane and Women's Hospital Foundation; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [APP1099452, APP1044941]; Intensive Care Foundation; National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [APP1117065]; intramural HILF program of the Hannover Medical School"	"Caleb Economou was supported by funding from the Royal Brisbane and Women's Hospital Foundation. We wish to recognise funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and Project Grant (APP1044941) and funding from the Intensive Care Foundation. Jason Roberts is funded in part by a Practitioner Fellowship (APP1117065) from the National Health and Medical Research Council of Australia. Julius J. Schmidt was supported by the intramural HILF program of the Hannover Medical School."	24	8	10	0	6	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0924-8579"	"1872-7913"	"NA"	"INT J ANTIMICROB AG"	"Int. J. Antimicrob. Agents"	"AUG"	2018	52	2	151	157	"NA"	"10.1016/j.ijantimicag.2018.03.001"	7	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"GP2JE"	"WOS:000440655600004"	29526606	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Baey, C; Mathieu, A; Jullien, A; Trevezas, S; Cournede, PH"	"Baey, Charlotte; Mathieu, Amelie; Jullien, Alexandra; Trevezas, Samis; Cournede, Paul-Henry"	"NA"	"A"	"Mixed-Effects Estimation in Dynamic Models of Plant Growth for the Assessment of Inter-individual Variability"	"JOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS"	"English"	"Article"	"Brassica napus; GreenLab model; Inter-individual variability; MCMC; Nonlinear mixed model; nlme; Population model; SAEM algorithm; Winter oilseed rape; WOSR"	"STOCHASTIC VARIANTS; MAXIMUM-LIKELIHOOD; SPRING WHEAT; LIGHT; COMPONENTS; YIELD; RED"	"Modeling inter-individual variability in plant populations is a key issue to understand crop heterogeneity and its variations in response to the environment. Being able to describe the interactions among plants and explain the variability observed in the population could provide useful information on how to control it and improve global plant growth. We propose here a method to model plant variability within a field, by extending the so-called GreenLab functional-structural plant model from the individual to the population scale via nonlinear mixed-effects modeling. Parameter estimation of the population model is achieved using the stochastic approximation expectation maximization algorithm, implemented in the platform for plant growth modeling and analysis PyGMAlion. The method is first applied on a set of simulated data and then on a real dataset from a population of 34 winter oilseed rape plants at the rosette stage. Results show that our method allows for a good characterization of the variability in the population with only a limited number of parameters, which is a key point for plant models. Results on simulated data show that parameters associated with a low sensitivity index are inaccurately estimated by the algorithm when considered as random effects, but a good stability of the results can be obtained by considering them as fixed effects. These results open new ways for the analysis of inter-plant variability within a population and the study of plant-plant competition.Supplementary materials accompanying this paper appear online."	"[Baey, Charlotte] Univ Lille, Lab Paul Painleve, F-59655 Villeneuve Dascq, France; [Mathieu, Amelie; Jullien, Alexandra] Univ Paris Saclay, INRA, AgroParis Tech, UMRECOSYS, F-78850 Thiverval Grignon, France; [Trevezas, Samis] Univ Athens, Sect Stat & Operat Res, Dept Math, Athens 15784, Greece; [Cournede, Paul-Henry] Univ Paris Saclay, Cent Supelec, Lab Math Interact Comp Sci MICS, F-92290 Chatenay Malabry, France"	"Baey, C (corresponding author), Univ Lille, Lab Paul Painleve, F-59655 Villeneuve Dascq, France."	"charlotte.baey@univ-lille.fr"	"Cournede, Paul-Henry/AAS-8340-2020"	"Baey, Charlotte/0000-0002-1413-1058"	"NA"	"NA"	49	2	2	2	7	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1085-7117"	"1537-2693"	"NA"	"J AGR BIOL ENVIR ST"	"J. Agric. Biol. Environ. Stat."	"JUN"	2018	23	2	208	232	"NA"	"10.1007/s13253-017-0307-4"	25	"Biology; Mathematical & Computational Biology; Statistics & Probability"	"Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics"	"GG9GA"	"WOS:000433007800003"	"NA"	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Maseda, E; Grau, S; Luque, S; Castillo-Mafla, MP; Suarez-de-la-Rica, A; Montero-Feijoo, A; Salgado, P; Gimenez, MJ; Garcia-Bernedo, CA; Gilsanz, F; Roberts, JA"	"Maseda, Emilio; Grau, Santiago; Luque, Sonia; Castillo-Mafla, Maria-Pilar; Suarez-de-la-Rica, Alejandro; Montero-Feijoo, Ana; Salgado, Patricia; Gimenez, Maria-Jose; Garcia-Bernedo, Carlos A.; Gilsanz, Fernando; Roberts, Jason A."	"NA"	"A"	"Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients"	"CRITICAL CARE"	"English"	"Article"	"Morbid obesity; PK/PD; Monte-Carlo simulation; Intensive care unit; Candida spp."	"INTENSIVE-CARE-UNIT; PHARMACOKINETIC/PHARMACODYNAMIC ADEQUACY; INVASIVE CANDIDIASIS; PHARMACOKINETICS; CASPOFUNGIN; SCORE; ANIDULAFUNGIN; ECHINOCANDINS; BREAKPOINTS; OVERWEIGHT"	"Background: Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the micafungin probability of reaching adequate 24-h area under the curve (AUC(0-24h))/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. Methods: Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed micafungin treatment. Patients received once daily 100-150 mg micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total micafungin concentrations were determined by highperformance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC(0-24)/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs >= 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was >= 90%. Results: Overall, 100 mg of micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) <= 45 kg/m(2) and 150 mg for morbidly obese patients with BMI > 45 kg/m(2) (except two noncritically ill obese patients with BMI similar to 35 kg/m(2) receiving 150 mg, and one critically ill patient with BMI > 45 kg/m(2) receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. Conclusion: The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of micafungin dosing for nonalbicans Candida infections."	"[Maseda, Emilio; Castillo-Mafla, Maria-Pilar; Suarez-de-la-Rica, Alejandro; Montero-Feijoo, Ana; Salgado, Patricia; Gilsanz, Fernando] Hosp Univ La Paz, Dept Anesthesia & Surg Intens Care, Paseo Castellana 261, Madrid 28046, Spain; [Maseda, Emilio; Gilsanz, Fernando] Univ Autonoma Madrid, Madrid, Spain; [Grau, Santiago; Luque, Sonia] Hosp del Mar, Pharm Dept, Barcelona, Spain; [Grau, Santiago] Inst Hosp del Mar Invest Med IMIM, Barcelona, Spain; [Luque, Sonia] Univ Autonoma Barcelona, Barcelona, Spain; [Gimenez, Maria-Jose] PRISM AG, Madrid, Spain; [Garcia-Bernedo, Carlos A.] Hosp del Mar, Anesthesiol Dept, Barcelona, Spain; [Roberts, Jason A.] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England; [Roberts, Jason A.] Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Pharm Dept, Brisbane, Qld, Australia"	"Maseda, E (corresponding author), Hosp Univ La Paz, Dept Anesthesia & Surg Intens Care, Paseo Castellana 261, Madrid 28046, Spain.; Maseda, E (corresponding author), Univ Autonoma Madrid, Madrid, Spain."	"emilio.maseda@gmail.com"	"Roberts, Jason A/F-6272-2010"	"Roberts, Jason A/0000-0001-6218-435X; Gimenez, Maria-Jose/0000-0003-0830-4095; Suarez de la Rica, Alejandro/0000-0003-1139-8547; Maseda, Emilio/0000-0003-2898-7073"	"Astellas Pharma S.A. (Madrid, Spain)Astellas Pharmaceuticals; National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [APP1048652]"	"This work was supported in part by an unrestricted grant from Astellas Pharma S.A. (Madrid, Spain). The funder had no role in the study design, data collection and interpretation, or the decision to submit the work for publication. JAR is funded by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652)."	42	14	14	0	3	"BIOMED CENTRAL LTD"	"LONDON"	"236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND"	"1466-609X"	"1364-8535"	"NA"	"CRIT CARE"	"Crit. Care"	"APR 15"	2018	22	"NA"	"NA"	"NA"	94	"10.1186/s13054-018-2019-8"	9	"Critical Care Medicine"	"General & Internal Medicine"	"GC7NU"	"WOS:000429980800001"	29655372	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Sjovall, F; Alobaid, AS; Wallis, SC; Perner, A; Lipman, J; Roberts, JA"	"Sjovall, Fredrik; Alobaid, Abdulaziz S.; Wallis, Steven C.; Perner, Anders; Lipman, Jeffrey; Roberts, Jason A."	"NA"	"A"	"Maximally effective dosing regimens of meropenem in patients with septic shock"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"CRITICALLY-ILL PATIENTS; POPULATION PHARMACOKINETICS; SEPSIS; PHARMACODYNAMICS; DEFINITIONS; IMIPENEM"	"Objectives: To use a population pharmacokinetic approach to define maximally effective meropenem dosing recommendations for treatment of Acinetobacter baumannii and Pseudomonas aeruginosa infections in a large cohort of patients with septic shock. Methods: Adult patients with septic shock and conserved renal function, treated with meropenem, were eligible for inclusion. Seven blood samples were collected during a single dosing interval and meropenem concentrations were measured by a validated HPLC-MS/MS method. Monte Carlo simulations were employed to define optimum dosing regimens for treatment of empirical or targeted therapy of A. baumannii and P. aeruginosa. EudraCT-no. 2014-002555-26 and NCT02240277. Results: Fifty patients were included, 26 male and 24 female, with a median age of 64 years with an all-cause 90 day mortality of 34%. A two-compartment linear model including creatinine clearance (CLCR) as a covariate best described meropenem pharmacokinetics. For empirical treatment of A. baumannii, 2000 mg/6 h was required by intermittent (30 min) or prolonged (3 h) infusion, whereas 6000 mg/day was required with continuous infusion. For P. aeruginosa, 2000 mg/8 h or 1000 mg/6 h was required for both empirical and targeted treatment. In patients with a CLCR of <= 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. Conclusions: In patients with septic shock and possible augmented renal clearance, doses should be increased and/or administration should be performed by prolonged or continuous infusion to increase the likelihood of achieving therapeutic drug concentrations. In patients with normal renal function, however, standard dosing seems to be sufficient."	"[Sjovall, Fredrik; Perner, Anders] Copenhagen Univ Hosp, Rigshosp, Dept Intens Care, Copenhagen, Denmark; [Sjovall, Fredrik] Lund Univ, Skane Univ Hosp, Dept Intens Care & Perioperat Med, Lund, Sweden; [Sjovall, Fredrik] Lund Univ, Mitochondrial Med, Lund, Sweden; [Alobaid, Abdulaziz S.; Wallis, Steven C.; Lipman, Jeffrey; Roberts, Jason A.] Univ Queensland, Ctr Clin Res, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia; [Alobaid, Abdulaziz S.] King Saud Med City, Dept Pharm, Riyadh, Saudi Arabia; [Perner, Anders] Univ Copenhagen, Copenhagen, Denmark; [Lipman, Jeffrey; Roberts, Jason A.] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia; [Lipman, Jeffrey] Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Ctr Translat Pharmacodynam, Brisbane, Qld, Australia"	"Sjovall, F (corresponding author), Skane Univ Hosp, Dept Intens Care & Perioperat Med, Inga Marie Nilssons Gata 47,Pl 3, S-20502 Malmo, Sweden."	"fredrik.sjovall@med.lu.se"	"Lipman, Jeffrey/G-2211-2010; Roberts, Jason A/F-6272-2010; Wallis, Steven/F-2046-2010"	"Lipman, Jeffrey/0000-0002-5965-9876; Roberts, Jason A/0000-0001-6218-435X; Wallis, Steven/0000-0002-2392-9854; Sjovall, Fredrik/0000-0001-5612-0325"	"Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [APP1099452, APP1117065]; Skane Region Research Funds"	"We wish to recognize funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and Practitioner Fellowship (APP1117065) for J. A. R. and Skane Region Research Funds for F. S."	29	15	15	0	6	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JAN"	2018	73	1	191	198	"NA"	"10.1093/jac/dkx330"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"FS2JA"	"WOS:000419603500026"	28961812	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, M; Li, Z; Lee, EY; Lewis, MM; Zhang, LJ; Sterling, NW; Wagner, D; Eslinger, P; Du, GW; Huang, XM"	"Wang, Ming; Li, Zheng; Lee, Eun Young; Lewis, Mechelle M.; Zhang, Lijun; Sterling, Nicholas W.; Wagner, Daymond; Eslinger, Paul; Du, Guangwei; Huang, Xuemei"	"NA"	"A"	"Predicting the multi-domain progression of Parkinson's disease: a Bayesian multivariate generalized linear mixed-effect model"	"BMC MEDICAL RESEARCH METHODOLOGY"	"English"	"Article"	"Parkinson's disease; Multivariate longitudinal data; Generalized linear mixed-effect model; Dynamic prediction; Motor symptoms; Non-motor symptoms; Imbalance"	"COGNITIVE IMPAIRMENTS; R PACKAGE; MOTOR"	"Background: It is challenging for current statistical models to predict clinical progression of Parkinson's disease (PD) because of the involvement of multi-domains and longitudinal data. Methods: Past univariate longitudinal or multivariate analyses from cross-sectional trials have limited power to predict individual outcomes or a single moment. The multivariate generalized linear mixed-effect model (GLMM) under the Bayesian framework was proposed to study multi-domain longitudinal outcomes obtained at baseline, 18-, and 36-month. The outcomes included motor, non-motor, and postural instability scores from the MDS-UPDRS, and demographic and standardized clinical data were utilized as covariates. The dynamic prediction was performed for both internal and external subjects using the samples from the posterior distributions of the parameter estimates and random effects, and also the predictive accuracy was evaluated based on the root of mean square error (RMSE), absolute bias (AB) and the area under the receiver operating characteristic (ROC) curve. Results: First, our prediction model identified clinical data that were differentially associated with motor, non-motor, and postural stability scores. Second, the predictive accuracy of our model for the training data was assessed, and improved prediction was gained in particularly for non-motor (RMSE and AB: 2.89 and 2.20) compared to univariate analysis (RMSE and AB: 3.04 and 2.35). Third, the individual-level predictions of longitudinal trajectories for the testing data were performed, with similar to 80% observed values falling within the 95% credible intervals. Conclusions: Multivariate general mixed models hold promise to predict clinical progression of individual outcomes in PD. Trial registration: The data was obtained from Dr. Xuemei Huang's NIH grant R01 NS060722, part of NINDS PD Biomarker Program (PDBP). All data was entered within 24 h of collection to the Data Management Repository (DMR), which is publically available (https://pdbp. ninds. nih. gov/data-management)."	"[Wang, Ming; Li, Zheng; Eslinger, Paul] Penn State Univ, Hershey Med Ctr, Dept Publ Hlth Sci, Hershey, PA 17033 USA; [Lee, Eun Young; Lewis, Mechelle M.; Sterling, Nicholas W.; Wagner, Daymond; Eslinger, Paul; Du, Guangwei; Huang, Xuemei] Penn State Univ, Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA; [Zhang, Lijun] Penn State Univ, Hershey Med Ctr, Dept Biochem & Mol Biol, Hershey, PA 17033 USA; [Zhang, Lijun] Penn State Univ, Hershey Med Ctr, Inst Personalized Med, Hershey, PA 17033 USA; [Huang, Xuemei] Penn State Univ, Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA; [Huang, Xuemei] Penn State Univ, Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA; [Huang, Xuemei] Penn State Univ, Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA; [Huang, Xuemei] Penn State Univ, Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA"	"Wang, M (corresponding author), Penn State Univ, Hershey Med Ctr, Dept Publ Hlth Sci, Hershey, PA 17033 USA.; Huang, XM (corresponding author), Penn State Univ, Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA."	"mwang@phs.psu.edu; xuemei@psu.edu"	"NA"	"Wang, Ming/0000-0002-9977-7041"	"Junior Faculty Development Program; Department of Public Health Sciences at the Pennsylvania State University College of Medicine; National Center for Advancing Translational Sciences (NCATS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1 TR002014, KL2 TR002015]; National Institute of Neurological Disease and StrokeUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [NS060722, NS082151]; National Center for Advancing Translational SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1 TR000127, TR002014]; PA Department of Health Tobacco CURE Funds"	"Dr. Wang's research was supported partially by endowment funding from the Junior Faculty Development Program and the Department of Public Health Sciences at the Pennsylvania State University College of Medicine, and was also supported, in part, by Grant UL1 TR002014 and KL2 TR002015 from the National Center for Advancing Translational Sciences (NCATS). Dr. Huang's work also was supported by the National Institute of Neurological Disease and Stroke (NS060722 and NS082151), the National Center for Advancing Translational Sciences (Grant UL1 TR000127 and TR002014), and the PA Department of Health Tobacco CURE Funds. The content is solely the responsibility of the authors and does not represent the official views of the National Institute of Health and other research sponsors."	36	1	1	1	5	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1471-2288"	"NA"	"NA"	"BMC MED RES METHODOL"	"BMC Med. Res. Methodol."	"SEP 25"	2017	17	"NA"	"NA"	"NA"	147	"10.1186/s12874-017-0415-4"	10	"Health Care Sciences & Services"	"Health Care Sciences & Services"	"FI1JN"	"WOS:000411689300001"	28946857	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Roger, C; Wallis, SC; Muller, L; Saissi, G; Lipman, J; Bruggemann, RJ; Lefrant, JY; Roberts, JA"	"Roger, Claire; Wallis, Steven C.; Muller, Laurent; Saissi, Gilbert; Lipman, Jeffrey; Bruggemann, Roger J.; Lefrant, Jean-Yves; Roberts, Jason A."	"NA"	"A"	"Caspofungin Population Pharmacokinetics in Critically Ill Patients Undergoing Continuous Veno-Venous Haemofiltration or Haemodiafiltration"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"RENAL REPLACEMENT THERAPY; INTENSIVE-CARE-UNIT; CANDIDA SPP.; SEPTIC SHOCK; MULTICENTER; INFECTION; OUTCOMES; PHARMACODYNAMICS; ANIDULAFUNGIN; ECHINOCANDINS"	"Background and Objective Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes. Methods Patients receiving caspofungin and undergoing continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF) were eligible to take part in the study. Blood samples were collected at seven sampling times during a dosing interval. Demographics and clinical data were recorded. Population pharmacokinetic analysis and Monte-Carlo simulation were undertaken using Pmetrics. Results Twelve pharmacokinetic profiles from nine patients were analysed. The caspofungin CRRT clearance (CL) was 0.048 � 0.12 L/h for CVVH and 0.042 � 0.042 L/h for CVVHDF. A two-compartment linear model best described the data. Patient weight was the only covariate affecting drug CL and central volume. The mean (standard deviation) parameter estimates were 0.64 � 0.12 L/h for CL, 9.35 � 3.56 L for central volume, 0.25 � 0.19 per h for the rate constant for drug distribution from central to peripheral compartments and 0.19 � 0.10 per h from peripheral to central compartments. Based on simulation results, a caspofungin 100 mg loading dose followed by a 50 mg maintenance dose for patients with a total body weight of <= 80 kg best achieved the pharmacokinetic/PD targets whilst a 70 mg maintenance dose was required for patients with a weight of >80 kg. Conclusion No caspofungin dosing adjustment is necessary for patients undergoing either form of CRRT. However, higher than recommended loading doses of caspofungin are required to achieve pharmacokinetic/pharmacodynamic targets in critically ill patients."	"[Roger, Claire; Muller, Laurent; Saissi, Gilbert; Lefrant, Jean-Yves] CHU Nimes, Pole Anesthesie Reanimat Douleur Urgence, Serv Reanimat, Nimes, France; [Roger, Claire; Wallis, Steven C.; Lipman, Jeffrey; Roberts, Jason A.] Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia; [Lipman, Jeffrey; Roberts, Jason A.] Univ Queensland, Sch Pharm, Brisbane, Qld, Australia; [Lipman, Jeffrey; Roberts, Jason A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Bruggemann, Roger J.] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, Nijmegen, Netherlands; [Bruggemann, Roger J.] CWZ, Ctr Expertise Mycol Radboudumc, Nijmegen, Netherlands; [Bruggemann, Roger J.] Radboud Inst Hlth Sci, Nijmegen, Netherlands; [Roberts, Jason A.] Royal Brisbane & Womens Hosp, Pharm Dept, Brisbane, Qld, Australia"	"Roger, C (corresponding author), CHU Nimes, Pole Anesthesie Reanimat Douleur Urgence, Serv Reanimat, Nimes, France.; Roger, C (corresponding author), Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia."	"claire.roger@chu-nimes.fr"	"Bruggemann, Roger JM/A-7057-2015; Wallis, Steven/F-2046-2010; Roberts, Jason A/F-6272-2010; Lipman, Jeffrey/G-2211-2010"	"Bruggemann, Roger JM/0000-0002-7618-725X; Wallis, Steven/0000-0002-2392-9854; Roberts, Jason A/0000-0001-6218-435X; Lipman, Jeffrey/0000-0002-5965-9876"	"Nimes University Hospital"	"This work was supported by academic Grant from the Nimes University Hospital."	34	14	14	0	5	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"SEP"	2017	56	9	1057	1068	"NA"	"10.1007/s40262-016-0495-z"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FE1FN"	"WOS:000407963900006"	28035589	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Naik, BI; Roger, C; Ikeda, K; Todorovic, MS; Wallis, SC; Lipman, J; Roberts, JA"	"Naik, B. I.; Roger, C.; Ikeda, K.; Todorovic, M. S.; Wallis, S. C.; Lipman, J.; Roberts, J. A."	"NA"	"A"	"Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial"	"BRITISH JOURNAL OF ANAESTHESIA"	"English"	"Article"	"antibiotic prophylaxis; cefazolin; pharmacokinetics"	"SURGICAL INFECTION PREVENTION; CRITICALLY-ILL PATIENTS; ANTIMICROBIAL PROPHYLAXIS; POPULATION PHARMACOKINETICS; ANTIBIOTICS; CEFTAZIDIME; CEFOXITIN; OUTCOMES; PROJECT; PLASMA"	"Background. Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative redosing of cefazolin is commonly given between 2 and 5h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. Methods. Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h(-1)) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics (R) software. Calculations of PTA and FTA were performed for common pathogens. Results. Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44-80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean (SD) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h(-1). Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. Conclusions. Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens."	"[Naik, B. I.; Ikeda, K.] Dept Anesthesiol, POB 800710, Charlottesville, VA 22908 USA; [Naik, B. I.] Univ Virginia, Dept Neurosurg, Charlottesville, VA USA; [Roger, C.; Wallis, S. C.; Lipman, J.; Roberts, J. A.] Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia; [Todorovic, M. S.] Washington Univ, Dept Anesthesiol, St Louis, MO USA; [Lipman, J.; Roberts, J. A.] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia; [Roberts, J. A.] Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia; [Roberts, J. A.] Univ Queensland, Ctr Translat Antiinfect Pharmacodynam, Brisbane, Qld, Australia"	"Naik, BI (corresponding author), Univ Virginia, POB 800710, Charlottesville, VA 22908 USA."	"bin4n@virginia.edu"	"Lipman, Jeffrey/G-2211-2010; Naik, Bhiken/AAH-3831-2019; Wallis, Steven/F-2046-2010; Roberts, Jason A/F-6272-2010"	"Lipman, Jeffrey/0000-0002-5965-9876; Wallis, Steven/0000-0002-2392-9854; Roberts, Jason A/0000-0001-6218-435X"	"AztraZeneca"	"AztraZeneca speaking fees for J.L. The other authors declare no conflicts of interest."	23	7	7	0	4	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0007-0912"	"1471-6771"	"NA"	"BRIT J ANAESTH"	"Br. J. Anaesth."	"JUN"	2017	118	6	876	882	"NA"	"10.1093/bja/aex026"	7	"Anesthesiology"	"Anesthesiology"	"EW8BD"	"WOS:000402742200011"	28505360	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Drikvandi, R"	"Drikvandi, Reza"	"NA"	"M"	"Nonlinear mixed-effects models for pharmacokinetic data analysis: assessment of the random-effects distribution"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Diagnostic tool; Gradient function; Nonlinear mixed-effects models; Pharmacokinetic data; Random effects"	"OF-FIT TESTS; MISSPECIFICATION"	"Nonlinear mixed-effects models are frequently used for pharmacokinetic data analysis, and they account for inter-subject variability in pharmacokinetic parameters by incorporating subject-specific random effects into the model. The random effects are often assumed to follow a (multivariate) normal distribution. However, many articles have shown that misspecifying the random-effects distribution can introduce bias in the estimates of parameters and affect inferences about the random effects themselves, such as estimation of the inter-subject variability. Because random effects are unobservable latent variables, it is difficult to assess their distribution. In a recent paper we developed a diagnostic tool based on the so-called gradient function to assess the random-effects distribution in mixed models. There we evaluated the gradient function for generalized liner mixed models and in the presence of a single random effect. However, assessing the random-effects distribution in nonlinear mixed-effects models is more challenging, especially when multiple random effects are present, and therefore the results from linear and generalized linear mixed models may not be valid for such nonlinear models. In this paper, we further investigate the gradient function and evaluate its performance for such nonlinear mixed-effects models which are common in pharmacokinetics and pharmacodynamics. We use simulations as well as real data from an intensive pharmacokinetic study to illustrate the proposed diagnostic tool."	"[Drikvandi, Reza] Imperial Coll London, Stat Sect, Dept Math, London, England"	"Drikvandi, R (corresponding author), Imperial Coll London, Stat Sect, Dept Math, London, England."	"r.drikvandi@imperial.ac.uk"	"NA"	"Drikvandi, Reza/0000-0002-7245-9713"	"NA"	"NA"	25	5	5	0	6	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2017	44	3	223	232	"NA"	"10.1007/s10928-017-9510-8"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EU5GH"	"WOS:000401059100004"	28194555	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Alobaid, AS; Wallis, SC; Jarrett, P; Starr, T; Stuart, J; Lassig-Smith, M; Mejia, JLO; Roberts, MS; Roger, C; Udy, AA; Lipman, J; Roberts, JA"	"Alobaid, Abdulaziz S.; Wallis, Steven C.; Jarrett, Paul; Starr, Therese; Stuart, Janine; Lassig-Smith, Melissa; Mejia, Jenny Lisette Ordonez; Roberts, Michael S.; Roger, Claire; Udy, Andrew A.; Lipman, Jeffrey; Roberts, Jason A."	"NA"	"A"	"Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically III Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"antibiotics; creatinine clearance; dosing; morbid obesity; pharmacodynamics; pharmacokinetics"	"ILL PATIENTS; TAZOBACTAM; INFUSION; SEPSIS; PHARMACODYNAMICS; PATHOPHYSIOLOGY; INTERMITTENT; PREDICTION; CLEARANCE; PNEUMONIA"	"The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean � standard deviation age, weight, and BMI were 50 � 15 years, 104 � 35 kg, and 38.0 � 15.0 kg/m(2), respectively. The concentration-time data were best described by a two-compartment linear model. The mean � SD parameter estimates for the final covariate model were a clearance of 14.0 � 7.1 liters/h, a volume of distribution of the central compartment of 49.0 � 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 � 0.6 liters . h(-1), and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 � 2.8 liters . h(-1). A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations."	"[Alobaid, Abdulaziz S.; Wallis, Steven C.; Mejia, Jenny Lisette Ordonez; Roger, Claire; Lipman, Jeffrey; Roberts, Jason A.] Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia; [Alobaid, Abdulaziz S.] King Saud Med City, Dept Pharm, Riyadh, Saudi Arabia; [Roberts, Michael S.] Queen Elizabeth Hosp, Basil Hetzel Inst Translat Hlth Res, Therapeut Res Ctr, Adelaide, SA, Australia; [Jarrett, Paul; Starr, Therese; Stuart, Janine; Lassig-Smith, Melissa; Lipman, Jeffrey; Roberts, Jason A.] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia; [Lipman, Jeffrey] Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia; [Roberts, Jason A.] Univ Queensland, Sch Pharm, Ctr Translat Pharmacodynam, Brisbane, Qld, Australia; [Roger, Claire] Univ Nimes Hosp, Dept Anesthesiol Crit Care Pain & Emergency Med, Nimes, France; [Udy, Andrew A.] The Alfred, Dept Intens Care & Hyperbar Med, Melbourne, Vic, Australia; [Udy, Andrew A.] Monash Univ, The Alfred, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia"	"Roberts, JA (corresponding author), Univ Queensland, Burns Trauma & Crit Care Res Ctr, Brisbane, Qld, Australia.; Roberts, JA (corresponding author), Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia.; Roberts, JA (corresponding author), Univ Queensland, Sch Pharm, Ctr Translat Pharmacodynam, Brisbane, Qld, Australia."	"roberts2@uq.edu.au"	"Lipman, Jeffrey/G-2211-2010; Wallis, Steven/F-2046-2010; Roberts, Jason A/F-6272-2010; Udy, Andrew/G-2538-2010; Roberts, Michael/C-5247-2014"	"Lipman, Jeffrey/0000-0002-5965-9876; Wallis, Steven/0000-0002-2392-9854; Roberts, Jason A/0000-0001-6218-435X; Udy, Andrew/0000-0002-6284-2022; Roberts, Michael/0000-0003-3894-5301"	"Australian National Health and Medical Research Council for a Centre of Research ExcellenceNational Health and Medical Research Council of Australia [APP1099452, 519702]; Intensive Care Foundation; Royal Embassy of Saudi Arabia; practitioner fellowshipNational Health and Medical Research Council of Australia [APP1117065]; National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [APP1107356]; Saudi Arabian Culture Mission (SACM)"	"We recognize funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence grant (APP1099452) and a project grant (519702), the Intensive Care Foundation, and the Saudi Arabian Culture Mission (SACM), an affiliate of the Royal Embassy of Saudi Arabia (for A. S. A.). J. A. R. received a practitioner fellowship (APP1117065) and M. S. R. received a research fellowship (APP1107356) from the National Health and Medical Research Council of Australia."	37	16	17	0	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"MAR"	2017	61	3	"NA"	"NA"	"e01276-16"	"10.1128/AAC.01276-16"	12	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"EL4QM"	"WOS:000394605900001"	28052849	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Lu, D; Gibiansky, L; Agarwal, P; Dere, RC; Li, C; Chu, YW; Hirata, J; Joshi, A; Jin, JY; Girish, S"	"Lu, D.; Gibiansky, L.; Agarwal, P.; Dere, R. C.; Li, C.; Chu, Y-W; Hirata, J.; Joshi, A.; Jin, J. Y.; Girish, S."	"NA"	"A"	"Integrated Two-Analyte Population Pharmacokinetic Model for Antibody-Drug Conjugates in Patients: Implications for Reducing Pharmacokinetic Sampling"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"METASTATIC BREAST-CANCER; CHRONIC LYMPHOCYTIC-LEUKEMIA; TRASTUZUMAB EMTANSINE T-DM1; DISPOSITION; PREDICTION"	"An integrated pharmacokinetics (PK) model that simultaneously describes concentrations of total antibody (Tab) and antibody-conjugated monomethyl auristatin E (acMMAE) following administration of monomethyl auristatin E (MMAE)-containing antibody-drug conjugates (ADCs) was developed based on phase I PK data with extensive sampling for two ADCs. Two linear two-compartment models that shared all parameters were used to describe the PK of Tab and acMMAE, except that the deconjugation rate was an additional clearance pathway included in the acMMAE PK model compared to Tab. Further, the model demonstrated its ability to predict Tab concentrations and PK parameters based on observed acMMAE PK and various reduced or eliminated Tab PK sampling schemes of phase II data. Thus, this integrated model allows for the reduction of Tab PK sampling in late-phase clinical development without compromising Tab PK characterization."	"[Lu, D.; Agarwal, P.; Dere, R. C.; Li, C.; Chu, Y-W; Hirata, J.; Joshi, A.; Jin, J. Y.; Girish, S.] Genentech Inc, San Francisco, CA 94080 USA; [Gibiansky, L.] QuantPharm LLC, North Potomac, MD USA"	"Lu, D (corresponding author), Genentech Inc, San Francisco, CA 94080 USA."	"lu.dan@gene.com"	"NA"	"NA"	"Genentech, Inc. of the Roche group; RocheRoche Holding; GenentechRoche HoldingGenentech"	"The analysis was funded by Genentech, Inc., a member of the Roche group. All of the authors, except Leonid Gibiansky, are employees of Genentech, Inc. and stockholders of the Roche group. Leonid Gibiansky is a paid consultant for Roche and Genentech."	25	6	6	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"DEC"	2016	5	12	665	673	"NA"	"10.1002/psp4.12137"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EG3DF"	"WOS:000390923300003"	27863168	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Illamola, SM; Colom, H; van Hasselt, JGC"	"Illamola, Silvia M.; Colom, Helena; van Hasselt, J. G. Coen"	"NA"	"A"	"Evaluating renal function and age as predictors of amikacin clearance in neonates: model-based analysis and optimal dosing strategies"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"amikacin; dosing guidelines; modelling and simulation; paediatric clinical pharmacology; population pharmacokinetics"	"POPULATION PHARMACOKINETIC ANALYSIS; GLOMERULAR-FILTRATION-RATE; INFANTS"	"AimsWe aimed to compare the performance of renal function and age as predictors of inter-individual variability (IIV) in clearance of amikacin in neonates through parallel development of population pharmacokinetic (PK) models and their associated impact on optimal dosing regimens. MethodsAmikacin concentrations were retrospectively collected for 149 neonates receiving amikacin (post-natal age (PNA) between 4-89 days). Two population PK models were developed in parallel, considering at least as predictors current body weight (WT), in combination with either creatinine clearance (CLcr) or age descriptors. Using stochastic simulations for both renal function or age-based dosing, we identified optimal dosing strategies that were based on attainment of optimal peak- (PCC) and trough target concentration coverage (TCC) windows associated with efficacy and toxicity. ResultsThe CLcr and age-based population PK models both included current body weight (WT) on CL, central distribution volume and intercompartmental clearance, in combination with either CLcr or PNA as predictors for IIV of clearance (CL). The WT-CLcr model explained 6.9% more IIV in CL compared with the WT-PNA model. Both models successfully described an external dataset (n=53) of amikacin PK. The simulation analysis of optimal dose regimens suggested similar performance of either CLcr or PNA based dosing. ConclusionCL(cr) predicted more IIV in CL, but did not translate into clinically relevant improvements of target concentrations. Our optimized dose regimens can be considered for further evaluation to optimize initial treatment with amikacin."	"[Illamola, Silvia M.] Univ Autonoma Barcelona, Biochem Serv, Hosp Univ Vall dHebron, E-08193 Barcelona, Spain; [Illamola, Silvia M.] Hop Europeen Georges Pompidou, Serv Biochem, 20 Rue Leblanc, F-75015 Paris, France; [Illamola, Silvia M.; Colom, Helena] Univ Barcelona, Dept Pharm & Pharmaceut Technol, Sch Pharm, E-08007 Barcelona, Spain; [van Hasselt, J. G. Coen] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands"	"Illamola, SM (corresponding author), Hop Europeen Georges Pompidou, Serv Biochem, 20 Rue Leblanc, F-75015 Paris, France."	"07silvia@gmail.com"	"van Hasselt, Coen/H-5593-2019"	"van Hasselt, J.G.C./0000-0002-1664-7314"	"NA"	"NA"	33	4	4	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2016	82	3	793	805	"NA"	"10.1111/bcp.13016"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DU9AZ"	"WOS:000382509900018"	27198625	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Cho, SH; Lee, JH; Lim, HS; Lee, KH; Kim, DY; Choe, S; Bae, KS; Lee, JH"	"Cho, Sang-Heon; Lee, Jung-Hee; Lim, Hyeong-Seok; Lee, Kyoo-Hyung; Kim, Dae-Young; Choe, Sangmin; Bae, Kyun-Seop; Lee, Je-Hwan"	"NA"	"A"	"Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation"	"KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY"	"English"	"Article"	"Adult; Busulfan; Drug dosage calculations; Hematopoietic stem cell transplantation; Pharmacokinetics"	"BONE-MARROW-TRANSPLANTATION; TOTAL-BODY IRRADIATION; VENOOCCLUSIVE DISEASE; POPULATION PHARMACOKINETICS; ORAL BUSULFAN; CYCLOPHOSPHAMIDE; BUSULFAN/CYCLOPHOSPHAMIDE; ASSOCIATION; FLUDARABINE; ENGRAFTMENT"	"The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23xABW(0.5) mg daily) targeting an area under the concentration-time curve (AUC) of 5924 mu M.min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUC(PRED)). The accuracy and precision of the AUC(PRED) values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 mu M.rnin. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUC(PRED) were -5.8% and 20.6%, respectively, in the conventional dosing group and -2.1% and 14.0%, respectively, in the new dosing scheme group. These findings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT."	"[Cho, Sang-Heon] Inha Univ, Sch Med, Dept Clin Pharmacol, Inha Univ Hosp, Inchon 22332, South Korea; [Lee, Jung-Hee; Lee, Kyoo-Hyung; Kim, Dae-Young; Lee, Je-Hwan] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Hematol, Seoul 05505, South Korea; [Lim, Hyeong-Seok; Bae, Kyun-Seop] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Clin Pharmacol & Therapeut, Seoul 05505, South Korea; [Choe, Sangmin] Pusan Natl Univ Hosp, Dept Clin Pharmacol & Therapeut, Busan 49241, South Korea"	"Bae, KS (corresponding author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Clin Pharmacol & Therapeut, Seoul 05505, South Korea."	"ksbae@amc.seoul.kr"	"NA"	"Lee, Je-Hwan/0000-0002-7060-1675; Bae, Kyun-Seop/0000-0001-7399-5879"	"Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI07C0001]"	"This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI07C0001)."	28	1	1	0	2	"KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY"	"SEOUL"	"C/O EDITORIAL OFFICE, 448-13 SEOKYO-DONG, SEOUL, SOUTH KOREA"	"1226-4512"	"2093-3827"	"NA"	"KOREAN J PHYSIOL PHA"	"KOREAN J. PHYSIOL. PHARMACOL."	"MAY"	2016	20	3	245	251	"NA"	"10.4196/kjpp.2016.20.3.245"	7	"Pharmacology & Pharmacy; Physiology"	"Pharmacology & Pharmacy; Physiology"	"DL1AX"	"WOS:000375365400003"	27162478	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Kyhl, LEB; Li, S; Faerch, KU; Soegaard, B; Larsen, F; Areberg, J"	"Kyhl, Lars-Erik Broksoe; Li, Shen; Faerch, Kirstine Ullitz; Soegaard, Birgitte; Larsen, Frank; Areberg, Johan"	"NA"	"A"	"Population pharmacokinetics of nalmefene in healthy subjects and its relation to -opioid receptor occupancy"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"alcohol dependence; healthy subjects; nalmefene; opioid antagonist; pharmacodynamics; pharmacokinetics"	"AS-NEEDED NALMEFENE; ALCOHOL DEPENDENCE; ANTAGONIST; EFFICACY; SAFETY; KINETICS; SINGLE; SYSTEM"	"AimsThe aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the -opioid receptor occupancy by simulations in the target population. MethodsData from nine phase I studies (243 subjects) with extensive blood sampling were pooled and used for the population PK model building. Data from four other phase I studies (85 subjects) were pooled and used as an external validation dataset. Eight subjects from an imaging study contributed occupancy data and the pharmacokinetic/pharmacodynamic (PK/PD) relationship was modelled. Combining the population PK model and the PK/PD relationship enabled simulations to predict -opioid occupancy. ResultsA two compartment model with first order absorption best described the nalmefene PK data. The typical subject in the population was estimated to have a systemic clearance of 60.4lh(-1) and a central volume of distribution of 266l. Absolute oral bioavailability was estimated to 41% without food intake and with food about 53%. Simulation of the -opioid receptor occupancy shows that the 95% confidence bound is within or above 60-90% occupancy for up to 22-24h after a single dose of 20mg nalmefene. ConclusionsA robust population PK model for nalmefene was developed. Based on the concentration-occupancy model the -opioid receptor occupancy after a single 20mg dose of nalmefene is predicted to be above the target therapeutic occupancy for about 24h in about 95% of the target population."	"[Kyhl, Lars-Erik Broksoe; Faerch, Kirstine Ullitz; Soegaard, Birgitte; Larsen, Frank; Areberg, Johan] H Lundbeck & Co AS, Clin & Quantitat Pharmacol, Ottiliavej 9, DK-2500 Valby, Denmark; [Li, Shen] Quintiles, 6700 W 115th St, Overland Pk, KS 66211 USA"	"Areberg, J (corresponding author), H Lundbeck & Co AS, Clin & Quantitat Pharmacol, Ottiliavej 9, DK-2500 Valby, Denmark."	"Joar@Lundbeck.com"	"NA"	"NA"	"H. Lundbeck A/S"	"All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare this analysis was funded by H. Lundbeck A/S. All authors are present or former employees of either H. Lundbeck A/S or of an organization contracted by H. Lundbeck A/S for this analysis and there are no other relationships or activities that could appear to have influenced the submitted work."	20	10	11	0	2	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"FEB"	2016	81	2	290	300	"NA"	"10.1111/bcp.12805"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DD7VK"	"WOS:000370132600011"	26483076	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Barrett, JS; Hirankarn, S; Holford, N; Hammer, GB; Drover, DR; Cohane, C; Anderson, B; Dombrowski, E; Reece, T; Zajicek, A; Schulman, SR"	"Barrett, Jeffrey S.; Hirankarn, Sarapee; Holford, Nick; Hammer, Gregory B.; Drover, David R.; Cohane, CarolA.; Anderson, Brian; Dombrowski, Erin; Reece, Tammy; Zajicek, Anne; Schulman, Scott R."	"NA"	"A"	"A hemodynamic model to guide blood pressure control during deliberate hypotension with sodium nitroprusside in children"	"FRONTIERS IN PHARMACOLOGY"	"English"	"Article"	"sodium nitroprusside; hemodynamics; models; biological; pediatrics; hypotension; controlled"	"PHARMACOKINETICS; METABOLISM; SIZE"	"Sodium nitroprusside (SNP) has been widely used to control blood pressure in infants and children. The goals of this analysis were to develop models that describe the hemodynamic response to SNP dosing in pediatric patients; examine sources of variation in dose-response, defining age, and size dependencies; and determine vulnerable populations or patient subtypes that may elicit dosing modifications. A multi-center, randomized, double-blinded, parallel-group, dose-ranging, effect-controlled study, followed by an open-label dose titration of an intravenous infusion of SNP was undertaken in 203 pediatric subjects, who required deliberate hypotension or controlled normotension during anesthesia. A total of 3464 MAP measurements collected from 202 patients during the study's blinded phase, including baseline measurements up to 6 min prior to the blinded were available for analysis. A population K-PD model was developed with a one-compartment model assumed for SNP. Size differences in CL and V of the effect compartment were described using theory-based allometry. An inhibitory sigmoidal E-max model was used to describe the effect of SNP. A power function of age was used to describe age-related differences in baseline MAP. A mixture model of two groups with low and high EC50 was used to explain variability in MAP response. Change in MAP was characterized by a linear disease progression slope during the blinded phase. In the final population model, CL and V increased with weight, and baseline MAP increased with age. The effect compartment half-life of SNP was 13.4 min. The infusion rate producing 50% of E-max (ER50) at steady state for high EC50, was 0.34 mu g/kg/min and for low EC50 0.103 mu g/kg/min. The K-PD model well-describes initial dosing of SNP under controlled circumstances; model-based dosing guidance agrees with current practice. An initial titration strategy supported via algorithm-based feedback should improve maintenance of target MAP."	"[Barrett, Jeffrey S.; Hirankarn, Sarapee; Dombrowski, Erin] Univ Penn, Childrens Hosp Philadelphia, Clin Pharmacol & Therapeut Div, Sch Med, Philadelphia, PA 19104 USA; [Barrett, Jeffrey S.; Hirankarn, Sarapee; Dombrowski, Erin] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA; [Holford, Nick] Univ Auckland, Dept Pharmacol & Clin Pharmacol & Anesthesia, Auckland 1, New Zealand; [Holford, Nick; Anderson, Brian] Univ Auckland, Dept Anesthesia, Auckland 1, New Zealand; [Hammer, Gregory B.; Drover, David R.; Cohane, CarolA.] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA; [Reece, Tammy; Schulman, Scott R.] Univ Durham, Med Ctr, Duke Clin Res Inst, Durham, NC USA; [Zajicek, Anne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA"	"Barrett, JS (corresponding author), Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Perelman Sch Med,Abramson Res Ctr, Colket Translat Res Bldg,Room 1210, Philadelphia, PA 19104 USA."	"jeffrey.barrett@sanofi.com"	"Zajicek, Anne/I-3448-2019; Holford, Nick/B-9774-2008"	"Holford, Nick/0000-0002-4031-2514; Zajicek, Anne/0000-0001-9113-2874"	"NICHD, Rockville, Maryland [NO1-HD-4-3385]"	"NO1-HD-4-3385 (NICHD, Rockville, Maryland)."	17	2	2	0	2	"FRONTIERS MEDIA SA"	"LAUSANNE"	"PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND"	"1663-9812"	"NA"	"NA"	"FRONT PHARMACOL"	"Front. Pharmacol."	"JUL 28"	2015	6	"NA"	"NA"	"NA"	151	"10.3389/fphar.2015.00151"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CW9PA"	"WOS:000365329500001"	26283961	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Andreu, F; Colom, H; Grinyo, JM; Torras, J; Cruzado, JM; Lloberas, N"	"Andreu, Franc; Colom, Helena; Grinyo, Josep M.; Torras, Joan; Cruzado, Josep M.; Lloberas, Nuria"	"NA"	"A"	"Development of a Population PK Model of Tacrolimus for Adaptive Dosage Control in Stable Kidney Transplant Patients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"tacrolimus; Pharmacometrics; renal transplant; therapeutic drug monitoring"	"SOLID-ORGAN TRANSPLANTATION; BAYESIAN-ESTIMATION; CLINICAL PHARMACOKINETICS; ALLOGRAFT-REJECTION; MYCOPHENOLIC-ACID; RECIPIENTS; CYCLOSPORINE; LIVER; POLYMORPHISMS; FK506"	"Background: Tacrolimus pharmacokinetics (PK) presents a high variability that hampers its therapeutic use. The aims of this study are to: (1) develop a population pharmacokinetic (PPK) model for tacrolimus and to identify the factors that contribute to the variability of tacrolimus PK in renal transplant patients; and (2) to establish a new Bayesian estimator that can easily and routinely be applied in the hospital. A new PPK model may allow efficacy to be optimized, improve dose regimens, minimize side effects, and decrease the cost of extensive area under the curve (AUC) monitoring. Methods: PPK analysis of the full PK profiles of 16 patients on 5 occasions was performed with NONMEM 7.2. Biochemical variables (hematocrit, hemoglobin, aspartate aminotransferase, and others) were analyzed. Results: A 2-open-compartment model with interoccasion variability best described the PK of tacrolimus. Three transit compartments provided the best description of the absorption process. The hematocrit, aspartate aminotransferase, and alanine aminotransferase were not significant in the covariate analysis. External validation with 91 patients proved the good predictability of the model with a bias and precision of 0.37 mcg/L (CI 95%, -0.11 to 1.20 mcg/L) and 0.38 mcg/L (CI 95%, 0.02 to 1.21 mcg/L), respectively. A limited sampling strategy using 1 sampling point at predose (trough concentrations) showed a good performance in AUC(0-12h) estimation with a correlation between AUC(full) and AUC(LSS,) bias and imprecision of r(2) = 0.75, 6.78% (range, -16.26% to 30.06%) and 1.42% (IC 95%, 0.14%-3.61%), respectively. Conclusions: The PPK model developed provides reliable prior information for Bayesian adaptive control of dosage regimens of tacrolimus to achieve the desired AUC goals in stable renal transplant patients."	"[Andreu, Franc; Colom, Helena] Univ Barcelona, Sch Pharm, Dept Pharm & Pharmaceut Technol, Barcelona 08907, Spain; [Andreu, Franc; Grinyo, Josep M.; Torras, Joan; Cruzado, Josep M.; Lloberas, Nuria] Hosp Univ Bellvitge, Serv Nephrol, Barcelona, Spain; [Andreu, Franc; Grinyo, Josep M.; Torras, Joan; Cruzado, Josep M.; Lloberas, Nuria] Hosp Univ Bellvitge, Lab Expt Nephrol, Barcelona, Spain"	"Lloberas, N (corresponding author), Univ Barcelona, Lab 4122, Serv Nephrol, Campus Bellvitge, Barcelona 08907, Spain."	"nlloberas@ub.edu"	"NA"	"NA"	"Instituto de Salud Carlos IIIInstituto de Salud Carlos III; Ministerio de Sanidad y Consumo MSPSI [EC10-144, PI12/01564]"	"Supported by grants from Instituto de Salud Carlos III and Ministerio de Sanidad y Consumo MSPSI (EC10-144) and PI12/01564."	43	23	25	0	7	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"APR"	2015	37	2	246	255	"NA"	"10.1097/FTD.0000000000000134"	10	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"CD3SW"	"WOS:000351002200014"	25254416	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Solana, MJ; Colom, H; Lopez-Herce, J; Urbano, J; Gonzalez, R; Lopez, J; Manzanares, C; Carrillo, A"	"Jose Solana, Maria; Colom, Helena; Lopez-Herce, Jesus; Urbano, Javier; Gonzalez, Rafael; Lopez, Jorge; Manzanares, Cecilia; Carrillo, Angel"	"NA"	"A"	"Population Pharmacokinetics of Omeprazole in Critically Ill Pediatric Patients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"omeprazole; population pharmacokinetics; nonlinear mixed-effects models; critically ill children; therapeutic drug monitoring"	"PROTON PUMP INHIBITORS; INTENSIVE-CARE-UNIT; STRESS-ULCER; INTRAVENOUS OMEPRAZOLE; BLEEDING PROPHYLAXIS; CRITICAL ILLNESS; INTRAGASTRIC PH; MUCOSAL DISEASE; CHILDREN; MODELS"	"Background: To develop a population pharmacokinetic model for intravenous omeprazole in critically ill children. Methods: One hundred eighty-six omeprazole concentration-time data from 40 critically ill children were analyzed using the nonlinear mixed-effects approach with the nonlinear mixed-effects modeling software, version 7.2 software. Patients were randomized into 2 groups and received intravenous omeprazole at a dose of 0.5 or 1 mg/kg twice daily. Blood samples were drawn at 0.5, 2, 6, 12, 24, and 48 hours after the first infusion. Results: The pharmacokinetic profile was best described by a 2-compartment model with a first-order elimination process. Between-patient variability could only be associated with plasma clearance (CL). The typical values for plasma CL were 24.9 L.h(-1).70 kg(-1) (10.08%), with a distributional clearance of 53.9 L.h(-1).70 kg(-1) (11.00%) and central and peripheral compartment distribution volumes of 4.23 L/70 kg (19.62%) and 674 L/70 kg (0.89%), respectively. Allometric size models seemed to predict changes adequately in all the pharmacokinetic parameters. High values of between-patient variability of CL [75.50% (2.60%)] and residual variability [130.0% (5.26%)] were still found in the final model. Model-based simulations suggested that the most suitable dose was 1 mg/kg because this yielded similar exposure (defined by the area under the concentration-time curve) to that obtained in adults after a 20-mg dose of omeprazole intravenously. Conclusions: An allometric size model allows changes to be predicted in all the pharmacokinetic parameters, making dose adjustment by body weight important to achieve the most effective omeprazole exposure. This is the first step toward a population pharmacokinetic study, including more data to develop a predictable model to be used during therapeutic drug monitoring."	"[Jose Solana, Maria; Lopez-Herce, Jesus; Urbano, Javier; Gonzalez, Rafael; Lopez, Jorge; Carrillo, Angel] Hosp Gen Univ Gregorio Maraon, Paediat Intens Care Dept, Madrid 28009, Spain; [Colom, Helena] Univ Barcelona, Sch Pharm, Biopharm & Pharmacokinet Dept, E-08007 Barcelona, Spain; [Manzanares, Cecilia] Hosp Gen Univ Gregorio Maraon, Serv Pharm, Madrid 28009, Spain"	"Lopez-Herce, J (corresponding author), Hosp Gen Univ Gregorio Maraon, Serv Cuidados Intens Pediat, Dr Castelo 47, Madrid 28009, Spain."	"pielvi@hotmail.com"	"Lopez-Herce, Jesus/A-1602-2019"	"Lopez-Herce, Jesus/0000-0001-6105-9178; SOLANA, MARIA JOSE/0000-0001-6083-2528; Urbano, Javier/0000-0002-3511-2905; Gonzalez Cortes, Rafael/0000-0002-3259-7898"	"Spanish Health Institute Carlos IIIInstituto de Salud Carlos III [EC07/90670, RD08/0072]"	"Supported by a grant from the Spanish Health Institute Carlos III (grants N. EC07/90670 and RD08/0072: Maternal, Child Health and Development Network) within the framework of the VI National I  D  i Research Programme (2008-2011)."	40	3	3	0	3	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"AUG"	2014	36	4	519	527	"NA"	"NA"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"AL6OI"	"WOS:000339251800015"	24365987	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Colom, H; Lloberas, N; Andreu, F; Caldes, A; Torras, J; Oppenheimer, F; Sanchez-Plumed, J; Gentil, MA; Kuypers, DR; Brunet, M; Ekberg, H; Grinyoo, JM"	"Colom, Helena; Lloberas, Nuria; Andreu, Franc; Caldes, Ana; Torras, Joan; Oppenheimer, Federico; Sanchez-Plumed, Jaime; Gentil, Miguel A.; Kuypers, Dirk R.; Brunet, Merce; Ekberg, Henrik; Grinyo, Josep M."	"NA"	"A"	"Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients"	"KIDNEY INTERNATIONAL"	"English"	"Article"	"enterohepatic circulation; MRP2 polymorphism; mycophenolic acid; population pharmacokinetics; renal transplant"	"POPULATION PHARMACOKINETICS; GLUCURONIDE METABOLITE; PROTEIN-BINDING; CYCLOSPORINE-A; MOFETIL; KIDNEY; TACROLIMUS; VARIABILITY; PREDICTION; SIROLIMUS"	"Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (C-troughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher C-troughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and C-troughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure."	"[Colom, Helena; Andreu, Franc] Univ Barcelona, Dept Pharm & Pharmaceut Technol, Sch Pharm, E-08028 Barcelona, Spain; [Lloberas, Nuria; Andreu, Franc; Caldes, Ana; Torras, Joan; Grinyo, Josep M.] Hosp Univ Bellvitge, Serv Nephrol, Barcelona, Spain; [Lloberas, Nuria; Andreu, Franc; Caldes, Ana; Torras, Joan; Grinyo, Josep M.] Hosp Univ Bellvitge, Lab Expt Nephrol, Barcelona, Spain; [Lloberas, Nuria] Pharmacogenet Grp Symphony Study Spain, Barcelona, Spain; [Oppenheimer, Federico] Hosp Clin Barcelona, Serv Nephrol, Barcelona, Spain; [Sanchez-Plumed, Jaime] Hosp La Fe, Serv Nephrol, E-46009 Valencia, Spain; [Gentil, Miguel A.] Hosp Virgen Rocio, Serv Nephrol, Seville, Spain; [Kuypers, Dirk R.] Univ Hosp, Dept Nephrol & Transplantat, Louvain, Belgium; [Brunet, Merce] Ctr Diagnost Biomed, Barcelona, Spain; [Ekberg, Henrik] Univ Hosp, Dept Nephrol & Transplantat, Malmo, Sweden"	"Colom, H (corresponding author), Univ Barcelona, Dept Pharm & Pharmaceut Technol, Sch Pharm, Ave Joan XXIII S-N, E-08028 Barcelona, Spain."	"helena.colom@ub.edu"	"Kuypers, Dirk RJ/D-4393-2018"	"Kuypers, Dirk RJ/0000-0001-5546-9680; Brunet, Merce/0000-0002-7154-916X"	"Hoffmann La-Roche and Instituto de Salud Carlos III (Miguel Servet) [CP06/00067, PI12/01564]"	"We are sincerely grateful to all the patients who have contributed to the study, to the Biochemistry Department (Hospital Clinic) for their help in determining drug concentrations in plasma, and to the nurses of the nephrology departments of the nine hospitals who have participated in this study for their technical support in the MMF administration and blood sampling. Funding for this study was provided by Hoffmann La-Roche and Instituto de Salud Carlos III (Miguel Servet CP06/00067 and FIS PI12/01564)."	51	22	22	0	14	"ELSEVIER SCIENCE INC"	"NEW YORK"	"STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA"	"0085-2538"	"1523-1755"	"NA"	"KIDNEY INT"	"Kidney Int."	"JUN"	2014	85	6	1434	1443	"NA"	"10.1038/ki.2013.517"	10	"Urology & Nephrology"	"Urology & Nephrology"	"AI4FG"	"WOS:000336820500026"	24402086	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Hoeben, E; Neyens, M; Mannaert, E; Schmidt, M; Vermeulen, A"	"Hoeben, Eef; Neyens, Martine; Mannaert, Erik; Schmidt, Mark; Vermeulen, An"	"NA"	"A"	"Population Pharmacokinetics of JNJ-37822681, a Selective Fast-Dissociating Dopamine D-2-Receptor Antagonist, in Healthy Subjects and Subjects with Schizophrenia and Dose Selection Based on Simulated D-2-Receptor Occupancy"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"ATYPICAL ANTIPSYCHOTICS; RECEPTOR ANTAGONIST; DOUBLE-BLIND; STATE"	"JNJ-37822681 is a selective, fast-dissociating dopamine D-2-receptor antagonist currently in development as a candidate antipsychotic. The aim of the analyses was to develop a population pharmacokinetic model to describe the pharmacokinetics of JNJ-37822681 in healthy subjects and patients with schizophrenia and to identify covariates of interest. The model was then used to simulate D-2-receptor occupancy in support of dose selection for subsequent studies. Data were obtained from 378 subjects enrolled in three phase I and two phase II studies. Nonlinear mixed effects modeling of pooled data was conducted using NONMEMA (R) to estimate population pharmacokinetic parameters and the effect of covariates on these parameters. The model was evaluated on a subset of data that was not used for model building and was subsequently used to simulate steady-state exposure for each subject in the phase IIb study. Striatal D-2-receptor occupancy was predicted using simulated exposure combined with pharmacodynamic parameters from a sigmoid maximum effect model established from previous [C-11]raclopride positron emission tomography studies. A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Significant covariates were sex and bioavailability on apparent clearance and food intake on the absorption rate constant. Clearance was 11 % higher in females compared with males. The model passed external evaluation. The estimated pharmacokinetic parameters for the phase IIb study were similar to those observed in the phase IIa study. D-2-receptor occupancy was predicted to be in the 65-80 % range at 10 mg twice daily and partially or fully reaching the 80 % threshold at doses of 20 and 30 mg twice daily. The population pharmacokinetic model of JNJ-37822681 successfully described the pharmacokinetics of JNJ-37822681 and allowed the reliable determination of individual exposure parameters in a phase IIb study. It was concluded that 5 or 7.5 mg twice daily would likely be minimal- or no-effect doses, whereas 10 mg twice daily was expected to provide an optimal balance of efficacy and tolerability."	"[Hoeben, Eef; Neyens, Martine; Vermeulen, An] Janssen Res & Dev, Div Janssen Pharmaceut NV, Model Based Drug Dev, B-2340 Beerse, Belgium; [Mannaert, Erik] Janssen Res & Dev, Div Janssen Pharmaceut NV, Clin Pharmacol, B-2340 Beerse, Belgium; [Schmidt, Mark] Janssen Res & Dev, Div Janssen Pharmaceut NV, Expt Med Europe, B-2340 Beerse, Belgium"	"Hoeben, E (corresponding author), Janssen Res & Dev, Div Janssen Pharmaceut NV, Model Based Drug Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium."	"ehoeben@its.jnj.com"	"Schmidt, Mark/I-5052-2016"	"Schmidt, Mark/0000-0003-3417-8977"	"Janssen Research and Development"	"The research was funded entirely by Janssen Research and Development. All authors are employees of Janssen Research and Development and potentially own stock and/or stock options in the company."	19	3	3	0	5	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NOV"	2013	52	11	1005	1015	"NA"	"10.1007/s40262-013-0084-3"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"238QC"	"WOS:000325961500006"	23754735	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Sostelly, A; Payen, L; Guitton, J; Di Pietro, A; Falson, P; Honorat, M; Valdameri, G; Geze, A; Boumendjel, A; Freyer, G; Tod, M"	"Sostelly, Alexandre; Payen, Lea; Guitton, Jerome; Di Pietro, Attilio; Falson, Pierre; Honorat, Mylene; Valdameri, Glaucio; Geze, Annabelle; Boumendjel, Ahcene; Freyer, Gilles; Tod, Michel"	"NA"	"A"	"A template model for studying anticancer drug efflux transporter inhibitors in vitro"	"FUNDAMENTAL & CLINICAL PHARMACOLOGY"	"English"	"Article"	"drug resistance; efflux transporter; in vitro experiments; mechanistic modelling; NONMEM"	"P-GLYCOPROTEIN INHIBITOR; TRIHYDROCHLORIDE LY335979; RESISTANCE; TRIAL; COMBINATION; DOXORUBICIN; ZOSUQUIDAR"	"Efflux transporters play an important role in drug absorption and also in multidrug resistance. ABCG2 (BCRP) is an efflux transporter conferring cross-resistance to mitoxantrone (Mit), irinotecan (CPT11), and its active metabolite SN38. MBLI87, a new ABCG2 inhibitor has proven its efficacy against ABCG2-mediated efflux in vitro and in vivo. This work aimed at modeling and quantifying the cellular interaction between MBLI87 and different substrates using a mechanistic template model. An in vitro competition experiment study was carried out with HEK293 cells overexpressing ABCG2 exposed to fixed concentrations of substrates (Mit, CPT11, SN38) and to MBLI87 at several concentration levels. A nonlinear mixed-effects transport inhibition model was developed to fit intracellular drug concentrations. In this model, drugs cross the cell membrane through passive diffusion, active drug efflux is ABCG2 mediated, interaction between substrates and inhibitor occurs within the transporter. The interaction was found to be noncompetitive. The MBLI87 Ki was estimated to 141nm for Mit, 289nm for CPT11, and 1160nm for SN38. The ratio of intrinsic transport clearance divided by diffusion clearance was estimated to 2.5 for Mit, 1.01 for CPT11, and 5.4 for SN38. The maximal increase in the intracellular substrate concentration that is possible to achieve by inhibition of the transporter was estimated to 1.5 for Mit, 0.1 for CPT11, and 4.4 for SN38. This mechanistic template model describes both drug accumulation and cellular transport, and the mixed-effects approach allows an estimation of intra- and interassay variability. This model is of great interest to study cytotoxic cellular pharmacokinetics."	"[Sostelly, Alexandre; Guitton, Jerome; Freyer, Gilles; Tod, Michel] Fac Med & Maieut Lyon Sud Charles Marieux, EMR 3738, Oullins, France; [Sostelly, Alexandre; Honorat, Mylene; Freyer, Gilles; Tod, Michel] Univ Lyon, Lyon, France; [Payen, Lea; Guitton, Jerome; Tod, Michel] Univ Lyon 1, Inst Sci Pharmaceut & Biol, F-69365 Lyon, France; [Payen, Lea; Honorat, Mylene] Leon Berard FNCLCC, Ctr Cancerol Lyon CRCL, INSERM, U1052, Lyon, France; [Payen, Lea; Guitton, Jerome] Hosp Civils Lyon, Biochem Lab Lyon Sud CBS, Oullins, France; [Di Pietro, Attilio; Falson, Pierre; Valdameri, Glaucio] Univ Lyon, Inst Biol & Chim Prot, Equipe Labellisee Ligue 2009, BMSSI,UMR CNRS 5086, Lyon, France; [Geze, Annabelle; Boumendjel, Ahcene] Univ Grenoble, Dept Pharmacochim Mol, CNRS, UMR5063, Grenoble, France; [Freyer, Gilles] Ctr Hosp Lyon Sud, Dept Med Oncol, F-69495 Pierre Benite, France; [Tod, Michel] Hop Croix Rousse, F-69317 Lyon 04, France"	"Sostelly, A (corresponding author), Fac Med & Maieut Lyon Sud Charles Marieux, EMR 3738, Oullins, France."	"alexandre.sostelly@gmail.com"	"Valdameri, Glaucio/A-8909-2013; Valdameri, Glaucio/G-8354-2017"	"Valdameri, Glaucio/0000-0003-1882-1512; Valdameri, Glaucio/0000-0003-1882-1512; Guitton, Jerome/0000-0001-6180-5708; Falson, Pierre/0000-0002-9760-4577"	"NA"	"NA"	20	3	3	0	25	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0767-3981"	"1472-8206"	"NA"	"FUND CLIN PHARMACOL"	"Fundam. Clin. Pharmacol."	"OCT"	2013	27	5	544	556	"NA"	"10.1111/j.1472-8206.2012.01054.x"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"198HI"	"WOS:000322912700010"	22882086	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wong, WK"	"Wong, Weng Kee"	"NA"	"M"	"Web-based tools for finding optimal designs in biomedical studies"	"COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE"	"English"	"Article"	"Continuous design; Dose response design; Multiple-objective optimal design"	"CLINICAL-TRIALS; CONSTRUCTION; PREDICTION; ALGORITHM"	"Experimental costs are rising and applications of optimal design ideas are increasingly applied in many disciplines. However, the theory for constructing optimal designs can be esoteric and its implementation can be difficult. To help practitioners have easier access to optimal designs and better appreciate design issues, we present a web site at http://optimal-design.biostat.ucla.edu/optimal/ capable of generating different types of tailor-made optimal designs for popular models in the biological sciences. This site also evaluates various efficiencies of a user-specified design and so enables practitioners to appreciate robustness properties of the design before implementation. (c) 2013 Elsevier Ireland Ltd. All rights reserved."	"Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA"	"Wong, WK (corresponding author), Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, 10833 Le Conte Ave, Los Angeles, CA 90095 USA."	"wkwong@ucla.edu"	"NA"	"NA"	"National Institute of General Medical SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01GM072876]"	"The construction of the web site at http://optimal-design.biostat.ucla.edu/optimal/ was entirely funded by a National Institute of General Medical Sciences grant award R01GM072876."	49	2	2	0	8	"ELSEVIER IRELAND LTD"	"CLARE"	"ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND"	"0169-2607"	"1872-7565"	"NA"	"COMPUT METH PROG BIO"	"Comput. Meth. Programs Biomed."	"SEP"	2013	111	3	701	710	"NA"	"10.1016/j.cmpb.2013.05.004"	10	"Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics"	"Computer Science; Engineering; Medical Informatics"	"186SB"	"WOS:000322063800017"	23806678	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Delavenne, X; Zufferey, P; Nguyen, P; Rosencher, N; Samama, CM; Bazzoli, C; Mismetti, P; Laporte, S"	"Delavenne, Xavier; Zufferey, Paul; Philippe Nguyen; Rosencher, Nadia; Samama, Charles-Marc; Bazzoli, Celine; Mismetti, Patrick; Laporte, Silvy"	"PROPICE Study Grp"	"A"	"Pharmacokinetics of fondaparinux 1.5 mg once daily in a real-world cohort of patients with renal impairment undergoing major orthopaedic surgery"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Fondaparinux; Orthopaedic surgery; Pharmacokinetics; Renal impairment; Simulations"	"VENOUS THROMBOEMBOLISM; SERUM CREATININE; PREDICTION; PREVENTION"	"Fondaparinux, a selective activator factor X (factor Xa) inhibitor, is effective and safe for preventing venous thromboembolism after major orthopaedic surgery (MOS) at the once-daily subcutaneous dose of 2.5 mg. As the drug is mainly eliminated by the kidneys, a reduced dosage (1.5 mg once daily) was developed for patients with renal impairment. We studied the pharmacokinetics (PK) of this dosage regimen using data from a real-world cohort of 442 patients with renal impairment (creatinine clearance 20-50 ml/min) undergoing MOS. Data were analysed using NON-linear Mixed Effect Modelling software (NONMEM) software. Fondaparinux PK was modelled using a two-compartment model with first-order absorption. This analysis confirmed the relationship between renal function and fondaparinux PK profiles. The mean predicted steady-state area under the plasma concentration time curve, peak and trough plasma concentrations of fondaparinux were lower by 15.6 %, 13.0 % and 10.3 %, respectively, in patients with renal impairment treated with 1.5 mg compared with patients with normal renal function treated with 2.5 mg (p < 0.01). Although administration of 1.5 mg fondaparinux in patients with renal impairment resulted in a predicted exposure slightly lower than that achieved with 2.5 mg in patients with normal renal function, fondaparinux 1.5 mg is a valuable thromboprophylactic option in MOS patients with renal impairment who are at risk of bleeding."	"[Delavenne, Xavier] Univ Hosp St Etienne, Lab Pharmacol & Toxicol, F-42055 St Etienne, France; [Delavenne, Xavier; Zufferey, Paul; Mismetti, Patrick; Laporte, Silvy] Univ St Etienne, Thrombosis Res Grp, EA 3065, F-42023 St Etienne, France; [Zufferey, Paul] Univ Hosp, Dept Anesthesiol & Intens Care, F-42055 St Etienne, France; [Philippe Nguyen] Hop Robert Debre, Cent Hematol Lab, Reims, France; [Rosencher, Nadia] Paris Descartes Univ, Cochin Dept Anesthesiol & Intens Care, AP HP, Paris, France; [Samama, Charles-Marc] Paris Descartes Univ, Dept Anesthesiol & Intens Care, Hotel Dieu Hosp, AP HP, Paris, France; [Bazzoli, Celine] Paris Descartes Univ, INSERM, UMR 738, Paris, France; [Mismetti, Patrick; Laporte, Silvy] Univ Hosp, Dept Clin Pharmacol, F-42055 St Etienne, France; [Laporte, Silvy] INSERM, CIE3, F-42005 St Etienne, France"	"Delavenne, X (corresponding author), Univ Hosp St Etienne, Lab Pharmacol & Toxicol, F-42055 St Etienne, France."	"xavier.delavenne@chu-st-etienne.fr"	"Rosencher, Nadia/AAS-3888-2020"	"Rosencher, Nadia/0000-0003-0615-4804; Delavenne, Xavier/0000-0001-7134-0713"	"Saint-Etienne University Hospital (France); GlaxoSmithKlineGlaxoSmithKline"	"The study was sponsored by Saint-Etienne University Hospital (France). The study was supported by a grant from GlaxoSmithKline, which also provided study medication but had no role in data collection, data management or statistical analysis. The trial was supervised by a steering committee of five people, including one nonvoting GlaxoSmithKline representative. All authors had full access to all data and analyses, contributed to the writing of the manuscript, and take complete responsibility for data accuracy and completeness. All authors had final responsibility for deciding to submit for publication."	17	9	10	0	0	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"OCT"	2012	68	10	1403	1410	"NA"	"10.1007/s00228-012-1263-0"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"003YH"	"WOS:000308646800007"	22447298	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Nguyen, THT; Comets, E; Mentre, F"	"Thi Huyen Tram Nguyen; Comets, Emmanuelle; Mentre, France"	"NA"	"M"	"Extension of NPDE for evaluation of nonlinear mixed effect models in presence of data below the quantification limit with applications to HIV dynamic model"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Model evaluation; Nonlinear mixed effect models; Prediction discrepancies; Normalised prediction distribution errors; Limit of quantification; HIV dynamic model"	"CENSORED-DATA; REPLACEMENT; NONMEM; IMPACT"	"Data below the quantification limit (BQL data) are a common challenge in data analyses using nonlinear mixed effect models (NLMEM). In the estimation step, these data can be adequately handled by several reliable methods. However, they are usually omitted or imputed at an arbitrary value in most evaluation graphs and/or methods. This can cause trends to appear in diagnostic graphs, therefore, confuse model selection and evaluation. We extended in this paper two metrics for evaluating NLMEM, prediction discrepancies (pd) and normalised prediction distribution errors (npde), to handle BQL data. For a BQL observation, the pd is randomly sampled in a uniform distribution over the interval from 0 to the probability of being BQL predicted by the model, estimated using Monte Carlo (MC) simulation. To compute npde in presence of BQL observations, we proposed to impute BQL values in both validation dataset and MC samples using their computed pd and the inverse of the distribution function. The imputed dataset and MC samples contain original data and imputed values for BQL data. These data are then decorrelated using the mean and variance-covariance matrix to compute npde. We applied these metrics on a model built to describe viral load obtained from 35 patients in the COPHAR 3-ANRS 134 clinical trial testing a continued antiretroviral therapy. We also conducted a simulation study inspired from the real model. The proposed metrics show better behaviours than naive approaches that discard BQL data in evaluation, especially when large amounts of BQL data are present."	"[Thi Huyen Tram Nguyen; Comets, Emmanuelle; Mentre, France] Univ Paris Diderot, INSERM, UMR 738, F-75018 Paris, France; [Mentre, France] Hosp Bichat, AP HP, Serv Biostat, F-75018 Paris, France"	"Nguyen, THT (corresponding author), Univ Paris Diderot, INSERM, UMR 738, F-75018 Paris, France."	"thi-huyen.nguyen@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"Novartis Pharma"	"We would like to thank Professor Cecile Goujard (Hospital Bicetre), principal investigator of the COPHAR 3-ANRS 134 trial, to let us have access to the viral load data. We also want to thank Novartis Pharma for funding the PhD of T.H.T. Nguyen during which a part of this work was completed."	30	19	19	0	8	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"OCT"	2012	39	5	499	518	"NA"	"10.1007/s10928-012-9264-2"	20	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"008MX"	"WOS:000308962200006"	22886041	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Comets, E; Brendel, K; Mentre, F"	"Comets, Emmanuelle; Brendel, Karl; Mentre, France"	"NA"	"M"	"Why Should Prediction Discrepancies Be Renamed Standardized Visual Predictive Check?"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Letter"	"NA"	"NA"	"NA"	"[Comets, Emmanuelle] Univ Paris 07, INSERM, UMR738, F-75018 Paris, France; [Comets, Emmanuelle; Mentre, France] Univ Paris Diderot, Paris, France; [Brendel, Karl] IRIS, Neuilly Sur Seine, France"	"Comets, E (corresponding author), Univ Paris 07, INSERM, UMR738, 16 Rue Henri Huchard, F-75018 Paris, France."	"emmanuelle.comets@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"NA"	"NA"	7	1	1	0	1	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"0091-2700"	"NA"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"AUG"	2012	52	8	1284	1285	"NA"	"10.1177/0091270011412963"	2	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"979UD"	"WOS:000306844400016"	21908878	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Lee, SH; Park, HW; Kim, MJ; Noh, MH; Yoon, HS; Choi, BM; Lee, EK; Noh, GJ"	"Lee, S. -H.; Park, H. -W.; Kim, M. -J.; Noh, M. -H.; Yoon, H. -S.; Choi, B. -M.; Lee, E. -K.; Noh, G. -J."	"NA"	"A"	"External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long-chain triglyceride emulsion propofol in beagle dogs"	"JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS"	"English"	"Article"	"NA"	"COMPUTER-CONTROLLED INFUSION; TARGET-CONTROLLED INFUSION; EFFECT-SITE CONCENTRATION; PREDICTIVE PERFORMANCE; VOLUNTEERS; ANESTHESIA; SURGERY; TIME"	"Lee, S.-H., Park, H.-W., Kim, M.-J., Noh, M.-H., Yoon, H.-S., Choi, B.-M., Lee, E.-K., Noh, G.-J. External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long-chain triglyceride emulsion propofol in beagle dogs. J. vet. Pharmacol. Therap. 35, 329-341. This study aimed at assessing the predictive performance of a target-controlled infusion (TCI) system, which incorporates canine PKPD models for microemulsion and long-chain triglyceride emulsion (LCT) propofol and at investigating time independency of propofol effect on the observed electroencephalographic approximate entropy (ApEn) in TCI. Using a crossover design with a 7-day washout period, 28 healthy beagle dogs were randomized to receive TCI of both formulations in a stepwise or constant manner. Plasma propofol concentrations and ApEn were measured at preset intervals. Pooled biases, inaccuracies, divergences, and wobbles in pharmacokinetic and pharmacodynamic predictions were 2.1% (95% CI: -0.8 to 4.9), 18.1% (15.620.5), 1.9%/h, 7.3% (5.49.3), and -0.5% (-2.6 to 1.6), 8.7% (7.310.1), 2.5%/h, 6.0% (4.17.2) for microemulsion propofol, and -9.3% (-11.6 to -6.9), 20.1% (18.222.0), 5.1%/h, 7.6% (6.19.1) and 5.6% (4.17.1), 8.0% (6.99.3), 4.7%/h, 4.1% (3.15.1) for LCT propofol. Observed ApEn values over time were statistically not different across all time points in a TCI with constant manner. Canine PKPD model of microemulsion propofol showed good predictive performances. Propofol effect (ApEn) was time independent as long as time is allowed for equilibration."	"[Lee, S. -H.; Kim, M. -J.; Noh, G. -J.] Univ Ulsan, Dept Clin Pharmacol & Therapeut, Asan Med Ctr, Coll Med, Seoul 138736, South Korea; [Park, H. -W.] Korea Adv Inst Sci & Technol, Grad Sch Biomed Sci & Engn, Taejon 305701, South Korea; [Noh, M. -H.] Kookmin Univ, Sch Automot Engn, Seoul, South Korea; [Yoon, H. -S.] Chungnam Natl Univ, Coll Med, Dept Anesthesiol & Pain Med, Taejon, South Korea; [Lee, E. -K.] Ewha Womans Univ, Dept Stat, Seoul, South Korea; [Noh, G. -J.] Univ Ulsan, Dept Anesthesiol & Pain Med, Asan Med Ctr, Coll Med, Seoul 138736, South Korea"	"Noh, GJ (corresponding author), Univ Ulsan, Dept Clin Pharmacol & Therapeut, Asan Med Ctr, Coll Med, 388-1,Pungnap 2 Dong, Seoul 138736, South Korea."	"nohgj@amc.seoul.kr"	"Lee, Soohan/AAP-6976-2020"	"NA"	"National Research Foundation of KoreaNational Research Foundation of Korea; Korean GovernmentKorean Government [NRF-2009-351-E00054]; University of Ulsan College of Medicine, Seoul, Korea [10-11]; Industry Trust Research Service [2008-0648]; University of Ulsan College of Medicine; Bionet Co., Ltd., Seoul, Korea"	"This work was supported by a National Research Foundation of Korea Grant funded by the Korean Government (no. NRF-2009-351-E00054), a Student Research Grant (10-11) of the University of Ulsan College of Medicine, Seoul, Korea, and a grant (No. 2008-0648) from the Industry Trust Research Service established by the University of Ulsan College of Medicine and Bionet Co., Ltd., Seoul, Korea. We are deeply grateful to Do-Yang Park, A. S., at the Department of Clinical Pharmacology and Therapeutics, and Ae-Kyung Hwang, B. S., Hyun-Jeong Park, B. S., and Arum Kim, B. S. at the Clinical Research Center of Asan Medical Center, Seoul, Korea, for performing the animal experiments and measuring propofol concentrations, respectively."	35	11	13	0	8	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0140-7783"	"NA"	"NA"	"J VET PHARMACOL THER"	"J. Vet. Pharmacol. Ther."	"AUG"	2012	35	4	329	341	"NA"	"10.1111/j.1365-2885.2011.01321.x"	13	"Pharmacology & Pharmacy; Veterinary Sciences"	"Pharmacology & Pharmacy; Veterinary Sciences"	"968SW"	"WOS:000306006100003"	21790660	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Neely, MN; van Guilder, MG; Yamada, WM; Schumitzky, A; Jelliffe, RW"	"Neely, Michael N.; van Guilder, Michael G.; Yamada, Walter M.; Schumitzky, Alan; Jelliffe, Roger W."	"NA"	"A"	"Accurate Detection of Outliers and Subpopulations With Pmetrics, a Nonparametric and Parametric Pharmacometric Modeling and Simulation Package for R"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"pharmacometrics; software; R; nonparametric; population modeling"	"MONTE-CARLO-SIMULATION"	"Introduction: Nonparametric population modeling algorithms have a theoretical superiority over parametric methods to detect pharmacokinetic and pharmacodynamic subgroups and outliers within a study population. Methods: The authors created Pmetrics, a new Windows and Unix R software package that updates the older MM-USCPACK software for nonparametric and parametric population modeling and simulation of pharmacokinetic and pharmacodynamic systems. The parametric iterative 2-stage Bayesian and the nonparametric adaptive grid (NPAG) approaches in Pmetrics were used to fit a simulated population with bimodal elimination (Kel) and unimodal volume of distribution (Vd), plus an extreme outlier, for a 1-compartment model of an intravenous drug. Results: The true means (SD) for Kel and Vd in the population sample were 0.19 (0.17) and 102 (22.3), respectively. Those found by NPAG were 0.19 (0.16) and 104 (22.6). The iterative 2-stage Bayesian estimated them to be 0.18 (0.16) and 104 (24.4). However, given the bimodality of Kel, no subject had a value near the mean for the population. Only NPAG was able to accurately detect the bimodal distribution for Kel and to find the outlier in both the population model and in the Bayesian posterior parameter estimates. Conclusions: Built on over 3 decades of work, Pmetrics adopts a robust, reliable, and mature nonparametric approach to population modeling, which was better than the parametric method at discovering true pharmacokinetic subgroups and an outlier."	"[Neely, Michael N.; van Guilder, Michael G.; Yamada, Walter M.; Schumitzky, Alan; Jelliffe, Roger W.] Univ So Calif, Keck Sch Med, Lab Appl Pharmacokinet, Los Angeles, CA 90033 USA"	"Neely, MN (corresponding author), 2250 Alcazar St,CSC 134B, Los Angeles, CA 90033 USA."	"mneely@usc.edu"	"NA"	"Yamada, Walter/0000-0003-3512-9202"	"National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K23 AI076106, R01 HD070996, R01 GM068968, R01 EB005803]"	"Supported by several grants from the National Institutes of Health: K23 AI076106 and R01 HD070996 (M.N.N.), R01 GM068968 (all), and R01 EB005803 (all)."	17	241	241	1	17	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA"	"0163-4356"	"NA"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"AUG"	2012	34	4	467	476	"NA"	"10.1097/FTD.0b013e31825c4ba6"	10	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"972PW"	"WOS:000306290500016"	22722776	"Green Accepted"	"Y"	"N"	"2020-10-01"
"J"	"Gibiansky, L; Frey, N"	"Gibiansky, Leonid; Frey, Nicolas"	"NA"	"A"	"Linking interleukin-6 receptor blockade with tocilizumab and its hematological effects using a modeling approach"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Interleukin-6 receptor; Mechanism of action; Neutrophils; Platelets; Rheumatoid arthritis; Tocilizumab; Target-mediated drug disposition"	"MEDIATED DRUG DISPOSITION; RHEUMATOID-ARTHRITIS; POPULATION PHARMACOKINETICS; DISEASE-ACTIVITY; TARGET; INHIBITION; IDENTIFIABILITY; APPROXIMATIONS; PARAMETERS; TRIAL"	"Tocilizumab is a recombinant humanized antihuman interleukin-6 receptor monoclonal antibody, which inhibits binding of IL-6 to its soluble (sIL-6R) and membrane-expressed (mIL-6R) receptors. The work investigated whether the observed decline in peripheral neutrophil and platelet counts after tocilizumab administration can be directly explained by tocilizumab IL-6R blockade, thus demonstrating the mechanism of tocilizumab action. Tocilizumab and total sIL-6R concentrations, neutrophil and platelet counts from 4 phase 3 studies in rheumatoid arthritis patients were available. Patients received 4 or 8 mg/kg tocilizumab intravenous infusions every 4 weeks for a total of 6 doses. A population approach was applied to describe the relationship between tocilizumab and sIL-6R concentrations and subsequent changes in neutrophil and platelet counts. Following tocilizumab administration, concentrations of total sIL-6R increased, while neutrophil and platelet counts declined. These changes were transient, with counts returning to their respective baseline levels soon after tocilizumab is eliminated from the body. Tocilizumab concentrations were described by a two compartment model with parallel linear and Michaelis-Menten elimination. The quasi-steady-state target-mediated drug disposition model described tocilizumab relationships to total sIL-6R, which allowed computation of unobserved unbound sIL-6R concentrations. The neutrophil counts were described as a direct function of unbound sIL-6R concentrations. The platelet counts were described by the transit-compartment life-span model with inhibition of production that depended on the unbound sIL-6R concentrations. Thus, the observed changes in sIL-6R, neutrophil, and platelet data are consistent with the tocilizumab mechanism of action and can be fully explained by tocilizumab binding to sIL-6R and mIL-6R."	"[Gibiansky, Leonid] QuantPharm LLC, N Potomac, MD 20878 USA; [Frey, Nicolas] F Hoffman La Roche Ltd, Pharma Res & Early Dev PRED & Translat Res Sci TR, Nutley, NJ USA"	"Gibiansky, L (corresponding author), QuantPharm LLC, 49 Flints Grove Dr, N Potomac, MD 20878 USA."	"lgibiansky@quantpharm.com"	"NA"	"NA"	"NA"	"NA"	34	24	27	0	3	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"NA"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"FEB"	2012	39	1	5	16	"NA"	"10.1007/s10928-011-9227-z"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"913HC"	"WOS:000301866700003"	22101760	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gosselin, F"	"Gosselin, Frederic"	"NA"	"A"	"A New Calibrated Bayesian Internal Goodness-of-Fit Method: Sampled Posterior p-Values as Simple and General p-Values That Allow Double Use of the Data"	"PLOS ONE"	"English"	"Article"	"NA"	"COMPOSITE NULL MODELS; ASYMPTOTIC-DISTRIBUTION; 2ND LEVELS; INFERENCE; CHECKING; TESTS"	"Background: Recent approaches mixing frequentist principles with Bayesian inference propose internal goodness-of-fit (GOF) p-values that might be valuable for critical analysis of Bayesian statistical models. However, GOF p-values developed to date only have known probability distributions under restrictive conditions. As a result, no known GOF p-value has a known probability distribution for any discrepancy function. Methodology/Principal Findings: We show mathematically that a new GOF p-value, called the sampled posterior p-value (SPP), asymptotically has a uniform probability distribution whatever the discrepancy function. In a moderate finite sample context, simulations also showed that the SPP appears stable to relatively uninformative misspecifications of the prior distribution. Conclusions/Significance: These reasons, together with its numerical simplicity, make the SPP a better canonical GOF p-value than existing GOF p-values."	"Irstea, UR EFNO, Nogent Sur Vernisson, France"	"Gosselin, F (corresponding author), Irstea, UR EFNO, Nogent Sur Vernisson, France."	"frederic.gosselin@cemagref.fr"	"NA"	"Gosselin, Frederic/0000-0003-3737-106X"	"NA"	"NA"	37	12	13	0	2	"PUBLIC LIBRARY SCIENCE"	"SAN FRANCISCO"	"1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA"	"1932-6203"	"NA"	"NA"	"PLOS ONE"	"PLoS One"	"MAR 18"	2011	6	3	"NA"	"NA"	"e14770"	"10.1371/journal.pone.0014770"	10	"Multidisciplinary Sciences"	"Science & Technology - Other Topics"	"737CD"	"WOS:000288545100006"	21445246	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Hulin, A; Blanchet, B; Audard, V; Barau, C; Furlan, V; Durrbach, A; Taieb, F; Lang, P; Grimbert, P; Tod, M"	"Hulin, Anne; Blanchet, Benoit; Audard, Vincent; Barau, Caroline; Furlan, Valerie; Durrbach, Antoine; Taieb, Fabrice; Lang, Philippe; Grimbert, Philippe; Tod, Michel"	"NA"	"A"	"Comparison of 3 Estimation Methods of Mycophenolic Acid AUC based on a Limited Sampling Strategy in Renal Transplant Patients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"mycophenolate mofetil; population pharmacokinetics; therapeutic drug monitoring; Monolix software"	"ACUTE REJECTION; KIDNEY-TRANSPLANTATION; BAYESIAN-ESTIMATION; MOFETIL; PHARMACOKINETICS; TACROLIMUS; RECIPIENTS; PREVENTION; MODEL; COMBINATION"	"A significant relationship between mycophenolic acid (MPA) area under the plasma concentration-time curve (AUC) and the risk for rejection has been reported. Based oil 3 concentration measurements, 3 approaches have been proposed for the estimation of MPA AUC, involving either a multilinear regression approach model (MLRA) or a Bayesian estimation using either gamma absorption or zero-order absorption population models. The aim of the study was to compare the 3 approaches for the estimation of MPA AUC in 150 renal transplant patients treated with mycophenolate mofetil and tacrolimus. The population parameters were determined in 77 patients (learning study). The AUC estimation methods were compared in the learning population and in 73 patients from another center (validation study). In the latter study, the reference AUCs were estimated by the trapezoidal rule on 8 measurements. MPA concentrations were measured by liquid chromatography. The gamma absorption model gave the best fit. In the learning study., the AUCs estimated by both Bayesian methods were very similar, whereas the multilinear approach was highly correlated but yielded estimates about 20% lower than Bayesian methods. This resulted in dosing recommendations differing by 250 mg/12 h or more in 27% of cases. In the validation study, AUC estimates based on the Bayesian method with gamma absorption model and multilinear regression approach model were, respectively, 12% higher and 7% lower than the reference values. To conclude, the bicompartmental model with gamma absorption rate gave the best fit. The 3 AUC estimation methods are highly correlated but not concordant. For a given patient, the same estimation method should always be used."	"[Tod, Michel] GH Cochin, Lab Pharm & Toxicol, CNRS, UMR 7054, F-75679 Paris 14, France; [Audard, Vincent; Lang, Philippe; Grimbert, Philippe] CHU Henri Mondor, AP HP, Dept Nephrol, F-94010 Creteil, France; [Barau, Caroline; Furlan, Valerie] CHU Bicetre, Toxicol Lab, Le Kremlin Bicetre, France; [Durrbach, Antoine] CHU Bicetre, AP HP, Dept Nephrol, Le Kremlin Bicetre, France; [Tod, Michel] Univ Lyon, F-69008 Lyon, France; [Tod, Michel] Univ Lyon 1, F-69622 Villeurbanne, France; [Blanchet, Benoit; Taieb, Fabrice; Tod, Michel] GH Cochin St Vincent de Paul, Lab Pharm & Toxicol, AP HP, AU 1, Paris, France"	"Tod, M (corresponding author), GH Cochin, Lab Pharm & Toxicol, CNRS, UMR 7054, 27 Rue Fauborg St Jacques, F-75679 Paris 14, France."	"michel.tod@cch.aphp.fr"	"grimbert, philippe/Q-5337-2018"	"AUDARD, Vincent/0000-0001-5343-2550; Barau, Caroline/0000-0003-4289-3276"	"NA"	"NA"	29	6	6	0	4	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"APR"	2009	31	2	224	232	"NA"	"10.1097/FTD.0b013e31819c077c"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"425ED"	"WOS:000264618900011"	19214145	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gagnieu, MC; El Barkil, M; Livrozet, JM; Cotte, L; Miailhes, P; Boibieux, A; Guitton, J; Tod, M"	"Gagnieu, Marie-Claude; El Barkil, Mirna; Livrozet, Jean-Michel; Cotte, Laurent; Miailhes, Patrick; Boibieux, Andre; Guitton, Jerome; Tod, Michel"	"NA"	"A"	"Population Pharmacokinetics of Tenofovir in AIDS Patients"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Tenofovir; pharmacokinetics; drug interaction; intraindividual variability"	"HUMAN-IMMUNODEFICIENCY-VIRUS; DISOPROXIL FUMARATE; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; DRUG-INTERACTIONS; KIDNEY-DISEASE; LOPINAVIR/RITONAVIR; VARIABILITY; ABSORPTION; SAFETY"	"The interindividual variability of tenofovir pharmacokinetics in HIV patients is quite large, but the sources of variability are incompletely understood. Intraindividual variability has not been characterized, although it may have an impact on efficacy and therapeutic drug monitoring. The aims of the study were to estimate intraindividual variability of tenofovir clearance and to assess interactions with associated antiviral drugs. Tenofovir concentrations (median 2; range, 1-5) were measured in 175 patients during several dosing intervals. Covariates and dosing regimen of associated antiretroviral drugs were recorded prospectively. The data were analyzed by a population approach. The final model was a 2-compartment model with first-order absorption rate, The elimination clearance was found to be related to the ratio of body weight to serum creatinine. Among the 15 drugs coadministered, no interaction on tenofovir kinetics was significant. The global variability of CLIF after accounting for variability to variation of body weight and serum creatinine, was about 50%, with 20% due to interindividual variability and 30% due to interoccasion variability. In a few patients, clearance (and AUC) could vary by a factor of 2 between occasions. The interoccasion variability was not related to the delay between occasions. In the context Of drug monitoring, for a given patient, the dose should not be adapted unless the variation of concentration between 2 occasions is large, or the 24-hour trough concentration at steady state is lower than 12 mu g/L."	"[El Barkil, Mirna; Guitton, Jerome; Tod, Michel] Univ Lyon, Toxicol Lab, ISPB, Fac Pharm, Lyon, France; [Gagnieu, Marie-Claude] Hop Edouard Herriot, Hosp Civils Lyon, Pharmacol Lab, Lyon, France; [Guitton, Jerome] Ctr Hosp Lyon Sud, Lab Ciblage Therapeut Cancerol, Hosp Civils Lyon, F-69310 Pierre Benite, France; [Livrozet, Jean-Michel] Hop Edouard Herriot, Serv Immunol Clin, Hosp Civils Lyon, Lyon, France; [Cotte, Laurent; Miailhes, Patrick] Hop Hotel Dieu, Serv Gastroenterol, Hosp Civils Lyon, F-69288 Lyon, France; [Boibieux, Andre] Hop Croix Rousse, Serv Malad Infect & Trop, Hosp Civils Lyon, F-69317 Lyon, France"	"Guitton, J (corresponding author), Univ Lyon 1, Toxicol Lab, ISPB, 8 Ave Rockefeller, F-69373 Lyon, France."	"jerome.guitton@recherche.univ-lyon1.fr"	"NA"	"Guitton, Jerome/0000-0001-6180-5708"	"NA"	"NA"	21	32	32	0	1	"SAGE PUBLICATIONS INC"	"THOUSAND OAKS"	"2455 TELLER RD, THOUSAND OAKS, CA 91320 USA"	"0091-2700"	"NA"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"NOV"	2008	48	11	1282	1288	"NA"	"10.1177/0091270008322908"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"365DN"	"WOS:000260386200003"	18779377	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Comets, E; Brendel, K; Mentre, F"	"Comets, Emmanuelle; Brendel, Karl; Mentre, France"	"NA"	"M"	"Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: The npde add-on package for R"	"COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE"	"English"	"Article"	"population pharmacokinetics; population pharmacodynamics; model evaluation; nonlinear mixed-effects model; npde"	"P-VALUES; POPULATION; DESIGNS; NONMEM"	"Pharmacokinetic/pharmacodynamic data are often analysed using nonlinear mixed-effect models, and model evaluation should be an important part of the analysis. Recently, normalised prediction distribution errors (npde) have been proposed as a model evaluation tool. In this paper, we describe an add-on package for the open source statistical package R, designed to compute npde. npde take into account the full predictive distribution of each individual observation and handle multiple observations within subjects. Under the null hypothesis that the model under scrutiny describes the validation dataset, npde should follow the standard normal distribution. Simulations need to be performed before hand, using for example the software used for model estimation. we illustrate the use of the package with two simulated datasets, one under the true model and one with different parameter values, to show how npde can be used to evaluate models. Model estimation and data simulation were performed using NONMEM version 5.1. (c) 2007 Elsevier Ireland Ltd. All rights reserved"	"[Comets, Emmanuelle; Mentre, France] Univ Paris 07, INSERM, U78, UFR Med, F-75018 Paris, France; [Comets, Emmanuelle; Mentre, France] INSERM, U738, Paris, France; [Brendel, Karl] Inst Rech Int Servier, F-92415 Courbevoie, France; [Mentre, France] Hop Bichat Claude Bernard, AP HP, UF Biostat, F-75877 Paris, France"	"Comets, E (corresponding author), Univ Paris 07, INSERM, U78, UFR Med, Site Bichat,16 Rue Henri Huchard, F-75018 Paris, France."	"emmanuelle.comets@bichat.inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"NA"	"NA"	30	267	275	0	12	"ELSEVIER IRELAND LTD"	"CLARE"	"ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND"	"0169-2607"	"NA"	"NA"	"COMPUT METH PROG BIO"	"Comput. Meth. Programs Biomed."	"MAY"	2008	90	2	154	166	"NA"	"10.1016/j.cmpb.2007.12.002"	13	"Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics"	"Computer Science; Engineering; Medical Informatics"	"294CM"	"WOS:000255381700007"	18215437	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Post, TM; Freijer, JI; Ploeger, BA; Danhof, M"	"Post, Teun M.; Freijer, Jan I.; Ploeger, Bart A.; Danhof, Meindert"	"NA"	"M"	"Extensions to the Visual Predictive Check to facilitate model performance evaluation"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Visual Predictive Check; pharmacokinetics; pharmacodynamics; disease progression; evaluation; validation; qualification; model performance"	"POPULATION PHARMACOKINETICS; DISEASE PROGRESSION; LONGITUDINAL DATA; DRUG; PIOGLITAZONE; GLICLAZIDE"	"The Visual Predictive Check (VPC) is a valuable and supportive instrument for evaluating model performance. However in its most commonly applied form, the method largely depends on a subjective comparison of the distribution of the simulated data with the observed data, without explicitly quantifying and relating the information in both. In recent adaptations to the VPC this drawback is taken into consideration by presenting the observed and predicted data as percentiles. In addition, in some of these adaptations the uncertainty in the predictions is represented visually. However, it is not assessed whether the expected random distribution of the observations around the predicted median trend is realised in relation to the number of observations. Moreover the influence of and the information residing in missing data at each time point is not taken into consideration. Therefore, in this investigation the VPC is extended with two methods to support a less subjective and thereby more adequate evaluation of model performance: (i) the Quantified Visual Predictive Check (QVPC) and (ii) the Bootstrap Visual Predictive Check (BVPC). The QVPC presents the distribution of the observations as a percentage, thus regardless the density of the data, above and below the predicted median at each time point, while also visualising the percentage of unavailable data. The BVPC weighs the predicted median against the 5th, 50th and 95th percentiles resulting from a bootstrap of the observed data median at each time point, while accounting for the number and the theoretical position of unavailable data. The proposed extensions to the VPC are illustrated by a pharmacokinetic simulation example and applied to a pharmacodynamic disease progression example."	"[Ploeger, Bart A.; Danhof, Meindert] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Pharmacol, NL-2300 RA Leiden, Netherlands; [Post, Teun M.] NV Organon, NL-5340 BH Oss, Netherlands; [Ploeger, Bart A.; Danhof, Meindert] Leiden Experts Adv Pharmacokinet & Pharmacodynam, Leiden, Netherlands; [Freijer, Jan I.] Astellas Pharma, Leiderdorp, Netherlands"	"Danhof, M (corresponding author), Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands."	"m.danhof@lacdr.leidenuniv.nl"	"NA"	"NA"	"NA"	"NA"	23	143	146	0	6	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"APR"	2008	35	2	185	202	"NA"	"10.1007/s10928-007-9081-1"	18	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"303BC"	"WOS:000256013500003"	18197467	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Hooker, AC; Staatz, CE; Karlsson, MO"	"Hooker, Andrew C.; Staatz, Christine E.; Karlsson, Mats O."	"NA"	"M"	"Conditional weighted residuals (CWRES): A model diagnostic for the FOCE method"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"conditional estimation; model diagnostics; modeling; non-linear mixed effect models; NONMEM; pharmacometrics; statistics; weighted residuals"	"MIXED-EFFECTS MODELS; DRUG DEVELOPMENT; NONMEM"	"Purpose. Population model analyses have shifted from using the first order (FO) to the first-order with conditional estimation (FOCE) approximation to the true model. However, the weighted residuals (WRES), a common diagnostic tool used to test for model misspecification, are calculated using the FO approximation. Utilizing WRES with the FOCE method may lead to misguided model development/evaluation. We present a new diagnostic tool, the conditional weighted residuals (CWRES), which are calculated based on the FOCE approximation. Materials and Methods. CWRES are calculated as the FOCE approximated difference between an individual's data and the model prediction of that data divided by the root of the covariance of the data given the model. Results. Using real and simulated data the CWRES distributions behave as theoretically expected under the correct model. In contrast, in certain circumstances, the WRES have distributions that greatly deviate from the expected, falsely indicating model misspecification. CWRES/WRES comparisons can also indicate if the FOCE estimation method will improve the results of an FO model fit to data. Conclusions. Utilization of CWRES could improve model development and evaluation and give a more accurate picture of if and when a model is misspecified when using the FO or FOCE methods."	"Uppsala Univ, Dept Pharmaceut Biosci, Fac Pharm, Div Pharmacokinet & Drug Therapy, S-75124 Uppsala, Sweden"	"Hooker, AC (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Fac Pharm, Div Pharmacokinet & Drug Therapy, Box 591, S-75124 Uppsala, Sweden."	"andrew.hooker@farmbio.uu.se"	"Hooker, Andrew/A-7794-2015; Staatz, Christine E/F-3971-2010"	"Hooker, Andrew/0000-0002-2676-5912; Staatz, Christine E/0000-0002-4595-9376"	"NA"	"NA"	22	211	215	0	9	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"NA"	"NA"	"PHARM RES"	"Pharm. Res."	"DEC"	2007	24	12	2187	2197	"NA"	"10.1007/s11095-007-9361-x"	11	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"228IB"	"WOS:000250722500002"	17612795	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Ribbing, J; Nyberg, J; Caster, O; Jonsson, EN"	"Ribbing, Jakob; Nyberg, Joakim; Caster, Ola; Jonsson, E. Niclas"	"NA"	"M"	"The lasso - a novel method for predictive covariate model building in nonlinear mixed effects models"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"least absolute shrinkage and selection operator; covariate analysis; model validation; model evaluation; data splitting; predictive modelling; mixed effects modelling"	"POPULATION PHARMACOKINETICS; EXTERNAL VALIDATION; REGRESSION; SELECTION; BOOTSTRAP; BIAS; VARIABILITY; PERFORMANCE; SIMULATION; PSN"	"Covariate models for population pharmacokinetics and pharmacodynamics are often built with a stepwise covariate modelling procedure (SCM). When analysing a small dataset this method may produce a covariate model that suffers from selection bias and poor predictive performance. The lasso is a method suggested to remedy these problems. It may also be faster than SCM and provide a validation of the covariate model. The aim of this study was to implement the lasso for covariate selection within NONMEM and to compare this method to SCM. In the lasso all covariates must be standardised to have zero mean and standard deviation one. Subsequently, the model containing all potential covariate-parameter relations is fitted with a restriction: the sum of the absolute covariate coefficients must be smaller than a value, t. The restriction will force some coefficients towards zero while the others are estimated with shrinkage. This means in practice that when fitting the model the covariate relations are tested for inclusion at the same time as the included relations are estimated. For a given SCM analysis, the model size depends on the P-value required for selection. In the lasso the model size instead depends on the value of t which can be estimated using cross-validation. The lasso was implemented as an automated tool using PsN. The method was compared to SCM in 16 scenarios with different dataset sizes, number of investigated covariates and starting models for the covariate analysis. Hundred replicate datasets were created by resampling from a PK-dataset consisting of 721 stroke patients. The two methods were compared primarily on the ability to predict external data, estimate their own predictive performance (external validation), and on the computer run-time. In all 16 scenarios the lasso predicted external data better than SCM with any of the studied P-values (5%, 1% and 0.1%), but the benefit was negligible for large datasets. The lasso cross-validation provided a precise and nearly unbiased estimate of the actual prediction error. On a single processor, the lasso was faster than SCM. Further, the lasso could run completely in parallel whereas SCM must run in steps. In conclusion, the lasso is superior to SCM in obtaining a predictive covariate model on a small dataset or on small subgroups (e.g. rare genotype). Run in parallel the lasso could be much faster than SCM. Using cross-validation, the lasso provides a validation of the covariate model and does not require the user to specify a P-value for selection."	"Uppsala Univ, Dept Pharmaceut Biosci, Div Pharmacokinet & Drug Therapy, S-75124 Uppsala, Sweden; F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland"	"Ribbing, J (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Div Pharmacokinet & Drug Therapy, Box 591, S-75124 Uppsala, Sweden."	"jakob.ribbing@farmbio.uu.se"	"NA"	"Caster, Ola/0000-0002-2259-1716"	"NA"	"NA"	45	35	37	0	10	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"AUG"	2007	34	4	485	517	"NA"	"10.1007/s10928-007-9057-1"	33	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"189RS"	"WOS:000248006800003"	17516152	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Dasari, S; Viele, K; Turner, AC; Cooper, RL"	"Dasari, Sameera; Viele, Kert; Turner, A. Clay; Cooper, Robin L."	"NA"	"A"	"Influence of PCPA and MDMA (ecstasy) on physiology, development and behavior in Drosophila melanogaster"	"EUROPEAN JOURNAL OF NEUROSCIENCE"	"English"	"Article"	"CNS; dopamine; drugs of abuse; ecstasy; MDMA; PCPA; synapse"	"ENTERIC NERVOUS-SYSTEM; BIOGENIC-AMINE SYSTEMS; STRIATE CORTEX; 5-HT RECEPTORS; NEUROMUSCULAR-JUNCTIONS; MUSHROOM BODIES; MULTIPLE ROLES; ANTENNAL LOBE; FRUIT-FLY; SEROTONIN"	"The effects of para-chlorophenylalanine (PCPA) and 3,4 methylenedioxy-methamphetamine (MDMA, 'ecstasy') were investigated in relation to development, behavior and physiology in larval Drosophila. PCPA blocks the synthesis of serotonin (5-HT) and MDMA is known to deplete 5-HT in mammalian neurons; thus these studies were conducted primarily to target the serotonergic system. Treatment with PCPA and MDMA delayed time to pupation and eclosion. The developmental rate was investigated with a survival analysis statistical approach that is unique for Drosophila studies. Locomotion and eating were reduced in animals exposed to MDMA or PCPA. Sensitivity to exogenously applied 5-HT on an evoked sensory-central nervous system (CNS)-motor circuit showed that the CNS is sensitive to 5-HT but that when depleted of 5-HT by PCPA a decreased sensitivity occurred. A diet with MDMA produced an enhanced response to exogenous 5-HT on the central circuit. Larvae eating MDMA from the first to third instar did not show a reduction in 5-HT within the CNS; however, eating PCPA reduced 5-HT as well as dopamine content as measured by high performance liquid chromatography from larval brains. As the heart serves as a good bioindex of 5-HT exposure, it was used in larvae fed PCPA and MDMA but no significant effects occurred with exogenous 5-HT. In summary, the action of these pharmacological compounds altered larval behaviors and development. PCPA treatment changed the sensitivity in the CNS to 5-HT, suggesting that 5-HT receptor regulation is modulated by neural activity of the serotonergic neurons. The actions of acute MDMA exposure suggest a 5-HT agonist action or possible dumping of 5-HT from neurons."	"Univ Kentucky, Dept Biol, Lexington, KY 40506 USA; Univ Kentucky, Dept Stat, Lexington, KY 40506 USA"	"Cooper, RL (corresponding author), Univ Kentucky, Dept Biol, 675 Rose St, Lexington, KY 40506 USA."	"RLCOOP1@pop.uky.edu"	"Cooper, Robin/L-7362-2019"	"NA"	"NCRR NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [2P20 RR 016481-04] Funding Source: Medline"	"NA"	91	24	25	0	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0953-816X"	"1460-9568"	"NA"	"EUR J NEUROSCI"	"Eur. J. Neurosci."	"JUL"	2007	26	2	424	438	"NA"	"10.1111/j.1460-9568.2007.05655.x"	15	"Neurosciences"	"Neurosciences & Neurology"	"197ZX"	"WOS:000248597600015"	17650115	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Brendel, K; Comets, E; Laffont, C; Laveille, C; Mentre, F"	"Brendel, Karl; Comets, Emmanuelle; Laffont, Celine; Laveille, Christian; Mentre, France"	"NA"	"M"	"Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"external validation; metrics; model evaluation; population pharmacokinetics; posterior predictive check"	"DRUG DEVELOPMENT; PREDICTIVE PERFORMANCE; MODIFIED RELEASE; VALIDATION; SIMULATION"	"Purpose. The aim of this study is to define and illustrate metrics for the external evaluation of a population model. Materials and Methods. In this paper, several types of metrics are defined: based on observations (standardized prediction error with or without simulation and normalized prediction distribution error); based on hyperparameters (with or without simulation); based on the likelihood of the model. All the metrics described above are applied to evaluate a model built from two phase II studies of gliclazide. A real phase I dataset and two datasets simulated with the real dataset design are used as external validation datasets to show and compare how metrics are able to detect and explain potential adequacies or inadequacies of the model. Results. Normalized prediction errors calculated without any approximation, and metrics based on hyperparameters or on objective function have good theoretical properties to be used for external model evaluation and showed satisfactory behaviour in the simulation study. Conclusions. For external model evaluation, prediction distribution errors are recommended when the aim is to use the model to simulate data. Metrics through hyperparameters should be preferred when the aim is to compare two populations and metrics based on the objective function are useful during the model building process."	"INSERM, U738, Paris, France; Univ Paris 07, Paris, France; Hop Bichat, AP HP, F-75877 Paris, France; Inst Rech Int Servier, F-92415 Courbevoie, France; Exprimo NV, Lummen, Belgium"	"Brendel, K (corresponding author), INSERM, U738, Paris, France."	"karl.brendel@bch.aphp.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"NA"	"NA"	33	219	225	0	11	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"NA"	"NA"	"PHARM RES"	"Pharm. Res."	"SEP"	2006	23	9	2036	2049	"NA"	"10.1007/s11095-006-9067-5"	14	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"081IN"	"WOS:000240310700010"	16906454	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Brockmeyer, JM; Wise, RT; Burgener, EB; Milla, C; Frymoyer, A"	"Brockmeyer, Jake M.; Wise, Russell T.; Burgener, Elizabeth B.; Milla, Carlos; Frymoyer, Adam"	"NA"	"A"	"Area under the curve achievement of once daily tobramycin in children with cystic fibrosis during clinical care"	"PEDIATRIC PULMONOLOGY"	"English"	"Article; Early Access"	"antibiotic therapy; cystic fibrosis; pharmacology; Pseudomonas aeruginosa"	"POPULATION PHARMACOKINETICS; PHARMACODYNAMICS; OPTIMIZATION; EXPOSURE"	"Background The area under the concentration-time curve over 24 hours (AUC(24)) is frequently utilized to monitor tobramycin exposure in children with cystic fibrosis (CF). An understanding of exposure target achievement during clinical implementation of an AUC(24)based approach in children is limited. Methods A retrospective chart review was performed in children with CF treated with once daily tobramycin and drug concentration monitoring at a pediatric CF center. During clinical care AUC(24)was estimated using a traditional log-linear regression approach (LLR). AUC(24)was also estimated retrospectively using a pharmacokinetic model-based Bayesian forecasting approach (BF). AUC(24)achievement after both approaches were compared. Results In 77 treatment courses (mean age, 12.7 � 5.0 years), a target AUC(24)100 to 125 mg h/L was achieved after starting dose in 21 (27%) and after initial dose adjustment in 35 (45%). In the first 7 days of treatment, 24 (32%) required >= 3 dose adjustments, and the mean number of drug concentrations measured was 7.1 � 3.2. Examination of a BF approach demonstrated adequate prediction of measured tobramycin concentrations (median bias -2.1% [95% CI -3.1 to -1.4]; median precision 7.6% [95% CI, 7.1%-8.2%]). AUC(24)estimates utilizing the BF approach were higher than the LLR approach with a mean difference of 6.4 mg h/L (95% CI, 4.8 to 8.0 mg h/L). Conclusions Achievement of a narrow AUC(24)target is challenging during clinical care, and dose individualization is needed in most children with CF. Implementing a BF approach for estimating AUC(24)in children with CF is supported."	"[Brockmeyer, Jake M.; Wise, Russell T.] Lucile Packard Childrens Hosp Stanford, Dept Pharm, Palo Alto, CA USA; [Burgener, Elizabeth B.; Milla, Carlos] Stanford Univ, Div Pediat Pulm Med, Stanford, CA 94305 USA; [Frymoyer, Adam] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA"	"Frymoyer, A (corresponding author), 750 Welch Rd,Suite 315, Palo Alto, CA 94143 USA."	"frymoyer@stanford.edu"	"NA"	"Wise, Russell/0000-0001-6985-9700; Burgener, Elizabeth/0000-0001-8969-6232"	"NA"	"NA"	31	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"8755-6863"	"1099-0496"	"NA"	"PEDIATR PULM"	"Pediatr. Pulmonol."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1002/ppul.25037"	8	"Pediatrics; Respiratory System"	"Pediatrics; Respiratory System"	"NI5BL"	"WOS:000565366900001"	32827334	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bensalem, A; Mulleman, D; Paintaud, G; Azzopardi, N; Gouilleux-Gruart, V; Cornec, D; Specks, U; Ternant, D"	"Bensalem, Amina; Mulleman, Denis; Paintaud, Gilles; Azzopardi, Nicolas; Gouilleux-Gruart, Valerie; Cornec, Divi; Specks, Ulrich; Ternant, David"	"NA"	"A"	"Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; WEGENERS-GRANULOMATOSIS; CLINICAL UTILITY; MODEL; ELIMINATION; CYCLOPHOSPHAMIDE; PHARMACODYNAMICS; CHEMOTHERAPY; POLYANGIITIS; CLEARANCE"	"Background and Objectives Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients. Methods Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used. Results Our pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) models satisfactorily described both concentration-time and concentration-effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 x 10(-5) nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively. Conclusions A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab."	"[Bensalem, Amina; Mulleman, Denis; Paintaud, Gilles; Azzopardi, Nicolas; Gouilleux-Gruart, Valerie; Ternant, David] Univ Tours, EA 7501, GICC, Tours, France; [Mulleman, Denis] CHRU Tours, Dept Rheumatol, Tours, France; [Paintaud, Gilles; Ternant, David] CHRU Tours, Dept Med Pharmacol, Tours, France; [Azzopardi, Nicolas] CNRS, ERL 7001, Tours, France; [Cornec, Divi; Specks, Ulrich] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA; [Gouilleux-Gruart, Valerie] CHRU Tours, Lab Immunol, Tours, France; [Cornec, Divi] Brest Univ Hosp, Rheumatol Dept, Brest, France; [Cornec, Divi] INSERM U1227, Brest, France; [Ternant, David] CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France"	"Ternant, D (corresponding author), Univ Tours, EA 7501, GICC, Tours, France.; Ternant, D (corresponding author), CHRU Tours, Dept Med Pharmacol, Tours, France.; Ternant, D (corresponding author), CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"Mulleman, Denis/O-3221-2019"	"Mulleman, Denis/0000-0003-4089-7513; Ternant, David/0000-0003-4020-4545"	"NA"	"NA"	46	1	1	1	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"APR"	2020	59	4	519	530	"NA"	"10.1007/s40262-019-00826-5"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KY6EG"	"WOS:000522664700007"	31586310	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Mukai, M; Maeda, H; Narushima, K; Mould, DR; Greene, D"	"Mukai, Mayumi; Maeda, Hiroshi; Narushima, Kazuya; Mould, Diane R.; Greene, Douglas"	"NA"	"A"	"Population Pharmacokinetic Modeling of Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma or Adult T-Cell Lymphoma"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article; Early Access"	"adult T-cell lymphoma; cutaneous T-cell lymphoma; mogamulizumab; pharmacokinetics"	"MONOCLONAL-ANTIBODY KW-0761; LEUKEMIA-LYMPHOMA; CCR4 EXPRESSION; CLASSIFICATION"	"Cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATL) are rare non-Hodgkin lymphomas commonly expressing C-C chemokine receptor 4 (CCR4). Mogamulizumab is a humanized monoclonal antibody against CCR4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sezary syndrome, the most common forms of CTCL. Pharmacokinetic (PK) and clinical study data from 444 adult patients with ATL or CTCL collected during 6 clinical trials of mogamulizumab were used to construct a population PK model, which was best described by a 2-compartment model with linear clearance. Albumin, aspartate aminotransferase, mild-to-moderate hepatic impairment, and sex were statistically significant predictors of clearance; albumin was also a statistically significant predictor of peripheral volume of distribution; and body surface area was a statistically significant predictor for central volume of distribution. None of the other covariates-for example, age, body weight, body mass index, bilirubin, creatinine clearance, disease type (ATL and CTCL), ATL subtype (acute, lymphoma, and chronic), CTCL subtype (mycosis fungoides and Sezary syndrome), CCR4 expression (status or degree), race (Japanese and non-Japanese), renal impairment (normal, mild, moderate, and severe), or performance status-had a statistically significant impact. Performance of the final population PK model was acceptable. This model will be valuable for guiding further studies of mogamulizumab."	"[Mukai, Mayumi; Greene, Douglas] Kyowa Kirin Pharmaceut Dev Inc, Princeton, NJ USA; [Mukai, Mayumi; Maeda, Hiroshi; Narushima, Kazuya] Kyowa Kirin Co Ltd, Tokyo, Japan; [Mould, Diane R.] Project Res Inc, Phoenixville, PA USA; [Mould, Diane R.; Greene, Douglas] Amer Coll Clin Pharmacol, Ashburn, VA USA"	"Mukai, M (corresponding author), Kyowa Kirin Co Ltd, Otemachi Financial City Grand Cube, Chiyoda Ku, 1-9-2 Otemachi, Tokyo 1000004, Japan."	"mayumi.mukai.6z@kyowakirin.com"	"NA"	"NA"	"Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey"	"This study was supported and funded by Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey."	23	0	0	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1002/jcph.1564"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JV8VC"	"WOS:000502637800001"	31840838	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Bensalem, A; Mulleman, D; Paintaud, G; Azzopardi, N; Gouilleux-Gruart, V; Cornec, D; Specks, U; Ternant, D"	"Bensalem, Amina; Mulleman, Denis; Paintaud, Gilles; Azzopardi, Nicolas; Gouilleux-Gruart, Valerie; Cornec, Divi; Specks, Ulrich; Ternant, David"	"NA"	"A"	"Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited"	"CLINICAL PHARMACOKINETICS"	"English"	"Article; Early Access"	"NA"	"POPULATION PHARMACOKINETICS; WEGENERS-GRANULOMATOSIS; CLINICAL UTILITY; MODEL; ELIMINATION; CYCLOPHOSPHAMIDE; PHARMACODYNAMICS; CHEMOTHERAPY; POLYANGIITIS; CLEARANCE"	"Background and Objectives Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients. Methods Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used. Results Our pharmacokinetic and pharmacokinetic-pharmacodynamic (PK-PD) models satisfactorily described both concentration-time and concentration-effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 x 10(-5) nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively. Conclusions A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab."	"[Bensalem, Amina; Mulleman, Denis; Paintaud, Gilles; Azzopardi, Nicolas; Gouilleux-Gruart, Valerie; Ternant, David] Univ Tours, EA GICC 7501, Tours, France; [Mulleman, Denis] CHRU Tours, Dept Rheumatol, Tours, France; [Paintaud, Gilles; Ternant, David] CHRU Tours, Dept Med Pharmacol, Tours, France; [Azzopardi, Nicolas] CNRS, ERL 7001, Tours, France; [Cornec, Divi; Specks, Ulrich] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA; [Gouilleux-Gruart, Valerie] CHRU Tours, Lab Immunol, Tours, France; [Cornec, Divi] Brest Univ Hosp, Rheumatol Dept, Brest, France; [Cornec, Divi] INSERM U1227, Brest, France; [Ternant, David] CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France"	"Ternant, D (corresponding author), Univ Tours, EA GICC 7501, Tours, France.; Ternant, D (corresponding author), CHRU Tours, Dept Med Pharmacol, Tours, France.; Ternant, D (corresponding author), CHRU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"Mulleman, Denis/O-3221-2019"	"Mulleman, Denis/0000-0003-4089-7513; Ternant, David/0000-0003-4020-4545"	"National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [N01-AI-15416, ITN021AI]; Genentech, Inc.Roche HoldingGenentech; Biogen IDEC, Inc.Biogen; French Society of Rheumatology, France; Brest University Hospital, France; Connor Group Foundation; Mayo Foundation; French Higher Education and Research Ministry under the program 'Investissements d'avenir'French National Research Agency (ANR) [LabEx MAbImprove ANR-10-LABX-53-01]"	"The RAVE (Rituximab in ANCA-Associated Vasculitis) trial, from which these data were obtained, was supported by a grant from the National Institute of Allergy and Infectious Diseases to the Immune Tolerance Network (grant N01-AI-15416; protocol no. ITN021AI). Genentech, Inc. and Biogen IDEC, Inc. provided the study medications and partial funding for the trial. Genentech, Inc. performed the rituximab concentration measurements by ELISA for the trial. The ANCA measurements by ELISA were performed at the Mayo Clinic using test kits provided by Euroimmun, Inc. Divi Cornec received fellowship grants from the French Society of Rheumatology and from Brest University Hospital, France. Ulrich Speck's laboratory is supported by funds from the Connor Group Foundation and the Mayo Foundation. This work was partly supported by the French Higher Education and Research Ministry under the program 'Investissements d'avenir' (grant agreement: LabEx MAbImprove ANR-10-LABX-53-01)."	47	1	1	1	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40262-019-00826-5"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JC0BS"	"WOS:000488944700001"	31586310	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Lu, D; Li, CZ; Riggs, M; Polhamus, D; French, J; Agarwal, P; Chen, SC; Vadhavkar, S; Patre, M; Strasak, A; Quartino, A; Jin, JY; Girish, S"	"Lu, Dan; Li, Chunze; Riggs, Matthew; Polhamus, Daniel; French, Jonathan; Agarwal, Priya; Chen, Shang-Chiung; Vadhavkar, Shweta; Patre, Monika; Strasak, Alexander; Quartino, Angelica; Jin, Jin Yan; Girish, Sandhya"	"NA"	"A"	"Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Trastuzumab emtansine (T-DM1); HER2; Pharmacokinetics; Previously untreated metastatic breast cancer; MARIANNE"	"POPULATION PHARMACOKINETICS; OPEN-LABEL; ANTIBODY; SURVIVAL; BENEFIT; SAFETY"	"PurposeThe phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug-drug interactions (DDIs) were assessed.MethodsPharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed. Observed pharmacokinetic data were summarized for all analytes. Historical population pharmacokinetic models for T-DM1 conjugate and pertuzumab in HER2-positive MBC were used to derive empirical Bayes estimates of pharmacokinetic parameters.ResultsIn MARIANNE (N=375), meanstandard deviation population pharmacokinetic model-predicted Cycle 1 C-max for T-DM1 conjugate was 74.4 � 10.1 mu g/mL, Cycle 1 C-trough was 1.34 � 0.802 mu g/mL, and area under the concentration-time curve from time zero to infinity after first dose (AUC(inf)) was 338 � 69.5 mu g*day/mL. These values were similar to other T-DM1 studies. Pharmacokinetics of T-DM1 conjugate and other analytes (total trastuzumab, DM1) were similar with or without pertuzumab. In the pertuzumab plus T-DM1 arm, mean model-predicted Cycle 1 pertuzumab C-max, C-trough, and AUC(inf) were 276 � 50.0 mu g/mL, 64.8 � 17.9g/mL, and 4470 � 1360 mu g*day/mL, respectively. These values were similar to other pertuzumab studies.Conclusions Based on the population pharmacokinetic analysis of T-DM1 conjugate and pertuzumab, pharmacokinetics are similar across different lines of treatment and stages of disease including previously untreated MBC patients, and no DDIs were identified for combined use of T-DM1 and pertuzumab."	"[Lu, Dan; Li, Chunze; Agarwal, Priya; Chen, Shang-Chiung; Vadhavkar, Shweta; Quartino, Angelica; Jin, Jin Yan; Girish, Sandhya] Genentech Inc, Dept Clin Pharmacol, 1 DNA Way, San Francisco, CA 94080 USA; [Riggs, Matthew; Polhamus, Daniel; French, Jonathan] Metrum Res Grp, 2 Tunxis Rd 112, Tariffville, CT USA; [Patre, Monika; Strasak, Alexander] F Hoffmann La Roche Ltd, Grenzacherstr 124, CH-4070 Basel, Switzerland"	"Lu, D (corresponding author), Genentech Inc, Dept Clin Pharmacol, 1 DNA Way, San Francisco, CA 94080 USA."	"lu.dan@gene.com"	"Riggs, Matthew/AAF-3325-2020; li, chunze/AAC-8730-2020"	"Quartino, Angelica/0000-0003-0184-4670"	"Genentech, Inc.Roche HoldingGenentech"	"This study was funded by Genentech, Inc. Support for third-party writing assistance for this manuscript was provided by Genentech, Inc."	27	1	1	1	7	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"JUL"	2019	84	1	175	185	"NA"	"10.1007/s00280-019-03852-z"	11	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"IC8NM"	"WOS:000471238200017"	31102024	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Maharaj, AR; Wu, HL; Hornik, CP; Cohen-Wolkowiez, M"	"Maharaj, Anil R.; Wu, Huali; Hornik, Christoph P.; Cohen-Wolkowiez, Michael"	"NA"	"M"	"Pitfalls of using numerical predictive checks for population physiologically-based pharmacokinetic model evaluation"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Physiologically-based pharmacokinetic; Model evaluation; Numerical predictive check; Prediction interval; Simulation-based study"	"TISSUE DISTRIBUTION; ADULT"	"Comparisons between observed data and model simulations represent a critical component for establishing confidence in population physiologically-based pharmacokinetic (Pop-PBPK) models. Numerical predictive checks (NPC) that assess the proportion of observed data that correspond to Pop-PBPK model prediction intervals (PIs) are frequently used to qualify such models. We evaluated the effects of three components on the performance of NPC for qualifying Pop-PBPK model concentration-time predictions: (1) correlations (multiple samples per subject), (2) residual error, and (3) discrepancies in the distribution of demographics between observed and virtual subjects. Using a simulation-based study design, we artificially created observed pharmacokinetic (PK) datasets and compared them to model simulations generated under the same Pop-PBPK model. Observed datasets containing uncorrelated and correlated observations (� residual error) were formulated using different random-sampling techniques. In addition, we created observed datasets where the distribution of subject body weights differed from that of the virtual population used to generate model simulations. NPC for each observed dataset were computed based on the Pop-PBPK model's 90% PI. NPC were associated with inflated type-I-error rates (> 0.10) for observed datasets that contained correlated observations, residual error, or both. Additionally, the performance of NPC were sensitive to the demographic distribution of observed subjects. Acceptable use of NPC was only demonstrated for the idealistic case where observed data were uncorrelated, free of residual error, and the demographic distribution of virtual subjects matched that of observed subjects. Considering the restricted applicability of NPC for Pop-PBPK model evaluation, their use in this context should be interpreted with caution."	"[Maharaj, Anil R.; Wu, Huali; Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Sch Med, Duke Clin Res Inst, 300 West Morgan St, Durham, NC 27710 USA; [Hornik, Christoph P.; Cohen-Wolkowiez, Michael] Duke Univ, Sch Med, Dept Pediat, Durham, NC 27710 USA"	"Cohen-Wolkowiez, M (corresponding author), Duke Univ, Sch Med, Duke Clin Res Inst, 300 West Morgan St, Durham, NC 27710 USA.; Cohen-Wolkowiez, M (corresponding author), Duke Univ, Sch Med, Dept Pediat, Durham, NC 27710 USA."	"michael.cohenwolkowiez@duke.edu"	"NA"	"NA"	"National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01-HD076676-01A1]"	"This study was funded by the National Institutes of Health (1R01-HD076676-01A1; M.C.W.)."	19	3	2	1	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2019	46	3	263	272	"NA"	"10.1007/s10928-019-09636-5"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HZ1HH"	"WOS:000468597100005"	31016557	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Hecht, M; Veigure, R; Couchman, L; Barker, CIS; Standing, JF; Takkis, K; Evard, H; Johnston, A; Herodes, K; Leito, I; Kipper, K"	"Hecht, Max; Veigure, Ruta; Couchman, Lewis; Barker, Charlotte I. S.; Standing, Joseph F.; Takkis, Kalev; Evard, Hanno; Johnston, Atholl; Herodes, Koit; Leito, Ivo; Kipper, Karin"	"NA"	"M"	"Utilization of data below the analytical limit of quantitation in pharmacokinetic analysis and modeling: promoting interdisciplinary debate"	"BIOANALYSIS"	"English"	"Article"	"BLQ; LOD; LLOQ; pharmacodynamics; pharmacokinetic"	"TUBERCULOSIS PHARMACOMETRIC MODEL; CRITICALLY-ILL PATIENTS; BREAST-CANCER PATIENTS; ADVANCED SOLID TUMORS; MIXED EFFECT MODELS; POPULATION PHARMACOKINETICS; QUANTIFICATION LIMIT; HEALTHY-VOLUNTEERS; MONOCLONAL-ANTIBODY; IN-VITRO"	"Traditionally, bioanalytical laboratories do not report actual concentrations for samples with results below the LOQ (BLQ) in pharmacokinetic studies. BLQ values are outside the method calibration range established during validation and no data are available to support the reliability of these values. However, ignoring BLQ data can contribute to bias and imprecision in model-based pharmacokinetic analyses. From this perspective, routine use of BLQ data would be advantageous. We would like to initiate an interdisciplinary debate on this important topic by summarizing the current concepts and use of BLQ data by regulators, pharmacometricians and bioanalysts. Through introducing the limit of detection and evaluating its variability, BLQ data could be released and utilized appropriately for pharmacokinetic research."	"[Hecht, Max; Veigure, Ruta; Evard, Hanno; Herodes, Koit; Leito, Ivo; Kipper, Karin] Univ Tartu, Inst Chem, Chair Analyt Chem, 14a Ravila St, EE-50411 Tartu, Estonia; [Hecht, Max; Couchman, Lewis; Takkis, Kalev; Johnston, Atholl; Kipper, Karin] St Georges Univ London, Analyt Serv Int, Cranmer Terrace, London SW17 0RE, England; [Barker, Charlotte I. S.; Standing, Joseph F.] St Georges Univ London, Inst Infect & Immun, Paediat Infect Dis Res Grp, London SW17 0RE, England; [Barker, Charlotte I. S.; Standing, Joseph F.] UCL Great Ormond St Inst Child Hlth, Inflammat Infect & Rheumatol Sect, London WC1N 1EH, England; [Barker, Charlotte I. S.] St Georges Univ Hosp NHS Fdn Trust, Paediat Infect Dis Unit, London SW17 0RE, England; [Johnston, Atholl] Queen Mary Univ London, Barts & London Sch Med & Dent, Clin Pharmacol, London EC1M 6BQ, England"	"Leito, I; Kipper, K (corresponding author), Univ Tartu, Inst Chem, Chair Analyt Chem, 14a Ravila St, EE-50411 Tartu, Estonia.; Kipper, K (corresponding author), St Georges Univ London, Analyt Serv Int, Cranmer Terrace, London SW17 0RE, England."	"ivo.leito@ut.ee; karin.kipper@gmail.com"	"Kipper, Karin/F-1382-2016; Herodes, Koit/H-7714-2012; Leito, Ivo/U-9463-2019; Kipper, Karin/AAL-3397-2020; (Veigure) Hecht, Ruta/S-2935-2017"	"Kipper, Karin/0000-0002-7295-8993; Leito, Ivo/0000-0002-3000-4964; Kipper, Karin/0000-0002-7295-8993; (Veigure) Hecht, Ruta/0000-0002-4799-2938; Hecht, Max/0000-0003-2911-424X"	"UK NIH Research [ACF-2016-18-016]; UK Medical Research Council Fellowships [G1002305, M008665]; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust; University College London; Ministry of Education and Research of EstoniaMinistry of Education and Research, Estonia [IUT20-14, TLOKT14014I]; EU through the European Regional Development Fund [TK141]; Dora Plus PhD student mobility grant"	"C I S Barker receives funding from the UK NIH Research as an Academic Clinical Fellow (ACF-2016-18-016). J F Standing has received funding from UK Medical Research Council Fellowships (grants G1002305 and M008665) and by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. This work was supported by the institutional research grant of Ministry of Education and Research of Estonia IUT20-14 (TLOKT14014I) and by the EU through the European Regional Development Fund (TK141). M Hecht is supported by Dora Plus PhD student mobility grant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed."	263	6	6	1	6	"FUTURE SCI LTD"	"LONDON"	"UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND"	"1757-6180"	"1757-6199"	"NA"	"BIOANALYSIS"	"Bioanalysis"	"AUG"	2018	10	15	1229	1248	"NA"	"10.4155/bio-2018-0078"	20	"Biochemical Research Methods; Chemistry, Analytical"	"Biochemistry & Molecular Biology; Chemistry"	"GU0BE"	"WOS:000444911900009"	30033744	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Roberts, JK; Linakis, MW; Liu, XX; Sherwin, CMT; van den Anker, JN"	"Roberts, Jessica K.; Linakis, Matthew W.; Liu, Xiaoxi; Sherwin, Catherine M. T.; van den Anker, John N."	"NA"	"A"	"Evident bias in a paracetamol metabolite population pharmacokinetic model applied to an external dataset"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Letter"	"acetaminophen; external validation; neonate; NONMEM; paracetamol; population pharmacokinetics"	"GLUCURONIDATION; ACETAMINOPHEN"	"NA"	"[Roberts, Jessica K.; Linakis, Matthew W.; Liu, Xiaoxi; Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Div Clin Pharmacol, Salt Lake City, UT 84132 USA; [Linakis, Matthew W.; Sherwin, Catherine M. T.] Univ Utah, Coll Pharm, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA; [Sherwin, Catherine M. T.] Univ Utah, Dept Pharmacol & Toxicol, Coll Pharm, 112 Skaggs Hall, Salt Lake City, UT 84112 USA; [van den Anker, John N.] Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat Pharmacol & Physiol, Washington, DC 20052 USA; [van den Anker, John N.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Intens Care, Rotterdam, Netherlands; [van den Anker, John N.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, John N.] Univ Childrens Hosp Basel, Div Paediat Pharmacol & Pharmacometr, Basel, Switzerland"	"Sherwin, CMT (corresponding author), Univ Utah, Sch Med, Dept Pediat, Div Clin Pharmacol, Salt Lake City, UT 84132 USA."	"catherine.sherwin@hsc.utah.edu"	"Sherwin, Catherine Mary Turner/B-2888-2012"	"Sherwin, Catherine Mary Turner/0000-0002-0844-3207"	"National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD060543]; National Center for Advancing Translational SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000075]; McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA); Dutch Top Institute Pharma [D2-104]; Fund for Scientific Research, FlandersFWO [1700314 N]"	"The initial clinical trial data used for the external validation was supported by National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060543, to J.N.v.d.A.) and the National Center for Advancing Translational Sciences (UL1TR000075, to the Children's National Health System), and by a contract for analytical laboratory services from McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA). Collection of the data to populate the external dataset was supported by the Dutch Top Institute Pharma project number D2-104, and the Fund for Scientific Research, Flanders (1700314 N Fundamental Clinical Investigatorship)."	7	1	1	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUL"	2018	84	7	1628	1630	"NA"	"10.1111/bcp.13588"	3	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GJ5RT"	"WOS:000435440600029"	29667221	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Ji, XW; Ji, SM; He, XR; Zhu, X; Chen, R; Lu, W"	"Ji, Xi-wei; Ji, Shuang-min; He, Xiao-rong; Zhu, Xiao; Chen, Rong; Lu, Wei"	"NA"	"A"	"Influences of renal function descriptors on population pharmacokinetic modeling of vancomycin in Chinese adult patients"	"ACTA PHARMACOLOGICA SINICA"	"English"	"Article"	"vancomycin; population pharmacokinetics; Chinese adult patients; renal function; creatinine; glomerular filtration rate (GFR); NONMEM"	"TARGET CONCENTRATION INTERVENTION; GLOMERULAR-FILTRATION-RATE; CRITICALLY-ILL PATIENTS; CHRONIC KIDNEY-DISEASE; SERUM CREATININE; PREDICTIVE PERFORMANCE; BAYESIAN-ESTIMATION; EQUATIONS; ACCURACY; DIET"	"Vancomycin, a glycopeptide antibiotic for the treatment of grampositive infections, is mainly eliminated via glomerular filtration. Thus, its therapeutic effects are affected predominantly by renal function. The aim of this study was to develop a population pharmacokinetic model of vancomycin for Chinese adult patients and to investigate the influence of different renal function descriptors on the predictability of the model. A retrospective analysis was performed based on the blood concentrations of vancomycin in 218 Chinese adult patients. Among these patients, the data from 160 were used to establish the population pharmacokinetic model, and the data from the remaining 58 patients were used for external model validation. A simulation was employed to determine the appropriate initial vancomycin dosage regimens in adult Chinese patients for reaching the target steady-state trough concentrations of 10-15 mg/L and 15-20 mg/L. We developed a one-compartment model with first-order absorption to characterize the concentration-time profile of vancomycin. There was a positive correlation between the body clearance of vancomycin and renal function; both creatinine clearance (CLCr) and age were the covariates that influenced the PK of vancomycin, and the excretion of vancomycin decreased as renal function diminishing with age. The typical clearance (CL) value was 2.829 L/h for 75-year-old patients with CLCr values of 80 mL/min, and the rate constant of CL with the CLCr changing at 1 mL/min was 0.00842. The influence coefficient of age on CL was 0.08143. The external validation results revealed that the current different descriptors of renal function behaved similarly to the predicted performance of the models. In conclusion, the developed model is appropriate for Bayesian dose predictions of vancomycin concentrations in the population of Chinese adult patients. Furthermore, the simulation provides a reference for clinical optimized antibacterial therapy with vancomycin."	"[Ji, Xi-wei] Peking Univ, Inst Clin Pharmacol, Hosp 1, Beijing 100191, Peoples R China; [Ji, Shuang-min] China Food & Drug Adm, Ctr Drug Evaluat, Beijing 100038, Peoples R China; [He, Xiao-rong] Beijing Hosp, Dept Pharm, Beijing Key Lab Drug Clin Risk & Personalized Med, Beijing 100730, Peoples R China; [Zhu, Xiao] Univ Otago, Sch Pharm, Dunedin, New Zealand; [Chen, Rong; Lu, Wei] Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China"	"Lu, W (corresponding author), Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China."	"luwei_pk@hsc.pku.edu.cn"	"NA"	"Zhu, Xiao/0000-0003-3295-619X"	"Research Foundation of Peking University First Hospital"	"This work was supported by the Research Foundation of Peking University First Hospital."	48	8	9	0	9	"ACTA PHARMACOLOGICA SINICA"	"SHANGHAI"	"294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA"	"1671-4083"	"1745-7254"	"NA"	"ACTA PHARMACOL SIN"	"Acta Pharmacol. Sin."	"FEB"	2018	39	2	286	293	"NA"	"10.1038/aps.2017.57"	8	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"FU5BQ"	"WOS:000423868000014"	28836582	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Lanoiselee, J; Zufferey, PJ; Ollier, E; Hodin, S; Delavenne, X"	"Lanoiselee, Julien; Zufferey, Paul J.; Ollier, Edouard; Hodin, Sophie; Delavenne, Xavier"	"PeriOpeRative Tranexamic Acid Hip"	"A"	"Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"arthroplasty; replacement; hip; blood loss; pharmacokinetics; tranexamic acid"	"RANDOMIZED-CONTROLLED-TRIAL; POPULATION PHARMACOKINETICS; CARDIOPULMONARY BYPASS; CARDIAC-SURGERY; DOUBLE-BLIND; REPLACEMENT; PREDICTION; PLASMA; QUANTIFICATION; APPROXIMATION"	"AimsTranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10mg l(-1)), and perioperative blood loss. MethodsData were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1g followed by a continuous infusion of either TXA 1g or placebo over 8h. A population pharmacokinetic study was conducted to quantify TXA exposure. ResultsIn total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10mg l(-1). The model-estimated time during which the TXA concentration was above 10mg l(-1) ranged from 3.3h to 16.3h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10mg l(-1) or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve). ConclusionIn hip arthroplasty, TXA plasma concentrations were maintained above 10mg l(-1) during surgery and for a minimum of 3h with a preoperative TXA dose of 1g. Keeping TXA concentrations above this threshold up to 16h conferred no advantage with regard to blood loss."	"[Lanoiselee, Julien; Zufferey, Paul J.; Ollier, Edouard; Delavenne, Xavier] INSERM, U1059, Dysfonct Vasc & Hemostase, F-42023 St Etienne, France; [Lanoiselee, Julien; Zufferey, Paul J.] CHU St Etienne, Dept Anesthesie Reanimat, F-42055 St Etienne, France; [Zufferey, Paul J.] CHU St Etienne, Unite Rech Clin Innovat & Pharmacol, F-42055 St Etienne, France; [Ollier, Edouard; Hodin, Sophie; Delavenne, Xavier] CHU St Etienne, Lab Pharmacol Toxicol, F-42055 St Etienne, France; [Delavenne, Xavier] Univ Lyon, F-42023 St Etienne, France"	"Zufferey, PJ (corresponding author), Univ Hosp St Etienne, Dept Anaesthesiol & Intens Care, F-42055 St Etienne 02, France."	"paul.zufferey@chu-st-etienne.fr"	"NA"	"Delavenne, Xavier/0000-0001-7134-0713"	"University Hospital of Saint Etienne, France [1308015]"	"This research received funding from the University Hospital of Saint Etienne, France, the study sponsor (sponsor protocol number 1308015). All the investigators are employees of the funding source, which had no role in the design or conduct of the study; the collection, management, analysis or interpretation of the data; the preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. No other conflicts of interest with respect to the conduct of this research or the contents of this article are declared."	30	4	4	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"FEB"	2018	84	2	310	319	"NA"	"10.1111/bcp.13460"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FX4IE"	"WOS:000426035900009"	29193211	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Zhu, R; Zheng, Y; Dirks, NL; Vadhavkar, S; Jin, JY; Peng, K; Holweg, CTJ; Olsson, J; Matthews, JG; Putnam, WS"	"Zhu, Rui; Zheng, Yanan; Dirks, Nathanael. L.; Vadhavkar, Shweta; Jin, Jin Yan; Peng, Kun; Holweg, Cecile T. J.; Olsson, Julie; Matthews, John G.; Putnam, Wendy S."	"NA"	"A"	"Model-based clinical pharmacology profiling and exposure-response relationships of the efficacy and biomarker of lebrikizumab in patients with moderate-to-severe asthma"	"PULMONARY PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"Asthma; Anti-IL-13; Lebrikizumab; Population PK; Exposure-response; Monoclonal antibody"	"DOUBLE-BLIND; UNCONTROLLED ASTHMA; PHARMACOKINETICS; TRALOKINUMAB; SAFETY; ADULTS; TRIAL"	"Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV1], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day(-1) for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients. (C) 2017 Genentech, Inc. Published by Elsevier Ltd."	"[Zhu, Rui; Zheng, Yanan; Vadhavkar, Shweta; Jin, Jin Yan; Peng, Kun; Holweg, Cecile T. J.; Olsson, Julie; Matthews, John G.; Putnam, Wendy S.] Genentech Inc, San Francisco, CA 94080 USA; [Dirks, Nathanael. L.] Metrum Res Grp, Tariffville, CT USA"	"Putnam, WS (corresponding author), Genentech Inc, Dept Clin Pharmacol, 1 DNA Way, San Francisco, CA 94080 USA."	"Putnam.Wendy@gene.com"	"NA"	"NA"	"GenentechRoche HoldingGenentech"	"This work was supported by Genentech."	22	5	5	0	4	"ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD"	"LONDON"	"24-28 OVAL RD, LONDON NW1 7DX, ENGLAND"	"1094-5539"	"NA"	"NA"	"PULM PHARMACOL THER"	"Pulm. Pharmacol. Ther."	"OCT"	2017	46	"NA"	88	98	"NA"	"10.1016/j.pupt.2017.08.010"	11	"Pharmacology & Pharmacy; Respiratory System"	"Pharmacology & Pharmacy; Respiratory System"	"FK0NV"	"WOS:000413177500012"	28843617	"Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Lioger, B; Edupuganti, SR; Mulleman, D; Passot, C; Desvignes, C; Bejan-Angoulvant, T; Thibault, G; Gouilleux-Gruart, V; Melet, J; Paintaud, G; Ternant, D"	"Lioger, Bertrand; Edupuganti, Soujanya Ratna; Mulleman, Denis; Passot, Christophe; Desvignes, Celine; Bejan-Angoulvant, Theodora; Thibault, Gilles; Gouilleux-Gruart, Valerie; Melet, Julien; Paintaud, Gilles; Ternant, David"	"NA"	"A"	"Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"elimination rate constant; immunoglobulin; pharmacokinetics; rheumatoid arthritis; rituximab"	"NEONATAL FC-RECEPTOR; POPULATION PHARMACOKINETICS; MONOCLONAL-ANTIBODY; MODEL; PHARMACOLOGY; ASSOCIATION; INFLIXIMAB; DEPLETION; KINETICS; GUIDE"	"AimsRituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19 cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients. MethodsIn a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19 cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis. ResultsA two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7l and 0.56lday(-1), respectively. Distribution and elimination half-lives were 0.9days and 17.3days, respectively. As expected, the central volume of distribution increased with body surface area (P=0.012) and was higher in male than in female (P=0.004). We found that the elimination rate constant (k(10)) increased with CD19 count (P=0.00022) and IgG concentration (P=7.4 x 10(-8)), and that k(10) decreased with time (P=0.00015), partly explained by a change in target-antigen amount. ConclusionsThe association between CD19 count and k(10) may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k(10) may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab."	"[Lioger, Bertrand; Edupuganti, Soujanya Ratna; Mulleman, Denis; Passot, Christophe; Desvignes, Celine; Bejan-Angoulvant, Theodora; Thibault, Gilles; Gouilleux-Gruart, Valerie; Melet, Julien; Paintaud, Gilles; Ternant, David] Univ Francois Rabelais Tours, CNRS, GICC, UMR 7292, Tours, France; [Lioger, Bertrand] CHRU Tours, Serv Med Interne, Tours, France; [Mulleman, Denis; Melet, Julien] CHRU Tours, Serv Rhumatol, Tours, France; [Passot, Christophe; Desvignes, Celine; Paintaud, Gilles; Ternant, David] CHRU Tours, Lab Pharmacol Toxicol, Tours, France; [Bejan-Angoulvant, Theodora] CHRU Tours, Serv Pharmacol Clin, Tours, France; [Thibault, Gilles; Gouilleux-Gruart, Valerie] CHRU Tours, Lab Immunol, Tours, France"	"Lioger, B (corresponding author), Hop Bretonneau, Serv Med Interne, 2 Blvd Tonnele, F-37044 Tours, France."	"bertrand.lioger@univ-tours.fr"	"Mulleman, Denis/O-3221-2019"	"Mulleman, Denis/0000-0003-4089-7513; Bejan-Angoulvant, Theodora/0000-0002-0018-9996; PAINTAUD, Gilles/0000-0003-0158-1356"	"ABIRISK consortium; PfizerPfizer; MSD; AbbottAbbott Laboratories; RocheRoche Holding; Bristol-Myers SquibbBristol-Myers Squibb; UCBUCB Pharma SA; European UnionEuropean Union (EU); French Higher Education and Research ministry under the program 'Investissements d'avenir' Grant Agreement: LabEx MAbImproveFrench National Research Agency (ANR) [ANR-10-LABX-53-01]"	"B.L. has given lectures for GSK and has been invited to attend international congresses by Shire, Amgen, Novartis and GSK. S.R.E. received her fellowship from the ABIRISK consortium (www.abirisk.eu). D.M. has received on behalf of his institution consulting fees and speaking fees from Pfizer and MSD (less than $10 000 each). He has participated on behalf of his institution in clinical trials sponsored by Abbott, Roche, Bristol-Myers Squibb, Pfizer, UCB and MSD. He has been invited to attend international congresses by MSD, Roche, Bristol-Myers Squibb and Abbott. C. P., C. D., T. B. A., V. G. G., G. T., and J. M. have no competing interests to declare. G. P.' s research team received grants from Novartis, Roche Pharma, Genzyme, MSD, Chugai and Pfizer, outside of the submitted work. D. T. has given lectures for Amgen and Sanofi.; Measurements of adalimumab serum concentrations were carried out within the CePiBAc platform. CePiBAc was cofinanced by the European Union. Europe is committed to the region Centre with the European Regional Development Fund. This work was partly supported by the French Higher Education and Research ministry under the program 'Investissements d'avenir' Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01."	32	16	15	0	5	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"AUG"	2017	83	8	1773	1781	"NA"	"10.1111/bcp.13270"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FA6IA"	"WOS:000405545300017"	28230269	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Jullien, V; Azoulay, E; Schwebel, C; Le Saux, T; Charles, PE; Cornet, M; Souweine, B; Klouche, K; Jaber, S; Trouillet, JL; Bruneel, F; Cour, M; Cousson, J; Meziani, F; Gruson, D; Paris, A; Darmon, M; Garrouste-Orgeas, M; Navellou, JC; Foucrier, A; Allaouchiche, B; Das, V; Gangneux, JP; Ruckly, S; Wolff, M; Timsit, JF"	"Jullien, Vincent; Azoulay, Elie; Schwebel, Carole; Le Saux, Thomas; Charles, Pierre Emmanuel; Cornet, Muriel; Souweine, Bertrand; Klouche, Kadda; Jaber, Samir; Trouillet, Jean-Louis; Bruneel, Fabrice; Cour, Martin; Cousson, Joel; Meziani, Ferhat; Gruson, Didier; Paris, Adeline; Darmon, Michael; Garrouste-Orgeas, Maite; Navellou, Jean-Christophe; Foucrier, Arnaud; Allaouchiche, Bernard; Das, Vincent; Gangneux, Jean-Pierre; Ruckly, Stephane; Wolff, Michel; Timsit, Jean-Francois"	"EMPIRICUS Trial Study Grp"	"A"	"Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"CRITICALLY-ILL PATIENTS; INTENSIVE-CARE-UNIT; HEALTHY-VOLUNTEERS; ADULT PATIENTS; PLASMA; ECHINOCANDINS; PHARMACODYNAMICS; CASPOFUNGIN"	"Objectives: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC. 5000 for non-parapsilosis Candida sp. and >= 285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. Methods: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. Results: Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was <= 25 g/L and CL decreased by 25% when SOFA score was >= 10. Body weight was related to CL, Vc and Vp by allometric models. PTA was >= 90% in Candida albicans and Candida glabrata infections, except when the MIC was >= 0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC >= 0.5 mg/L. Conclusions: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs >= 0.015 mg/L."	"[Jullien, Vincent; Le Saux, Thomas] Paris Descartes Univ, Georges Pompidou Hosp, Pharmacol Dept, Paris, France; [Azoulay, Elie] St Louis Univ Hosp, Med ICU, Paris, France; [Schwebel, Carole] Albert Michallon Univ Hosp, Med ICU, Grenoble, France; [Charles, Pierre Emmanuel] Francois Mitterand Univ Hosp, Med ICU, Dijon, France; [Cornet, Muriel] Grenoble Alpes Univ, Parasitol Mycol, Grenoble Alpes Univ Hosp, UMR5525,CNRS, Grenoble, France; [Souweine, Bertrand] Gabriel Montpied Univ Hosp, Med ICU, Clermont Ferrand, France; [Klouche, Kadda] Lapeyronie Univ Hosp, Med ICU, Montpellier, France; [Jaber, Samir] St Eloi Univ Hosp, Department Crit Care Med & Anesthesiol DAR B, Montpellier, France; [Jaber, Samir] Univ Montpellier, INSERM, U1046, Montpellier Sch Med,CNRS UMR 9214, Montpellier, France; [Trouillet, Jean-Louis] Hop La Pitie Salpetriere, AP HP, Inst Cardiol, Med ICU, Paris, France; [Bruneel, Fabrice] Andre Mignot Hosp, Med ICU, Versailles, France; [Cour, Martin] Edouard Herriot Univ Hosp, Med ICU, Lyon, France; [Cousson, Joel] CHU Reims, Med Surg ICU, Reims, France; [Meziani, Ferhat] Hop Univ Strasbourg, Nouvel Hop Civil, Serv Reanimat Med, Strasbourg, France; [Gruson, Didier] Bordeaux Univ Hosp, Med ICU, Bordeaux, France; [Paris, Adeline] Grenoble Alpes Univ Hosp, Clin Res & Innovat Direct, F-38043 Grenoble, France; [Darmon, Michael] St Etienne Univ Hosp, Med ICU, St Priest En Jarez, France; [Garrouste-Orgeas, Maite] St Joseph Hosp Network, Med Surg ICU, Paris, France; [Navellou, Jean-Christophe] CHU Jean Minjoz, Surg ICU, Besancon, France; [Foucrier, Arnaud] CHU Beaujon, APHP, Surg ICU, Clichy, France; [Allaouchiche, Bernard] Hosp Civils Lyon, Hop Sud, Surg ICU, Lyon, France; [Das, Vincent] CH Montreuil, Polyvalent ICU, Montreuil, France; [Gangneux, Jean-Pierre] Rennes Univ Hosp, Mycol Lab, Rennes, France; [Ruckly, Stephane] ICUREsearch, Dept Biostat, Paris, France; [Wolff, Michel; Timsit, Jean-Francois] Paris Diderot Univ, INSERM, IAME UMR1137, Paris, France; [Wolff, Michel; Timsit, Jean-Francois] Bichat Claude Bernard Univ Hosp, Med & Infect Dis ICU, Paris, France"	"Jullien, V (corresponding author), Hop Europe Georges Pompidou, Serv Pharmacol, 20 Rue Leblanc, F-75015 Paris, France."	"vincent.jullien@aphp.fr"	"PICOT, Stephane/F-5973-2014; Grenouillet, Frederic/R-5176-2016; Fekkar, Arnaud/P-2803-2017; Gangneux, Jean-Pierre/J-2960-2015; LAB, Carmen/X-8895-2019; Sonneville, Romain/AAE-7039-2020; Cornet, Muriel/M-6563-2014; Carmen, Team3/Y-7384-2019; Misset, Benoit/P-7817-2018"	"PICOT, Stephane/0000-0002-5735-6759; Grenouillet, Frederic/0000-0001-6001-3135; Sonneville, Romain/0000-0003-0245-309X; Cornet, Muriel/0000-0003-4155-3675; Carmen, Team3/0000-0002-3614-0924; Paugam-Burtz, Catherine/0000-0002-8168-7152; Lab, Carmen/0000-0002-5935-3236; Helms, Julie/0000-0003-0895-6800; Misset, Benoit/0000-0001-6466-0065; Darmon, Michael/0000-0003-4198-8038; cour, martin/0000-0003-4909-9761"	"University of Grenoble 1/Albert Michallon university hospital; Astellas company"	"The study was sponsored by the University of Grenoble 1/Albert Michallon university hospital. A research grant was obtained from Astellas company."	26	23	23	0	11	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JAN"	2017	72	1	181	189	"NA"	"10.1093/jac/dkw352"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"EK6MM"	"WOS:000394038700023"	27609051	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Chan, P; Mould, DR; Abu Tarif, M; Reynolds, L; LaCreta, F; Bertz, R; Bifano, M"	"Chan, Phyllis; Mould, Diane R.; Abu Tarif, Malaz; Reynolds, Laurie; LaCreta, Frank; Bertz, Richard; Bifano, Marc"	"NA"	"A"	"Using Population Pharmacokinetic and Pharmacodynamic Analyses of Entecavir in Pediatric Subjects to Simplify Dosing Recommendations"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"CHRONIC HEPATITIS-B; GUIDELINES"	"Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children aeyen2 years old (USA and EU). To develop simplified entecavir dosing recommendations for young children infected with CHB. Data from recent clinical trials were used to develop a population pharmacokinetic (PPK) model, which allowed us to estimate entecavir exposures in children and compare them to ranges known to be efficacious in adults. A population pharmacodynamic (PPD) model was generated to describe the concentration/effect relationship for entecavir in lamivudine treatment-na < ve children. The PPK dataset comprised three pediatric cohorts: 2 to < 6 years (n = 36); 6 to < 12 years (n = 43); and 12 to < 18 years (n = 74). Data from 177 adults were also included to enhance model stability and to aid in the covariate search. Entecavir concentration-time profiles were well-described by a two-compartment model with first-order absorption and first-order elimination. Age was not a statistically significant covariate after accounting for weight. For the PPD model, the HBV DNA concentration following entecavir exposure was adequately described using a direct effect inhibitory maximum effect (E (max)) model with additive residual error. Model-estimated, steady-state entecavir area under the concentration-time curve, in both the original (15 weight groups) and simplified (eight weight groups) pediatric dosing regimens, provided entecavir exposures consistent with those observed to be efficacious in adults, and resulted in the simplified dose algorithm for pediatric patients that is approved for the current entecavir label."	"[Chan, Phyllis; Abu Tarif, Malaz; Reynolds, Laurie; LaCreta, Frank; Bertz, Richard; Bifano, Marc] Bristol Myers Squibb, Route 206 & Prov Line Rd, Lawrenceville, NJ 08648 USA; [Mould, Diane R.] Projections Res Inc, Phoenixville, PA USA"	"Chan, P (corresponding author), Bristol Myers Squibb, Route 206 & Prov Line Rd, Lawrenceville, NJ 08648 USA."	"phyllis.chan@bms.com"	"NA"	"NA"	"Bristol-Myers SquibbBristol-Myers Squibb"	"The studies described in this report were funded by Bristol-Myers Squibb. Editorial assistance (writing, formatting, proof-reading, figure preparation, collation of the author comments) was provided by professional medical writers from ArticulateScience, funded by Bristol-Myers Squibb."	15	1	1	0	7	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2016	55	12	1559	1572	"NA"	"10.1007/s40262-016-0420-5"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EC5IV"	"WOS:000388169000007"	27319000	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Caulet, M; Lecomte, T; Bouche, O; Rollin, J; Gouilleux-Gruart, V; Azzopardi, N; Leger, J; Borg, C; Douillard, JY; Manfredi, S; Smith, D; Capitain, O; Ferru, A; Moussata, D; Terrebone, E; Paintaud, G; Ternant, D"	"Caulet, Morgane; Lecomte, Thierry; Bouche, Olivier; Rollin, Jerome; Gouilleux-Gruart, Valerie; Azzopardi, Nicolas; Leger, Julie; Borg, Christophe; Douillard, Jean-Yves; Manfredi, Sylvain; Smith, Denis; Capitain, Olivier; Ferru, Aurelie; Moussata, Driffa; Terrebone, Eric; Paintaud, Gilles; Ternant, David"	"NA"	"A"	"Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"NEONATAL FC-RECEPTOR; POPULATION PHARMACOKINETICS; PHASE-II; RANDOMIZED-TRIAL; BREAST-CANCER; TUMOR BURDEN; RITUXIMAB; CHEMOTHERAPY; TRASTUZUMAB; EXPOSURE"	"Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes. Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models. The bevacizumab volume of distribution increased with height (p = 10(-10)) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p = 0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p = 0.00029, 0.011, and 0.014). A bevacizumab trough concentration aecurrency sign15.5 mg/L was associated with both shorter overall survival and PFS (hazard ratio [95 % CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively). High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals."	"[Caulet, Morgane; Lecomte, Thierry; Paintaud, Gilles; Ternant, David] Univ Tours, CNRS, GICC UMR 7292, Tours, France; [Caulet, Morgane; Lecomte, Thierry; Rollin, Jerome; Gouilleux-Gruart, Valerie; Azzopardi, Nicolas; Moussata, Driffa] CHRU Tours, Dept Gastroenterol, Tours, France; [Bouche, Olivier] CHU Reims, Dept Gastroenterol & Digest Oncol, Reims, France; [Rollin, Jerome] CHU Tours, Lab Haematol Haemostasis, Tours, France; [Gouilleux-Gruart, Valerie] CHU Tours, Immunol Lab, Tours, France; [Leger, Julie] CHU Tours, INSERM, CIC 1415, Tours, France; [Borg, Christophe] CHU Besancon, Dept Oncol, Besancon, France; [Douillard, Jean-Yves] Ctr Rene Gauducheau, Inst Cancerol, Nantes, France; [Manfredi, Sylvain] CHU Rennes, Dept Gastroenterol, Rennes, France; [Smith, Denis] CHU Bordeaux, Dept Oncol, Bordeaux, France; [Capitain, Olivier] ICO, Dept Med Oncol, Angers, France; [Ferru, Aurelie] CHU Poitiers, Dept Med Oncol, Poitiers, France; [Terrebone, Eric] CHU Bordeaux, Dept Gastroenterol, Bordeaux, France; [Paintaud, Gilles; Ternant, David] CHU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France"	"Ternant, D (corresponding author), Univ Tours, CNRS, GICC UMR 7292, Tours, France.; Ternant, D (corresponding author), CHU Tours, Lab Pharmacol Toxicol, 2 Blvd Tonnelle, F-37044 Tours, France."	"david.ternant@univ-tours.fr"	"Jerome, Rollin/K-2157-2019"	"PAINTAUD, Gilles/0000-0003-0158-1356"	"Institut National du Cancer (INCa)Institut National du Cancer (INCA) France; Societe Nationale Francaise de Gastro-Enterologie (SNFGE); Roche Laboratories; Canceropole Grand-Ouest; French Higher Education and Research ministry under the program Investissements d'avenirFrench National Research Agency (ANR) [LabEx MAbImprove ANR-10-LABX-53-01]"	"This study was funded by the Institut National du Cancer (INCa), the Societe Nationale Francaise de Gastro-Enterologie (SNFGE), Roche Laboratories, and Canceropole Grand-Ouest. Measurement of bevacizumab serum concentrations was carried out within the CePiBAc (Centre Pilote de suivi Biologique des traitements par Anticorps) platform. CePiBAc is supported by the French Higher Education and Research ministry under the program Investissements d'avenir Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01."	36	25	27	1	9	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NOV"	2016	55	11	1381	1394	"NA"	"10.1007/s40262-016-0406-3"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EA4LX"	"WOS:000386585300005"	27312193	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Cook, SF; Stockmann, C; Samiee-Zafarghandy, S; King, AD; Deutsch, N; Williams, EF; Wilkins, DG; Sherwin, CMT; van den Anker, JN"	"Cook, Sarah F.; Stockmann, Chris; Samiee-Zafarghandy, Samira; King, Amber D.; Deutsch, Nina; Williams, Elaine F.; Wilkins, Diana G.; Sherwin, Catherine M. T.; van den Anker, John N."	"NA"	"A"	"Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"INTRAVENOUS PARACETAMOL; INTERINDIVIDUAL VARIABILITY; PRETERM; INFANTS; HEPATOTOXICITY; EXCRETION; QUANTIFICATION; PROPACETAMOL; ELIMINATION; DISPOSITION"	"This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites. Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (< 28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (aeyen28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased < 15 % when plotted against weight or postnatal age. The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability."	"[Cook, Sarah F.; King, Amber D.; Wilkins, Diana G.] Univ Utah, Dept Pharmacol & Toxicol, Ctr Human Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA; [Stockmann, Chris; Sherwin, Catherine M. T.] Univ Utah, Div Clin Pharmacol, Dept Pediat, Sch Med, 295 Chipeta Way, Salt Lake City, UT 84108 USA; [Stockmann, Chris; Sherwin, Catherine M. T.] Univ Utah, Dept Pharmacol & Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA; [Samiee-Zafarghandy, Samira; Williams, Elaine F.; van den Anker, John N.] Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA; [Samiee-Zafarghandy, Samira] McMaster Univ, Div Neonatol, Dept Pediat, Hamilton, ON, Canada; [Deutsch, Nina] Childrens Natl Hlth Syst, Div Anesthesiol Sedat & Perioperat Med, Washington, DC USA; [Wilkins, Diana G.] Univ Utah, Sch Med, Dept Pathol, Div Med Lab Sci, Salt Lake City, UT USA; [Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Clin Trials Off, Salt Lake City, UT 84108 USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Physiol & Pharmacol, Washington, DC 20052 USA; [van den Anker, John N.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Intens Care, Rotterdam, Netherlands; [van den Anker, John N.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, John N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol, Basel, Switzerland"	"Sherwin, CMT (corresponding author), Univ Utah, Div Clin Pharmacol, Dept Pediat, Sch Med, 295 Chipeta Way, Salt Lake City, UT 84108 USA.; Sherwin, CMT (corresponding author), Univ Utah, Dept Pharmacol & Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA.; Sherwin, CMT (corresponding author), Univ Utah, Sch Med, Dept Pediat, Clin Trials Off, Salt Lake City, UT 84108 USA."	"catherine.sherwin@hsc.utah.edu"	"Cook, Sarah/P-8387-2019; Cook, Sarah F/O-3532-2018; Williams, Elaine/AAD-2284-2019; Sherwin, Catherine Mary Turner/B-2888-2012; Samiee-Zafarghandy, Samira/AAU-4010-2020"	"Cook, Sarah/0000-0001-8612-882X; Williams, Elaine/0000-0003-0655-1535; Sherwin, Catherine Mary Turner/0000-0002-0844-3207; Deutsch, Nina/0000-0001-7137-4737"	"National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD060543]; National Center for Advancing Translational SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000075]; McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA); Howard Hughes Medical Institute (Med into Grad Initiative)Howard Hughes Medical Institute; American Foundation for Pharmaceutical Education"	"This work was supported by the National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060543; to John van den Anker) and the National Center for Advancing Translational Sciences (UL1TR000075; to Children's National Health System) and by a contract for analytical laboratory services from McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA; to Diana Wilkins). Sarah Cook received stipend support from the Howard Hughes Medical Institute (Med into Grad Initiative). Sarah Cook and Chris Stockmann were supported by pre-doctoral fellowships from the American Foundation for Pharmaceutical Education."	51	17	19	0	8	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NOV"	2016	55	11	1395	1411	"NA"	"10.1007/s40262-016-0408-1"	17	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EA4LX"	"WOS:000386585300006"	27209292	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Cook, SF; Roberts, JK; Samiee-Zafarghandy, S; Stockmann, C; King, AD; Deutsch, N; Williams, EF; Allegaert, K; Wilkins, DG; Sherwin, CMT; van den Anker, JN"	"Cook, Sarah F.; Roberts, Jessica K.; Samiee-Zafarghandy, Samira; Stockmann, Chris; King, Amber D.; Deutsch, Nina; Williams, Elaine F.; Allegaert, Karel; Wilkins, Diana G.; Sherwin, Catherine M. T.; van den Anker, John N."	"NA"	"A"	"Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"BODY-SIZE; INFANTS; PAIN; GLUCURONIDATION; PROPACETAMOL; PHARMACOLOGY; DISPOSITION; SIMULATION; CLEARANCE; CHILDREN"	"Objectives The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset. Methods Nonlinear mixed-effects models were constructed from paracetamol concentration-time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors. Results The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were welldescribed by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1-14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1-28.1). Conclusions Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations."	"[Cook, Sarah F.; King, Amber D.; Wilkins, Diana G.] Univ Utah, Dept Pharmacol & Toxicol, Ctr Human Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA; [Roberts, Jessica K.; Stockmann, Chris; Sherwin, Catherine M. T.] Univ Utah, Sch Med, Div Clin Pharmacol, Dept Pediat, 295 Chipeta Way, Salt Lake City, UT 84108 USA; [Samiee-Zafarghandy, Samira; Williams, Elaine F.; van den Anker, John N.] Childrens Natl Hlth Syst, Div Clin Pharmacol, Washington, DC USA; [Samiee-Zafarghandy, Samira] McMaster Univ, Dept Pediat, Div Neonatol, Hamilton, ON, Canada; [Stockmann, Chris] Univ Utah, Dept Pharmacol & Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA; [Deutsch, Nina] Childrens Natl Hlth Syst, Div Anesthesiol Sedat & Perioperat Med, Washington, DC USA; [Allegaert, Karel] Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium; [Allegaert, Karel] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Wilkins, Diana G.] Univ Utah, Sch Med, Dept Pathol, Div Med Lab Sci, Salt Lake City, UT USA; [van den Anker, John N.] George Washington Univ, Dept Pediat, Sch Med & Hlth Sci, Washington, DC 20052 USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Pharmacol, Washington, DC 20052 USA; [van den Anker, John N.] George Washington Univ, Sch Med & Hlth Sci, Dept Physiol, Washington, DC 20052 USA; [van den Anker, John N.] Sophia Childrens Univ Hosp, Erasmus Med Center, Intens Care & Dept Pediat Surg, Rotterdam, Netherlands; [van den Anker, John N.] Univ Childrens Hosp Basel, Dept Paediat Pharmacol, Basel, Switzerland"	"Sherwin, CMT (corresponding author), Univ Utah, Sch Med, Div Clin Pharmacol, Dept Pediat, 295 Chipeta Way, Salt Lake City, UT 84108 USA."	"catherine.sherwin@hsc.utah.edu"	"Roberts, Jessica Krystle/H-9785-2019; Cook, Sarah/P-8387-2019; Williams, Elaine/AAD-2284-2019; Samiee-Zafarghandy, Samira/AAU-4010-2020; Cook, Sarah F/O-3532-2018; Sherwin, Catherine Mary Turner/B-2888-2012; allegaert, karel/C-3611-2016"	"Cook, Sarah/0000-0001-8612-882X; Williams, Elaine/0000-0003-0655-1535; Sherwin, Catherine Mary Turner/0000-0002-0844-3207; allegaert, karel/0000-0001-9921-5105; Deutsch, Nina/0000-0001-7137-4737"	"National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD060543]; National Center for Advancing Translational SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000075]; Fundamental Clinical Investigatorship from the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium) [1800214N]; Howard Hughes Medical Institute (Med into Grad Initiative)Howard Hughes Medical Institute; American Foundation for Pharmaceutical Education; Primary Children's Hospital Foundation (Salt Lake City, UT, USA)"	"This work was supported by National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060543, to John N. van den Anker) and the National Center for Advancing Translational Sciences (UL1TR000075, to the Children's National Health System), and by a contract for analytical laboratory services from McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA, to Diana G. Wilkins). Karel Allegaert was supported by a Fundamental Clinical Investigatorship (1800214N) from the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium). Sarah F. Cook received stipend support from the Howard Hughes Medical Institute (Med into Grad Initiative); Sarah F. Cook and Chris Stockmann were supported by pre-doctoral fellowships from the American Foundation for Pharmaceutical Education; and Jessica K. Roberts was supported by a Pharmacotherapy Subspecialty Award from the Primary Children's Hospital Foundation (Salt Lake City, UT, USA)."	47	24	24	0	12	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JAN"	2016	55	1	107	119	"NA"	"10.1007/s40262-015-0301-3"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DE1IK"	"WOS:000370380300007"	26201306	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Stockmann, C; Hersh, AL; Roberts, JK; Bhongsatiern, J; Korgenski, EK; Spigarelli, MG; Sherwin, CMT; Frymoyer, A"	"Stockmann, Chris; Hersh, Adam L.; Roberts, Jessica K.; Bhongsatiern, Jiraganya; Korgenski, Ernest K.; Spigarelli, Michael G.; Sherwin, Catherine M. T.; Frymoyer, Adam"	"NA"	"A"	"Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates"	"INFECTIOUS DISEASES AND THERAPY"	"English"	"Article"	"Infectious diseases; MRSA; Neonates; Pharmacokinetics; Staphylococcus aureus; Vancomycin"	"NA"	"Introduction: The pharmacokinetics of vancomycin are highly variable among neonates, which makes dosing challenging in this population. However, adequate drug exposure is critical, especially when treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Utilization of population pharmacokinetic models and Bayesian methods offers the potential for developing individualized therapeutic approaches. To meet this need, a neonatal vancomycin population pharmacokinetic model was recently published. The current study sought to externally evaluate the predictive performance and generalizability of this model. Methods: A retrospective chart review of neonates who received vancomycin and had >= 1 peak and >= 1 trough concentrations at five Intermountain Healthcare neonatal intensive care units from 2006 to 2013 was performed and served as the external validation cohort. The published population pharmacokinetic model was implemented in NONMEM 7.2 with the structural and variance parameter values set equal to the estimates reported previously. The model was then used to predict the first peak and trough concentration for each neonate in the validation cohort and the model prediction error and absolute prediction error were calculated. Normalized prediction distribution errors (NPDE) were also evaluated. Results: A total of 243 neonates were studied with a median postmenstrual age of 33 (range: 23-54) weeks and a median weight of 1.6 (range: 0.4-6.8) kg. The model predicted the observed vancomycin concentrations with reasonable precision. For all vancomycin concentrations, the median prediction error was -0.8 (95% CI: -1.4 to -0.4) mg/L and the median absolute prediction error was 3.0 (95% CI: 2.7-3.5) mg/L. No trends in NPDE across weight, postmenstrual age, serum creatinine, or time after dose were observed. Conclusion: An evaluation of a recently published neonatal vancomycin population pharmacokinetic model in a large external dataset supported the predictive performance and generalizability of the model. This model may be useful in evaluating neonatal vancomycin dosing regimens and estimating the extent of drug exposure."	"[Stockmann, Chris; Roberts, Jessica K.; Spigarelli, Michael G.; Sherwin, Catherine M. T.] Univ Utah, Sch Med, Dept Pediat, Div Clin Pharmacol, Salt Lake City, UT USA; [Stockmann, Chris; Hersh, Adam L.] Univ Utah, Sch Med, Dept Pediat, Div Pediat Infect Dis, Salt Lake City, UT 84112 USA; [Bhongsatiern, Jiraganya] Univ Cincinnati, James L Winkle Coll Pharm, Cincinnati, OH USA; [Korgenski, Ernest K.] Intermt Healthcare, Pediat Clin Program, Salt Lake City, UT USA; [Frymoyer, Adam] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA"	"Stockmann, C (corresponding author), Univ Utah, Sch Med, Dept Pediat, Div Pediat Infect Dis, Salt Lake City, UT 84112 USA."	"Chris.Stockmann@hsc.utah.edu"	"Roberts, Jessica Krystle/H-9785-2019; Sherwin, Catherine Mary Turner/B-2888-2012"	"Sherwin, Catherine Mary Turner/0000-0002-0844-3207"	"American Foundation for Pharmaceutical Education; Primary Children's Hospital Foundation; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA"	"The authors received financial support from the American Foundation for Pharmaceutical Education, Primary Children's Hospital Foundation, and the National Institutes of Health, which supported their effort spent conducting this study as noted in the conflict of interest section. No funding or sponsorship was received for the publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICJME) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published."	21	22	24	0	1	"SPRINGER LONDON LTD"	"LONDON"	"236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND"	"2193-8229"	"2193-6382"	"NA"	"INFECT DIS THER"	"Infect. Dis. Ther."	"JUN"	2015	4	2	187	198	"NA"	"10.1007/s40121-015-0067-9"	12	"Infectious Diseases"	"Infectious Diseases"	"V26VV"	"WOS:000215320600004"	25998107	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"du Rieu, QC; Fouliard, S; Jacquet-Bescond, A; Robert, R; Kloos, I; Depil, S; Chatelut, E; Chenel, M"	"du Rieu, Quentin Chalret; Fouliard, Sylvain; Jacquet-Bescond, Anne; Robert, Renata; Kloos, Ioana; Depil, Stephane; Chatelut, Etienne; Chenel, Marylore"	"NA"	"A"	"Application of Hematological Toxicity Modeling in Clinical Development of Abexinostat (S-78454, PCI-24781), A New Histone Deacetylase Inhibitor"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"abexinostat; NONMEM; population PK/PD; simulations; thrombocytopenia"	"CANCER; CHEMOTHERAPY; TRIALS; DRUGS; PHARMACOKINETICS; THROMBOCYTOPENIA; CARBOPLATIN; THERAPIES; ONCOLOGY"	"A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the thrombocytopenia (dose-limiting toxicity) of abexinostat, a new histone deacetylase inhibitor. An optimal administration schedule of the drug was determined using a simulation-based approach. Early PK and PK/PD data were analysed using a sequential population modeling approach (NONMEM 7), allowing for the description of a PK profile and platelet-count decrease after abexinostat administration with various administration schedules. Simulations of platelet count with several administration schedules over 3-week treatment cycles (ASC) and over a day (ASD) were computed to define the optimal schedule that limits the depth of thrombocytopenia. An intermediate PK/PD model accurately described the data. The administration of abexinostat during the first 4 days of each week in a 3-week cycle resulted in fewer adverse events (with no influence of ASD on platelet count profiles), and corresponded to the optimal treatment schedule. This administration schedule was clinically evaluated in a phase I clinical trial and allowed for the definition of a new maximum tolerated dose (MTD), leading to a nearly 30% higher dose-intensity than that of another previously tested schedule. Lastly, a final model was built using all of the available data. The final model, characterizing the dose-effect and the dose-toxicity relationships, provides a useful modeling tool for clinical drug development."	"[du Rieu, Quentin Chalret; Fouliard, Sylvain; Chenel, Marylore] Inst Rech Int Servier, Clin Pharmacokinet Dept, F-92284 Suresnes, France; [du Rieu, Quentin Chalret; Chatelut, Etienne] Univ Toulouse 3, EA4553, F-31062 Toulouse, France; [du Rieu, Quentin Chalret; Chatelut, Etienne] Inst Claudius Regaud, Toulouse, France; [Jacquet-Bescond, Anne; Robert, Renata; Kloos, Ioana; Depil, Stephane] Inst Rech Int Servier, Oncol Business Unit, Suresnes, France"	"Chenel, M (corresponding author), Inst Rech Int Servier, Clin Pharmacokinet Dept, 50 Rue Carnot, F-92284 Suresnes, France."	"marylore.chenel@fr.netgrs.com"	", Chatelut/I-7916-2014"	", Chatelut/0000-0002-7740-9096"	"Institut de Recherches Internationales ServierServier"	"This work was incorporated into a Ph. D. project (Quentin Chalret du Rieu), granted by Institut de Recherches Internationales Servier."	31	8	8	0	5	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"NA"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"OCT"	2013	30	10	2640	2653	"NA"	"10.1007/s11095-013-1089-1"	14	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"213RC"	"WOS:000324074800018"	23737346	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Delavenne, X; Ollier, E; Basset, T; Bertoletti, L; Accassat, S; Garcin, A; Laporte, S; Zufferey, P; Mismetti, P"	"Delavenne, Xavier; Ollier, Edouard; Basset, Thierry; Bertoletti, Laurent; Accassat, Sandrine; Garcin, Arnauld; Laporte, Silvy; Zufferey, Paul; Mismetti, Patrick"	"NA"	"A"	"A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"bioavailability; clarithromycin; dabigatran; drug-drug interaction; P-glycoprotein inhibition; population pharmacokinetics and pharmacodynamics"	"DIRECT THROMBIN INHIBITOR; POPULATION PHARMACOKINETIC ANALYSIS; TOTAL HIP; ETEXILATE; REPLACEMENT; TIME"	"Aim The aim of this study was to develop a PK/PD model to assess drug-drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp. Methods Ten healthy male volunteers were randomized to receive in the first treatment period a single 300mg dose of dabigatran etexilate (DE) and in the second treatment period 500mg clarithromycin twice daily during 3 days and then 300mg DE plus 500mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach. Results The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively. Conclusion The model proposed effectively describes the complex PK of dabigatran and takes into account drug-drug interactions with P-gp activity modulators, such as clarithromycin."	"[Delavenne, Xavier; Ollier, Edouard; Basset, Thierry] CHU St Etienne, Lab Pharmacol Toxicol, F-42055 St Etienne, France; [Delavenne, Xavier; Ollier, Edouard; Basset, Thierry; Bertoletti, Laurent; Laporte, Silvy; Zufferey, Paul; Mismetti, Patrick] Univ Lyon, F-42023 St Etienne, France; [Delavenne, Xavier; Basset, Thierry; Bertoletti, Laurent; Laporte, Silvy; Zufferey, Paul; Mismetti, Patrick] Univ St Etienne, EA3065, Grp Rech Thrombose, F-42023 St Etienne, France; [Bertoletti, Laurent; Accassat, Sandrine; Mismetti, Patrick] CHU St Etienne, Serv Med Therapeut, F-42055 St Etienne, France; [Garcin, Arnauld; Zufferey, Paul] CHU St Etienne, Dept Anesthesie Reanimat, F-42055 St Etienne, France; [Laporte, Silvy; Mismetti, Patrick] CHU St Etienne, Unite Rech Clin Innovat & Pharmacol, F-42055 St Etienne, France"	"Delavenne, X (corresponding author), Univ Hosp St Etienne, Lab Pharmacol & Toxicol, EA3065, F-42055 St Etienne, France."	"xavier.delavenne@chu-st-etienne.fr"	"Bertoletti, Laurent/X-1319-2019"	"Bertoletti, Laurent/0000-0001-8214-3010; Delavenne, Xavier/0000-0001-7134-0713"	"University Hospital of Saint-Etienne"	"This research has received funding support from the University Hospital of Saint-Etienne, and was promoted by the University Hospital of Saint-Etienne."	19	46	47	0	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUL"	2013	76	1	107	113	"NA"	"10.1111/bcp.12055"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"167ZU"	"WOS:000320674900011"	23210726	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Verstuyft, C; Delavenne, X; Rousseau, A; Robert, A; Tod, M; Diquet, B; Lebot, M; Jaillon, P; Becquemont, L"	"Verstuyft, Celine; Delavenne, Xavier; Rousseau, Alexandra; Robert, Annie; Tod, Michel; Diquet, Bertrand; Lebot, Martine; Jaillon, Patrice; Becquemont, Laurent"	"NA"	"A"	"A Pharmacokinetic-Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During Induction Therapy"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"ORAL ANTICOAGULANT; CYTOCHROME P4502C9; PATIENT CHARACTERISTICS; GENETIC-POLYMORPHISM; DOSE REQUIREMENTS; WARFARIN; PHARMACOGENETICS; VARIABILITY; PHENPROCOUMON; DETERMINANTS"	"Background and Objective: Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. Methods: Fluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. Results: A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic pharmacodynamic model of fluindione. Because some previous studies have shown a dose response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. Conclusion: During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors."	"[Verstuyft, Celine] Univ Paris Sud, CHU Bicetre, EA 4123, Serv Genet Mol Pharmacogenet & Hormonol, F-94275 Le Kremlin Bicetre, France; [Verstuyft, Celine; Becquemont, Laurent] Hop Bicetre, AP HP, Serv Genet Mol Pharmacogenet & Hormonol, Le Kremlin Bicetre, France; [Delavenne, Xavier] Univ St Etienne, EA3065, Grp Rech Thrombose, St Etienne, France; [Rousseau, Alexandra] Hop St Antoine, AP HP, Unite Rech Clin Paris Est, F-75571 Paris, France; [Robert, Annie] Hop St Antoine, AP HP, Lab Hematol Immunol, F-75571 Paris, France; [Tod, Michel] Hosp Civils Lyon, Hop Croix Rousse, Lyon, France; [Diquet, Bertrand] Ctr Hosp Univ Angers, Serv Pharmacol & Toxicol, Angers, France; [Lebot, Martine] Hop St Antoine, AP HP, Ctr Invest Clin, F-75571 Paris, France; [Jaillon, Patrice] Univ Paris 06, Dept Pharmacol, Fac Med Pierre & Marie Curie, Paris, France; [Becquemont, Laurent] Hop Bicetre, AP HP, Unite Rech Clin Paris Sud, Paris, France"	"Verstuyft, C (corresponding author), Univ Paris Sud, CHU Bicetre, EA 4123, Serv Genet Mol Pharmacogenet & Hormonol, 78 Rue Gen Leclerc, F-94275 Le Kremlin Bicetre, France."	"celine.verstuyft@bct.aphp.fr"	"NA"	"Delavenne, Xavier/0000-0001-7134-0713"	"Assistance Publique-Hopitaux de Paris (AP-HP) Programme Hospitalier de Recherche Clinique (PHRC) National [AOR03061-P030410]; Institut National de la Sante et de la Recherche Medicale (INSERM)Institut National de la Sante et de la Recherche Medicale (Inserm); AP-HP at the Centre d'Investigation Clinique (CIC), Hopital Saint Antoine (Paris, France); Sanofi-AventisSanofi-Aventis; PfizerPfizer; ServierServier; GenzymeGenzyme Corporation; GlaxoSmithKlineGlaxoSmithKline; Bristol-Myers SquibbBristol-Myers Squibb; WyethWyeth; Merck Sharp and DohmeMerck & Company"	"This work was funded and promoted by the Assistance Publique-Hopitaux de Paris (AP-HP) Programme Hospitalier de Recherche Clinique (PHRC) National 2003 (grant no. AOR03061-P030410). The study was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM) and AP-HP at the Centre d'Investigation Clinique (CIC), Hopital Saint Antoine (Paris, France).; Laurent Becquemont received consulting fees from Sanofi-Aventis, Pfizer and Servier, and lecture fees from Genzyme, GlaxoSmithKline, Bristol-Myers Squibb, Wyeth, and Merck Sharp and Dohme. His wife works for Sanofi-Aventis. None of the other authors have any potential conflicts of interest to declare that are directly relevant to the content of this study."	52	20	20	1	7	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2012	51	1	41	53	"NA"	"10.2165/11595560-000000000-00000"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"874RH"	"WOS:000298975300004"	22149257	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Rezai, K; Urien, S; Isambert, N; Roche, H; Dieras, V; Berille, J; Bonneterre, J; Brain, E; Lokiec, F"	"Rezai, Keyvan; Urien, S.; Isambert, N.; Roche, H.; Dieras, V.; Berille, J.; Bonneterre, J.; Brain, E.; Lokiec, F."	"NA"	"A"	"Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Vinorelbine; Lapatinib; Drug-interactions; Population pharmacokinetics; Anti-cancer agents"	"PLASMA; BLOOD"	"The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. Women with HER2  locally advanced or metastatic breast cancer progressing after a parts per thousand currency sign2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib  vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s). A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib. The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8."	"[Rezai, Keyvan; Urien, S.; Brain, E.; Lokiec, F.] Inst Curie Hop Rene Huguenin, St Cloud, France; [Urien, S.] Univ Paris 05, EA 3620, Paris, France; [Isambert, N.] Ctr Georges Francois Leclerc, Dijon, France; [Isambert, N.] Ctr Invest Clin Plurithemat, INSERM, Unite U803, Dijon, France; [Roche, H.] Inst Claudius Regaud, Toulouse, France; [Dieras, V.] Inst Curie, Paris, France; [Berille, J.] Federat Natl Ctr Lutte Canc, Paris, France; [Bonneterre, J.] Ctr Oscar Lambret, F-59020 Lille, France"	"Rezai, K (corresponding author), Inst Curie Hop Rene Huguenin, St Cloud, France."	"keyvan.rezai@curie.net"	"Roche, Henri/O-9211-2014; Urien, Saik/G-3240-2013"	"Roche, Henri/0000-0001-7463-205X; REZAI, Keyvan/0000-0002-3328-3102"	"Federation des Centres de Lutte Contre le Cancer (Groupe d'Etudes Precoces); GSK laboratories"	"We acknowledge Federation des Centres de Lutte Contre le Cancer (Groupe d'Etudes Precoces) for their support and contribution into management of this study. We would also like to acknowledge GSK laboratories for their support. We wish to thank Bernard Asselain, Biostatistics Department of Institut Curie for his help."	17	16	16	0	9	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"NA"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"DEC"	2011	68	6	1529	1536	"NA"	"10.1007/s00280-011-1650-8"	8	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"852GJ"	"WOS:000297344300018"	21519841	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Michelet, R; Melin, J; Parra-Guillen, ZP; Neumann, U; Whitaker, JM; Stachanow, V; Huisinga, W; Porter, J; Blankenstein, O; Ross, RJ; Kloft, C"	"Michelet, Robin; Melin, Johanna; Parra-Guillen, Zinnia P.; Neumann, Uta; Whitaker, J. Martin; Stachanow, Viktoria; Huisinga, Wilhelm; Porter, John; Blankenstein, Oliver; Ross, Richard J.; Kloft, Charlotte"	"NA"	"A"	"Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children"	"EUROPEAN JOURNAL OF ENDOCRINOLOGY"	"English"	"Article"	"NA"	"CONGENITAL ADRENAL-HYPERPLASIA; ORAL HYDROCORTISONE; 21-HYDROXYLASE DEFICIENCY; INFANTS; CORTISOL; GRANULES; COHORT; ADULTS; BIOAVAILABILITY; BIOEQUIVALENT"	"Context: Accurate hydrocortisone dosing in children with adrenal insufficiency is important to avoid the risks of over and under treatment including iatrogenic Cushing's syndrome and adrenal crisis. Objective: To establish a population pharmacokinetic model of hydrocortisone in children and use this to refine hydrocortisone replacement regimens. Design and methods: Pharmacokinetic study of hydrocortisone granules, available in 0.5, 1, 2 and 5 mg dose strengths, in 24 children with adrenal insufficiency aged 2 weeks to 6 years. Cortisol concentrations quantified by LC-MS/MS were used to refine an adult pharmacokinetic model to a paediatric population model which was then used to simulate seven different hydrocortisone treatment regimens. Results: Pre-dose cortisol levels were undetectable in 54% of the 24 children. The developed pharmacokinetic model had good predictive performance. Simulations for the seven treatment regimens using either three- or four-times daily dosing showed treatment regimens delivered an AUC(0-24h) within the 90% reference range for healthy children except in neonates where two regimens had an AUC below the 5th percentile. Cortisol concentrations at individual time points in the 24 h were outside the 90% reference range for healthy individuals in 50%, 55-65% and 70-75% for children, infants and neonates, respectively, with low cortisol levels being most prevalent. Conclusions: Current paediatric hydrocortisone treatment regimens based on either three- or four-times daily administration replicate cortisol exposure based on AUC(0-24h), but the majority of cortisol levels are above or below physiological cortisol levels with low levels very common before the next dose."	"[Michelet, Robin; Melin, Johanna; Parra-Guillen, Zinnia P.; Stachanow, Viktoria; Kloft, Charlotte] Free Univ Berlin, Inst Pharm, Dept Clin Pharm & Biochem, Berlin, Germany; [Melin, Johanna; Stachanow, Viktoria] PharMetrX, Grad Res Training Program, Berlin, Germany; [Parra-Guillen, Zinnia P.] Univ Navarra, Pharmacometr & Syst Pharmacol, Pamplona, Spain; [Neumann, Uta; Blankenstein, Oliver] Charite, Berlin, Germany; [Whitaker, J. Martin; Porter, John] Diurnai Ltd, Cardiff, Wales; [Huisinga, Wilhelm] Univ Potsdam, Inst Math, Potsdam, Germany; [Ross, Richard J.] Univ Sheffield, Sheffield, S Yorkshire, England"	"Kloft, C (corresponding author), Free Univ Berlin, Inst Pharm, Dept Clin Pharm & Biochem, Berlin, Germany."	"charlotte.kloft@fu-berlin.de"	"Michelet, Robin/AAM-7991-2020; Parra Guillen, Zinnia P/L-2862-2017"	"Michelet, Robin/0000-0002-5485-607X; Reis, AlessanRSS/0000-0001-8486-7469; Parra Guillen, Zinnia P/0000-0003-1503-2710"	"Freie Universitaet [281654]; European Commission FP7 Grant [281654]"	"The work was carried out under a Cooperation Agreement between Freie Universitaet and Diurnal funded by the European Commission FP7 Grant (No. 281654 TAIN)."	50	0	0	0	0	"BIOSCIENTIFICA LTD"	"BRISTOL"	"STARLING HOUSE, 1600 BRISTOL PARKWAY N, BRISTOL, ENGLAND"	"0804-4643"	"1479-683X"	"NA"	"EUR J ENDOCRINOL"	"Eur. J. Endocrinol."	"OCT"	2020	183	4	357	368	"NA"	"10.1530/EJE-20-0231"	12	"Endocrinology & Metabolism"	"Endocrinology & Metabolism"	"NI7QK"	"WOS:000565543400009"	32621587	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Liu, S; Huang, H; Chen, RX; Wang, Z; Guan, YP; Peng, C; Fang, XJ; Chen, ZJ; Guan, SX; Zhu, X; Ren, QG; Yao, YY; Huang, HB; Huang, M; Wang, XD; Lin, TY"	"Liu, Shu; Huang, He; Chen, Rong-xin; Wang, Zhao; Guan, Yan-ping; Peng, Chen; Fang, Xiao-jie; Chen, Zhuo-jia; Guan, Shao-xing; Zhu, Xia; Ren, Quan-guang; Yao, Yu-yi; Huang, Hong-bing; Huang, Min; Wang, Xue-ding; Lin, Tong-yu"	"NA"	"A"	"Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2"	"ACTA PHARMACOLOGICA SINICA"	"English"	"Article; Early Access"	"follicular lymphoma; rituximab; R-CHOP; tumor grade; pharmacokinetics; trough concentration"	"POPULATION PHARMACOKINETICS; MODEL; MULTICENTER; CORRELATE; INDOLENT; JAPANESE; TRIAL; 3B"	"For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix(R)NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimalC(1-trough)was 13.60 mu g/mL. Patients with grade 1/2 had significantly lowerC(1-trough)compared with grade 3 (12.21 mu g/mL vs. 23.45 mu g/mL,P < 0.001), only 30% patients with grade 1/2 could reach 13.60 mu g/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor forC(1-trough), accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, lowC(1-trough)accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL."	"[Liu, Shu; Guan, Shao-xing; Zhu, Xia; Huang, Min; Wang, Xue-ding] Sun Yat Sen Univ, Sch Pharmaceut Sci, Inst Clin Pharmacol, Guangzhou 510006, Peoples R China; [Liu, Shu; Huang, He; Wang, Zhao; Fang, Xiao-jie; Chen, Zhuo-jia; Ren, Quan-guang; Yao, Yu-yi; Huang, Hong-bing; Lin, Tong-yu] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr, Guangzhou 510060, Peoples R China; [Chen, Rong-xin] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510006, Peoples R China; [Guan, Yan-ping] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Pharm, Guangzhou 510120, Peoples R China; [Peng, Chen] Univ Hong Kong, Med Dept, Shen Zhen Hosp, Hong Kong, Peoples R China"	"Wang, XD (corresponding author), Sun Yat Sen Univ, Sch Pharmaceut Sci, Inst Clin Pharmacol, Guangzhou 510006, Peoples R China.; Lin, TY (corresponding author), Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr, Guangzhou 510060, Peoples R China."	"wangxd@mail.sysu.edu.cn; tongyu_lin@163.com"	"NA"	"NA"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81730103, 81473283, 81973398, 81573507]; Higher Education Discipline Innovation Project (the 111 Project) [B16047]; Natural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of Guangdong Province [2019A1515010742]; Wu Jie-ping Foundation of Clinical Pharmacy [320.6750.19090-14]"	"This work was supported by the National Natural Science Foundation of China (No. 81730103, 81473283, 81973398, 81573507); Higher Education Discipline Innovation Project (the 111 Project, No. B16047); the Natural Science Foundation of Guangdong Province (No. 2019A1515010742); and Wu Jie-ping Foundation of Clinical Pharmacy (No. 320.6750.19090-14)."	28	0	0	2	2	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1671-4083"	"1745-7254"	"NA"	"ACTA PHARMACOL SIN"	"Acta Pharmacol. Sin."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1038/s41401-020-0479-2"	7	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"MS5RG"	"WOS:000554332300003"	32737470	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Eloy, G; Lebeaux, D; Launay, M; Fernandez-Gerlinger, MP; Billaud, E; Douez, E; Mainardi, JL; Bouyer, B; Jullien, V"	"Eloy, Gauthier; Lebeaux, David; Launay, Manon; Fernandez-Gerlinger, Marie-Paule; Billaud, Eliane; Douez, Emmanuel; Mainardi, Jean-Luc; Bouyer, Benjamin; Jullien, Vincent"	"NA"	"A"	"Influence of Renal Function and Age on the Pharmacokinetics of Levofloxacin in Patients with Bone and Joint Infections"	"ANTIBIOTICS-BASEL"	"English"	"Article"	"levofloxacin; bone and joint infection; pharmacokinetics; glomerular filtration rate"	"POPULATION PHARMACOKINETICS; PENETRATION; PHARMACODYNAMICS; DOSAGE; PREDICTION; CLEARANCE; THERAPY; DISEASE; MODEL; FLUID"	"Despite its efficacy and toxicity being exposure-related, levofloxacin pharmacokinetics in patients with bone and joint infections has been poorly described to date, so the possible need for a dose adjustment is unknown in this population. A prospective population pharmacokinetic study was conducted in 59 patients to answer this question. The final model consisted of a one-compartment model with first-order absorption and elimination. Mean parameter estimates (% interindividual variability) were 0.895 h(-1)for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent clearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration rate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by power models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar GFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to 30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/ minimum inhibitory concentration (MIC) >= 100), with the possible exception of patients older than 60 years and with GFR <70 mL/min/m(2) who may necessitate a dose reduction, and patients with infections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose."	"[Eloy, Gauthier; Bouyer, Benjamin] Hop Europeen Georges Pompidou, AP HP, Serv Orthopedie & Traumatol, F-75015 Paris, France; [Lebeaux, David; Fernandez-Gerlinger, Marie-Paule; Mainardi, Jean-Luc] Hop Europeen Georges Pompidou, AP HP, Unite Mobile Microbiol Clin, Serv Microbiol, F-75015 Paris, France; [Lebeaux, David; Launay, Manon; Fernandez-Gerlinger, Marie-Paule; Billaud, Eliane; Mainardi, Jean-Luc] Univ Paris 05, Fac Med, F-75015 Paris, France; [Launay, Manon; Billaud, Eliane; Douez, Emmanuel] Hop Europeen Georges Pompidou, AP HP, Serv Pharmacol, F-75015 Paris, France; [Jullien, Vincent] Univ Paris 13, Unite Fonct Pharmacol, UFR SMBH, Grp Hosp Paris Seine St Denis, F-93000 Bobigny, France"	"Jullien, V (corresponding author), Univ Paris 13, Unite Fonct Pharmacol, UFR SMBH, Grp Hosp Paris Seine St Denis, F-93000 Bobigny, France."	"gauthier.eloy@aphp.fr; david.lebeaux@aphp.fr; Manon.Launay@chu-st-etienne.fr; marie-paule.gerlinger@aphp.fr; eliane.billaud@aphp.fr; edouez01@gmail.com; jean-luc.mainardi@aphp.fr; benjamin.bouyer@aphp.fr; vincent.jullien@aphp.fr"	"NA"	"Fernandez-Gerlinger, Marie-Paule/0000-0002-8475-6192; Eloy, Gauthier/0000-0002-2450-3951; Launay, Manon/0000-0003-3113-7301"	"NA"	"NA"	40	0	0	0	0	"MDPI"	"BASEL"	"ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND"	"2079-6382"	"NA"	"NA"	"ANTIBIOTICS-BASEL"	"Antibiotics-Basel"	"JUL"	2020	9	7	"NA"	"NA"	401	"10.3390/antibiotics9070401"	12	"Infectious Diseases; Pharmacology & Pharmacy"	"Infectious Diseases; Pharmacology & Pharmacy"	"MS2NM"	"WOS:000554119700001"	32664317	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Foissac, F; Zheng, Y; Hirt, D; Lui, G; Bouazza, N; Ville, Y; Goffinet, F; Rozenberg, P; Kayem, G; Mandelbrot, L; Benaboud, S; Jarreau, PH; Treluyer, JM"	"Foissac, Frantz; Zheng, Yi; Hirt, Deborah; Lui, Gabrielle; Bouazza, Nam; Ville, Yves; Goffinet, Francois; Rozenberg, Patrick; Kayem, Gilles; Mandelbrot, Laurent; Benaboud, Sihem; Jarreau, Pierre-Henri; Treluyer, Jean-Marc"	"NA"	"A"	"Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article; Early Access"	"NA"	"ANTENATAL CORTICOSTEROIDS; PLACENTAL-TRANSFER; MANAGEMENT; COURSES; SINGLE; BIRTH"	"Despite antenatal corticosteroids therapy, respiratory distress syndrome (RDS) is still a leading cause of neonatal morbidity and mortality in premature newborns. To date, the relationship between in utero fetal drug exposure and occurrence of RDS remains poorly evaluated. This study aims to describe the pharmacokinetics of betamethasone in pregnant women and to evaluate the transplacental drug transfer and administration scheme for the prevention of RDS. Pregnant women > 27 weeks' gestation and who received at least a single dose of betamethasone for prevention of RDS were enrolled. Maternal, cord blood, and amniotic fluid betamethasone time-courses were analyzed using the Monolix software. A total of 220 maternal blood, 56 cord blood, and 26 amniotic fluid samples were described by a two-compartment model with two effect compartments linked by rate transfer constants. Apparent clearances and volumes of distribution parameters were allometrically scaled for a 70 kg third trimester pregnant woman. The impact of a twin pregnancy was found to increase maternal clearance by 28%. Using a fetal-to-mother exposure ratio, the median (95% confidence interval (CI)) transplacental transfer of betamethasone was estimated to 35% (95% CI 0.11-0.67). After adjustment for gestational age and twin pregnancy, RDS was found to be associated to the time spent in utero below quantifiable concentrations (i.e., < 1 ng/mL): odds ratio of 1.10 (95% CI 1.01-1.19) per day increase (P < 0.05). Trying to take into account both efficacy and safety, we simulated different dosing schemes in order to maintain a maximum of fetuses above 1 ng/mL without exceeding the total standard dose."	"[Foissac, Frantz; Zheng, Yi; Hirt, Deborah; Lui, Gabrielle; Bouazza, Nam; Benaboud, Sihem; Treluyer, Jean-Marc] Univ Paris, Pediat & Perinatal Drug Evaluat & Pharmacol, Paris, France; [Foissac, Frantz; Bouazza, Nam; Treluyer, Jean-Marc] Necker Enfants Malad Hosp, AP HP, URC CIC Paris Descartes Necker Cochin, Paris, France; [Foissac, Frantz; Bouazza, Nam; Treluyer, Jean-Marc] Cochin Necker, CIC 1419 Inserm, Paris, France; [Zheng, Yi; Hirt, Deborah; Lui, Gabrielle; Benaboud, Sihem; Treluyer, Jean-Marc] Paris Ctr Hosp Grp, AP HP, Clin Pharmacol Dept, Paris, France; [Ville, Yves] Hop Necker Enfants Malad, AP HP, Matern, Paris, France; [Ville, Yves] Paris Descartes Univ, Sorbonne Paris Cite, EA 7328, Paris, France; [Goffinet, Francois] Cochin Hosp, AP HP, Port Royal Matern Unit, Paris, France; [Goffinet, Francois; Kayem, Gilles] Sorbonne Paris Cite, Res Ctr, Obstet Perinatal & Pediat Epidemiol Team & Biosta, U1153,INSERM, Paris, France; [Goffinet, Francois; Kayem, Gilles] Univ Paris 05, Paris, France; [Rozenberg, Patrick] Poissy St Germain Hosp, Dept Gynecol & Obstet, Poissy, France; [Rozenberg, Patrick] Paris Saclay Univ, EA 7285, Montigny Le Bretonneux, France; [Kayem, Gilles] Trousseau Hosp, AP HP, Dept Obstet & Gynecol, Paris, France; [Mandelbrot, Laurent] Louis Mourier Hosp, AP HP, Dept Obstet & Gynecol, Colombes, France; [Mandelbrot, Laurent] Univ Paris Diderot, Sorbonne Paris Cite, INSERM, IAME,UMR 1137, Paris, France; [Jarreau, Pierre-Henri] Univ Paris, Paris Ctr Univ Hosp, AP HP, Neonatal Intens Care Unit Port Royal, Paris, France; [Jarreau, Pierre-Henri] Univ Paris, Obstet Perinatal & Pediat Epidemiol Res Team, EPOPe, INSERM,INRA,CRESS, Paris, France"	"Foissac, F (corresponding author), Univ Paris, Pediat & Perinatal Drug Evaluat & Pharmacol, Paris, France.; Foissac, F (corresponding author), Necker Enfants Malad Hosp, AP HP, URC CIC Paris Descartes Necker Cochin, Paris, France.; Foissac, F (corresponding author), Cochin Necker, CIC 1419 Inserm, Paris, France."	"frantz.foissac@aphp.fr"	"NA"	", YI/0000-0002-1115-7121"	"French Ministry of Health [CRC 1076]; Departement de la Recherche Clinique et du Developpement de l'Assistance Publique-Hopitaux de Paris"	"This study was funded by a research grant from the French Ministry of Health (CRC 1076) and sponsored by the Departement de la Recherche Clinique et du Developpement de l'Assistance Publique-Hopitaux de Paris."	43	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1002/cpt.1887"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LV5WP"	"WOS:000538505400001"	32394434	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, YL; Guilhaumou, R; Blin, O; Velly, L; Marsot, A"	"Wang, Y. L.; Guilhaumou, R.; Blin, O.; Velly, L.; Marsot, Amelie"	"NA"	"A"	"External evaluation of population pharmacokinetic models for continuous administration of meropenem in critically ill adult patients"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Meropenem; Pharmacokinetics; Population; External evaluation; Intensive care"	"BETA-LACTAM ANTIBIOTICS; PREDICTIVE PERFORMANCE; DOSING REGIMEN; INFUSION; PHARMACODYNAMICS; AMIKACIN; PLASMA; FLUID"	"Purpose Beta-lactams (BL), the most commonly prescribed class of antibiotics, are recommended as the first-line therapy for multiple indications in infectious disease guidelines. Meropenem (MERO) is frequently used in intensive care units (ICU) to treat bacterial infections with or without sepsis. The pharmacokinetics of MERO display a large variability in patients admitted to ICUs due to altered pathophysiology. The aim of this study was to perform an external evaluation of published population pharmacokinetic models of MERO in order to test their predictive performance in a cohort of ICU adult patients. Methods A literature search in PubMed/Medline database was made following the PRISMA statement. External evaluation was performed using NONMEM software, and the bias and inaccuracy values were calculated. Results An external validation dataset from the Timone Hospital in Marseille, France, included 84 concentration samples from 27 patients. Four models of MERO were identified according to the inclusion criteria of the study. None of the models presented acceptable values of bias and inaccuracy. Conclusion While performing external evaluations on some populations may confirm a model's suitability to diverse groups of patients, there is still some variability that cannot be explained nor solved by the procedure. This brings to light the difficulty to develop only one model for ICU patients and the need to develop one specific model to each population of critically ill patients."	"[Wang, Y. L.; Marsot, Amelie] Univ Montreal, Lab Suivi Therapeut Pharmacol & Pharmacocinet, Fac Pharm, Pavillon Jean Coutu,2940 Chemin Polytech, Montreal, PQ H3T 1J4, Canada; [Wang, Y. L.; Marsot, Amelie] Univ Montreal, Fac Pharm, Montreal, PQ, Canada; [Guilhaumou, R.; Blin, O.] Hop La Timone, AP HM, Serv Pharmacol Clin & Pharmacovigilance, Marseille, France; [Guilhaumou, R.; Blin, O.] Aix Marseille Univ, Pharmacol Integree & Interface Clin & Ind, Inst Neurosci Syst, CNRS 7289, F-13385 Marseille, France; [Velly, L.] Hop La Timone, AP HM, Serv Antsthesie Reanimat, Marseille, France; [Marsot, Amelie] CHU St Justine, Ctr Rech, Montreal, PQ, Canada"	"Marsot, A (corresponding author), Univ Montreal, Lab Suivi Therapeut Pharmacol & Pharmacocinet, Fac Pharm, Pavillon Jean Coutu,2940 Chemin Polytech, Montreal, PQ H3T 1J4, Canada.; Marsot, A (corresponding author), Univ Montreal, Fac Pharm, Montreal, PQ, Canada.; Marsot, A (corresponding author), CHU St Justine, Ctr Rech, Montreal, PQ, Canada."	"amelie.marsot@umontreal.ca"	"NA"	"NA"	"NA"	"NA"	41	0	0	2	2	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"SEP"	2020	76	9	1281	1289	"NA"	"10.1007/s00228-020-02922-z"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MY2UF"	"WOS:000537658000001"	32495084	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Thirion, DJG; Pasche, V; Matouk, E; Marsot, A"	"Thirion, Daniel J. G.; Pasche, Valerian; Matouk, Elias; Marsot, Amelie"	"NA"	"A"	"Amikacin nomogram for treatment of adult cystic fibrosis exacerbations based on an external evaluation of a population pharmacokinetic model"	"PEDIATRIC PULMONOLOGY"	"English"	"Article"	"amikacin; cystic fibrosis; nomogram; pharmacokinetics; simulations"	"PREDICTIVE PERFORMANCE; OTOTOXICITY; VANCOMYCIN; INFUSION; CHILDREN; THERAPY"	"Background In patients with cystic fibrosis (CF), amikacin is the alternative for the treatment of acute pulmonary exacerbations associated with pathogens resistant to tobramycin. Population pharmacokinetic (PK) models of amikacin in adult patients with CF have been previously published. However, current dosing recommendations remain disputed (Illamola et al. Clin Pharmacokinet. 2018;57(10):1217-1228). We perform here the first external evaluation of a published amikacin adult CF population PK model and propose a dosing nomogram for initial dosing. Methods We retrospectively collected demographic, biological, and clinical data from the medical records of adult patients who had received intravenous amikacin. To assess the predictive performance of this model we applied visual comparison of predictions to observations, calculation of bias and inaccuracy, and simulation-based diagnostics. Monte Carlo simulations from the evaluated model were used to compare maximum concentration/minimum inhibitory concentration achieved with different dosing regimens. Results A total of 91 concentrations from 19 adult patients with CF were collected for external evaluation. The model predicted amikacin concentrations with reasonable bias (7.2% [95% confidence interval, CI: -0.7% to 15.0%]) and inaccuracy (18.2% [95% CI: 12.0%-24.4%]). Our simulations with this model suggest that administered amikacin doses must be adjusted to creatinine clearance and also adjusted to body weight (doses from 20 to 45 mg/kg/d). According to these simulations, we developed the Montreal amikacin nomogram to optimize amikacin dosing regimens in patients with CF. Conclusion In conclusion, we developed the first nomogram to optimize initial amikacin dosing regimens in patients with CF based on this external evaluation of a recently published amikacin population PK model."	"[Thirion, Daniel J. G.; Pasche, Valerian; Marsot, Amelie] Univ Montreal, Fac Pharm, Pavillon Jean Coutu,2940 Chemin Polytech, Montreal, PQ H3T 1J4, Canada; [Thirion, Daniel J. G.] McGill Univ, Dept Pharm, Ctr Hlth, Montreal, PQ, Canada; [Pasche, Valerian; Marsot, Amelie] Univ Montreal, Lab Suivi Therapeut Pharmacol & Pharmacocinet, Fac Pharm, Montreal, PQ, Canada; [Matouk, Elias] McGill Univ, Adult Cyst Fibrosis Clin, Montreal Chest Inst, Montreal, PQ, Canada; [Matouk, Elias] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada; [Matouk, Elias] McGill Univ, Dept Med, Montreal, PQ, Canada"	"Marsot, A (corresponding author), Univ Montreal, Fac Pharm, Pavillon Jean Coutu,2940 Chemin Polytech, Montreal, PQ H3T 1J4, Canada."	"amelie.marsot@umontreal.ca"	"NA"	"Thirion, Daniel/0000-0002-2474-2186"	"NA"	"NA"	35	0	0	2	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"8755-6863"	"1099-0496"	"NA"	"PEDIATR PULM"	"Pediatr. Pulmonol."	"MAY"	2020	55	5	1154	1160	"NA"	"10.1002/ppul.24689"	7	"Pediatrics; Respiratory System"	"Pediatrics; Respiratory System"	"LC6FX"	"WOS:000517354400001"	32119197	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Li, TF; Hu, L; Ma, XL; Huang, L; Liu, XM; Luo, XX; Feng, WY; Wu, CF"	"Li, Tai-feng; Hu, Lei; Ma, Xiao-lu; Huang, Lin; Liu, Xue-mei; Luo, Xing-xian; Feng, Wan-yu; Wu, Chun-fu"	"NA"	"A"	"Population pharmacokinetics of cyclosporine in Chinese children receiving hematopoietic stem cell transplantation"	"ACTA PHARMACOLOGICA SINICA"	"English"	"Article"	"cyclosporine; population pharmacokinetic model; hematopoietic stem cell transplantation; Chinese children"	"CYP3A5-ASTERISK-3 POLYMORPHISMS; GENETIC POLYMORPHISMS; DRUG-INTERACTIONS; TACROLIMUS; PHARMACOGENETICS; METABOLISM; RECIPIENTS; CYP3A5; CYP3A4-ASTERISK-18B; IMMUNOSUPPRESSANTS"	"Cyclosporine (CsA) is characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability, particularly in juvenile patients. The aims of this study were to build a population pharmacokinetic model of CsA in Chinese children with hematopathy who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify covariates affecting CsA pharmacokinetics. A total of 86 Chinese children aged 8.4 � 3.8 years (range 1.1-16.8 years) who received allo-HSCT were enrolled. Whole blood samples were collected before allo-HSCT. Genotyping was performed using an Agena MassARRAY system. A total of 1010 trough plasma concentration values of CsA and clinical data were collected. The population pharmacokinetic model of CsA was constructed using nonlinear mixed-effects modeling (NONMEM) software. The stability and performance of the final model were validated using bootstrapping and normalized prediction distribution errors. We showed that a one-compartment model with first-order elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL) and volume of distribution (V) were 42.3 L/h and 3100 L, respectively. Body weight, postoperative days, CYP3A4*1 G genotype, estimated glomerular filtration rate and coadministration of triazole antifungal drugs were identified as significant covariates for CL. Weight and postoperative days were significant covariates for the V of CsA. Our model can be adopted to optimize the CsA dosing regimen for Chinese children with hematopathy receiving allo-HSCT."	"[Li, Tai-feng; Wu, Chun-fu] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Liaoning, Peoples R China; [Hu, Lei; Huang, Lin; Liu, Xue-mei; Luo, Xing-xian; Feng, Wan-yu] Peking Univ, Dept Pharm, Peoples Hosp, Beijing 100044, Peoples R China; [Ma, Xiao-lu] Peking Univ, Dept Emergency, Peoples Hosp, Beijing 100044, Peoples R China"	"Wu, CF (corresponding author), Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Liaoning, Peoples R China.; Feng, WY (corresponding author), Peking Univ, Dept Pharm, Peoples Hosp, Beijing 100044, Peoples R China."	"renminyaojike@sina.com; wucf@syphu.edu.cn"	"NA"	"NA"	"National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [8177131171]; Beijing Municipal Natural Science FoundationBeijing Natural Science Foundation [7192218]"	"The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (Grant No. 8177131171) and the Beijing Municipal Natural Science Foundation (Grant No. 7192218)."	50	2	2	0	3	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1671-4083"	"1745-7254"	"NA"	"ACTA PHARMACOL SIN"	"Acta Pharmacol. Sin."	"DEC"	2019	40	12	1603	1610	"NA"	"10.1038/s41401-019-0277-x"	8	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"JS8IU"	"WOS:000500546400011"	31341257	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Deng, R; Gibiansky, L; Lu, T; Agarwal, P; Ding, H; Li, XB; Kshirsagar, S; Lu, D; Li, CZ; Girish, S; Wang, J; Boyer, M; Humphrey, K; Freise, KJ; Salem, AH; Seymour, JF; Kater, AP; Miles, D"	"Deng, Rong; Gibiansky, Leonid; Lu, Tong; Agarwal, Priya; Ding, Hao; Li, Xiaobin; Kshirsagar, Smita; Lu, Dan; Li, Chunze; Girish, Sandhya; Wang, Jue; Boyer, Michelle; Humphrey, Kathryn; Freise, Kevin J.; Salem, Ahmed Hamed; Seymour, John F.; Kater, Arnon P.; Miles, Dale"	"NA"	"A"	"Bayesian Population Model of the Pharmacokinetics of Venetoclax in Combination with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results from the Phase III MURANO Study"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"SELECTIVE BCL-2 INHIBITOR; PHARMACODYNAMICS; AMG-531"	"Background Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax-rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure-response analysis. Methods Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure-response analysis. Results The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21-39%). Apparent central volume of distribution was 30% lower (95% CI 22-38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes. Conclusions The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure-response evaluation."	"[Deng, Rong; Lu, Tong; Agarwal, Priya; Ding, Hao; Li, Xiaobin; Kshirsagar, Smita; Lu, Dan; Li, Chunze; Girish, Sandhya; Wang, Jue; Miles, Dale] Genentech Inc, San Francisco, CA 94080 USA; [Gibiansky, Leonid] QuantPharm LLC, North Potomac, MD USA; [Boyer, Michelle; Humphrey, Kathryn] Roche Prod Ltd, Welwyn Garden City, Herts, England; [Freise, Kevin J.; Salem, Ahmed Hamed] AbbVie, N Chicago, IL 60064 USA; [Seymour, John F.] Royal Melbourne Hosp, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia; [Seymour, John F.] Univ Melbourne, Melbourne, Vic, Australia; [Kater, Arnon P.] Univ Amsterdam, Amsterdam UMC, Dept Hematol, Amsterdam, Netherlands; [Deng, Rong] Genentech Res & Early Dev, Clin Pharmacol, 1 DNA Way,MS463a, San Francisco, CA 94080 USA"	"Deng, R (corresponding author), Genentech Inc, San Francisco, CA 94080 USA.; Deng, R (corresponding author), Genentech Res & Early Dev, Clin Pharmacol, 1 DNA Way,MS463a, San Francisco, CA 94080 USA."	"deng.rong@gene.com"	"li, chunze/AAC-8730-2020; Seymour, John/K-7326-2019"	"Seymour, John/0000-0003-2188-6835"	"GenentechRoche HoldingGenentech; AbbVie"	"Genentech and AbbVie provided financial support for this study."	33	2	2	1	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2019	58	12	1621	1634	"NA"	"10.1007/s40262-019-00788-8"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JR6KK"	"WOS:000499731700009"	31209657	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Colomban, O; Tod, M; Leary, A; Ray-Coquard, I; Lortholary, A; Hardy-Bessard, AC; Pfisterer, J; Du Bois, A; Kurzeder, C; Burges, A; Peron, J; Freyer, G; You, B"	"Colomban, Olivier; Tod, Michel; Leary, Alexandra; Ray-Coquard, Isabelle; Lortholary, Alain; Hardy-Bessard, Anne Claire; Pfisterer, Jacobus; Du Bois, Andreas; Kurzeder, Christian; Burges, Alexander; Peron, Julien; Freyer, Gilles; You, Benoit"	"NA"	"A"	"Early Modeled Longitudinal CA-125 Kinetics and Survival of Ovarian Cancer Patients: A GINECO AGO MRC CTU Study"	"CLINICAL CANCER RESEARCH"	"English"	"Article"	"NA"	"CARBOPLATIN PLUS PACLITAXEL; PHASE-III TRIAL; 1ST-LINE TREATMENT; EPITHELIAL OVARIAN; ANTIGEN 125; CHEMOTHERAPY; PREDICTION; BEVACIZUMAB; PARAMETER; SURROGATE"	"Purpose: Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup(GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments. Experimental Design: Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) � gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP � topotecan; n = 192); and ICON7 (validation set: CP � bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses. Results: The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM >= upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. <35 months). Conclusions: Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment-related variations in a GCIG meta-analysis is warranted."	"[Colomban, Olivier; Tod, Michel; Freyer, Gilles; You, Benoit] Univ Claude Bernard Lyon 1, Univ Lyon, Fac Med Lyon Sud, EMR,UCBL,HCL 3738, Lyon, France; [Tod, Michel] Hop Croix Rousse, Hosp Civils Lyon Pharm, Lyon, France; [Leary, Alexandra; Peron, Julien; You, Benoit] GINECO Grp Early Phase Studies GINEGEPS, Grp Invest Natl Canc Ovaire GINECO, Paris, France; [Leary, Alexandra] Inst Gustave Roussy, Villejuif, France; [Ray-Coquard, Isabelle] Univ Claude Bernard Lyon 1, Ctr Leon Berard, Lyon, France; [Ray-Coquard, Isabelle; Lortholary, Alain; Hardy-Bessard, Anne Claire] GINECO, Paris, France; [Lortholary, Alain] Ctr Catherine Sienne, Nantes, France; [Hardy-Bessard, Anne Claire] Ctr Armoricain Oncol, Plerin, France; [Pfisterer, Jacobus] Gynecol Oncol Ctr, Kiel, Germany; [Du Bois, Andreas; Kurzeder, Christian] Evang Huyssens Stiftung Knappschaft GmbH, Germany Kliniken Essen Mitte KEM, AGO, Essen, Ago, Germany; [Kurzeder, Christian] Univ Hosp Basel, Dept Gynecol Oncol, Basel, Switzerland; [Burges, Alexander] Univ Munich, Dept Gynecol & Obstet, Campus Grosshadern, Munich, Germany; [Peron, Julien; Freyer, Gilles; You, Benoit] Ctr Hosp Lyon Sud, AGO, Med Oncol, IC HCL,CITOHL, Lyon, France; [Peron, Julien] Univ Claude Bernard Lyon 1, Univ Lyon, CNRS, UMR 5558,Lab Biometrie & Biol Evolut,Equipe Biost, Villeurbanne, France"	"You, B (corresponding author), Hosp Civils Lyon, Inst Cancerol, F-69495 Lyon, France."	"benoit.you@laposte.net"	"NA"	"leary, alexandra/0000-0002-2043-2244; COLOMBAN, OLIVIER/0000-0003-1671-3470; du Bois, Andreas/0000-0002-8477-506X"	"Universite Claude Bernard Lyon 1; Association de Recherche sur les CAncers dont Gynecologiques (ARCAGY)-Groupe des Investigateurs Nationaux des Cancers de l'Ovaire (GINECO); Arbeitsgemeinschaft Gynakologische Onkologie (AGO); Gynecologic Cancer InterGroup (GCIG); MRC Clinical Trial Unit at University College London"	"The authors thank all the patients and their families, the investigators, the study nurses, pharmacists, pathologists, and all study teams, especially the Gynecologic Cancer Intergroup and MRC Clinical Trial Unit at University College London. This workwas supported by Universite Claude Bernard Lyon 1, Association de Recherche sur les CAncers dont Gynecologiques (ARCAGY)-Groupe des Investigateurs Nationaux des Cancers de l'Ovaire (GINECO), Arbeitsgemeinschaft Gynakologische Onkologie (AGO), Gynecologic Cancer InterGroup (GCIG), and MRC Clinical Trial Unit at University College London."	34	6	6	0	0	"AMER ASSOC CANCER RESEARCH"	"PHILADELPHIA"	"615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA"	"1078-0432"	"1557-3265"	"NA"	"CLIN CANCER RES"	"Clin. Cancer Res."	"SEP 1"	2019	25	17	5342	5350	"NA"	"10.1158/1078-0432.CCR-18-3335"	9	"Oncology"	"Oncology"	"IV2PE"	"WOS:000484118300019"	30936122	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bulitta, JB; Jiao, YY; Landersdorfer, CB; Sutaria, DS; Tao, X; Shin, EJ; Hohl, R; Holzgrabe, U; Stephan, U; Sorgel, F"	"Bulitta, Jurgen B.; Jiao, Yuanyuan; Landersdorfer, Cornelia B.; Sutaria, Dhruvitkumar S.; Tao, Xun; Shin, Eunjeong; Hoehl, Rainer; Holzgrabe, Ulrike; Stephan, Ulrich; Soergel, Fritz"	"NA"	"A"	"Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics"	"PHARMACEUTICS"	"English"	"Article"	"cystic fibrosis patients; healthy volunteers; fluoroquinolone; pefloxacin; absolute bioavailability; population pharmacokinetics; allometric scaling; body size; body composition; S-ADAPT"	"PHARMACODYNAMIC BREAKPOINTS; INTESTINAL ELIMINATION; ORAL BIOAVAILABILITY; GYRASE INHIBITORS; P-GLYCOPROTEIN; CIPROFLOXACIN; SECRETION; INVOLVEMENT; MECHANISM; PATHWAYS"	"Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 � 6.9 kg, average � SD) and ten healthy volunteers (FFM: 51.7 � 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups."	"[Bulitta, Jurgen B.; Jiao, Yuanyuan; Sutaria, Dhruvitkumar S.; Tao, Xun; Shin, Eunjeong] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Orlando, FL 32827 USA; [Landersdorfer, Cornelia B.] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia; [Hoehl, Rainer] Paracelsus Med Univ, Inst Clin Hyg Med Microbiol & Infectiol, Klinikum Nurnberg, D-90419 Nurnberg, Germany; [Holzgrabe, Ulrike] Univ Wurzburg, Inst Pharm & Food Chem, D-97074 Wurzburg, Germany; [Stephan, Ulrich; Soergel, Fritz] IBMP Inst Biomed & Pharmaceut Res, D-90562 Nurnberg, Germany; [Stephan, Ulrich; Soergel, Fritz] Univ Duisburg, Dept Pharmacol, D-47057 Essen, Germany"	"Bulitta, JB (corresponding author), Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Orlando, FL 32827 USA.; Sorgel, F (corresponding author), IBMP Inst Biomed & Pharmaceut Res, D-90562 Nurnberg, Germany.; Sorgel, F (corresponding author), Univ Duisburg, Dept Pharmacol, D-47057 Essen, Germany."	"jbulitta@cop.ufl.edu; Fritz.Soergel@ibmp.net"	"Bulitta, Jurgen B/P-3355-2018; Sutaria, Dhruvitkumar/I-2321-2019"	"Bulitta, Jurgen B/0000-0001-7352-3097; Sutaria, Dhruvitkumar/0000-0001-8149-3481; Landersdorfer, Cornelia/0000-0003-0928-4743"	"NA"	"NA"	64	1	1	3	3	"MDPI"	"BASEL"	"ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND"	"NA"	"1999-4923"	"NA"	"PHARMACEUTICS"	"Pharmaceutics"	"JUL"	2019	11	7	"NA"	"NA"	323	"10.3390/pharmaceutics11070323"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IN9JM"	"WOS:000478995100026"	31295857	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Glatard, A; Guidi, M; Dobrinas, M; Cornuz, J; Csajka, C; Eap, CB"	"Glatard, Anais; Guidi, Monia; Dobrinas, Maria; Cornuz, Jacques; Csajka, Chantal; Eap, Chin B."	"NA"	"A"	"Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Varenicline; Pharmacokinetics; Pharmacogenetics; Dose individualization; Variability"	"RECEPTOR PARTIAL AGONIST; X-RECEPTOR; SMOKING-CESSATION; GLUCURONOSYLTRANSFERASE 2B7; GENETIC POLYMORPHISMS; HEPATIC TRANSPORTERS; PHARMACOKINETICS; ASSOCIATION; VARIANTS; EFFICACY"	"PurposeThe abstinence rate to tobacco after varenicline treatment is moderate and might be partially affected by variability in varenicline concentrations. This study aimed at characterizing the sources of variability in varenicline pharmacokinetics and to relate varenicline exposure to abstinence.MethodsThe population pharmacokinetic analysis (NONMEM (R)) included 121 varenicline concentrations from 82 individuals and tested the influence of genetic and non-genetic characteristics on apparent clearance (CL/F) and volume of distribution (V/F). Model-based average concentrations over 24h (Cav) were used to test the impact of varenicline exposure on the input rate (Kin) expressed as a function of the number of cigarettes per day in a turnover model of 373 expired carbon monoxide levels.ResultsA one-compartment model with first-order absorption and elimination appropriately described varenicline concentrations. CL/F was 8.5L/h (coefficient of variation, 26%), V/F was 228L, and the absorption rate (k(a)) was fixed to 0.98h(-1). CL/F increased by 46% in 100-kg individuals compared to 60-kg individuals and was found to be 21% higher in UGT2B7 rs7439366 TT individuals. These covariates explained 14% and 9% of the interindividual variability in CL/F, respectively. No influence of varenicline Cav was found on Kin in addition to the number of cigarettes.ConclusionsBody weight mostly and to a smaller extent genetic polymorphisms of UGT2B7 can influence varenicline exposure. Dose adjustment based on body weight and, if available, on UGT2B7 genotype might be useful to improve clinical efficacy and tolerability of varenicline."	"[Glatard, Anais; Dobrinas, Maria; Eap, Chin B.] Univ Lausanne, Lausanne Univ Hosp, Unit Pharmacogenet & Clin Psychopharmacol, Dept Psychiat,Ctr Psychiat Neurosci,Hosp Cery, Prilly, Switzerland; [Glatard, Anais; Guidi, Monia; Csajka, Chantal] Univ Lausanne, Lausanne Univ Hosp, Dept Labs, Serv Clin Pharmacol, Lausanne, Switzerland; [Guidi, Monia; Csajka, Chantal; Eap, Chin B.] Univ Geneva, Univ Lausanne, Sch Pharmaceut Sci, Geneva, Switzerland; [Cornuz, Jacques] Univ Lausanne, Dept Ambulatory Care & Community Med, Lausanne, Switzerland"	"Eap, CB (corresponding author), Univ Lausanne, Lausanne Univ Hosp, Unit Pharmacogenet & Clin Psychopharmacol, Dept Psychiat,Ctr Psychiat Neurosci,Hosp Cery, Prilly, Switzerland.; Csajka, C (corresponding author), Univ Lausanne, Lausanne Univ Hosp, Dept Labs, Serv Clin Pharmacol, Lausanne, Switzerland.; Csajka, C; Eap, CB (corresponding author), Univ Geneva, Univ Lausanne, Sch Pharmaceut Sci, Geneva, Switzerland."	"Chantal.csajka@chuv.ch; Chin.eap@chuv.ch"	"NA"	"Eap, Chin/0000-0002-5439-0230; Guidi, Monia/0000-0002-6419-9317"	"Tobacco Prevention Fund; Swiss Federal Office of Public Health [06.004879]"	"This work was supported by a grant from the Tobacco Prevention Fund, Swiss Federal Office of Public Health (06.004879 to C. B. Eap)."	51	1	1	0	0	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JUL"	2019	75	7	939	949	"NA"	"10.1007/s00228-019-02662-9"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IE0AU"	"WOS:000472049600008"	30868192	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wellhagen, GJ; Kjellsson, MC; Karlsson, MO"	"Wellhagen, Gustaf J.; Kjellsson, Maria C.; Karlsson, Mats O."	"NA"	"M"	"A Bounded Integer Model for Rating and Composite Scale Data"	"AAPS JOURNAL"	"English"	"Article"	"Bounded integer model; Categorical data; Composite scale; Nonlinear mixed-effects modelling; Probit regression; Rating scale"	"ITEM RESPONSE THEORY; REGRESSION-MODELS; BETA REGRESSION; DISEASE; SIMULATION; SCORES; LASSO; PANSS"	"Rating and composite scales are commonly used to assess treatment efficacy. The two main strategies for modelling such endpoints are to treat them as a continuous or an ordered categorical variable (CV or OC). Both strategies have disadvantages, including making assumptions that violate the integer nature of the data (CV) and requiring many parameters for scales with many response categories (OC). We present a method, called the bounded integer (BI) model, which utilises the probit function with fixed cut-offs to estimate the probability of a certain score through a latent variable. This method was successfully implemented to describe six data sets from four different therapeutic areas: Parkinson's disease, Alzheimer's disease, schizophrenia, and neuropathic pain. Five scales were investigated, ranging from 11 to 181 categories. The fit (likelihood) was better for the BI model than for corresponding OC or CV models (AIC range 11-1555) in all cases but one (AIC -63), while the number of parameters was the same or lower. Markovian elements were successfully implemented within the method. The performance in external validation, assessed through cross-validation, was also in favour of the new model (OFV range 22-1694) except in one case (OFV -70). A residual for diagnostic purposes is discussed. This study shows that the BI model respects the integer nature of data and is parsimonious in terms of number of estimated parameters."	"[Wellhagen, Gustaf J.; Kjellsson, Maria C.; Karlsson, Mats O.] Uppsala Univ, Dept Pharmaceut Biosci, Pharmacometr Res Grp, Box 591, S-75124 Uppsala, Sweden"	"Karlsson, MO (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Pharmacometr Res Grp, Box 591, S-75124 Uppsala, Sweden."	"mats.karlsson@farmbio.uu.se"	"NA"	"Wellhagen, Gustaf/0000-0002-7228-0422"	"Swedish Research CouncilSwedish Research Council [2018-03317]"	"The authors wish to thank Dr. Yasunori Aoki for the valuable input. This work was financially supported by the Swedish Research Council Grant 2018-03317."	31	5	5	0	1	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JUL"	2019	21	4	"NA"	"NA"	74	"10.1208/s12248-019-0343-9"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IC2FW"	"WOS:000470776700002"	31172350	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Bae, DJ; Kim, SY; Bae, SM; Hwang, AK; Pak, KC; Yoon, S; Lim, HS"	"Bae, Dong-Jun; Kim, Sang-Yeob; Bae, Sang Mun; Hwang, Ae-Kyung; Pak, Kwan Cheol; Yoon, SeokKyu; Lim, Hyeong-Seok"	"NA"	"A"	"Whole-Body Physiologically Based Pharmacokinetic Modeling of Trastuzumab and Prediction of Human Pharmacokinetics"	"JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"whole-body physiologically based pharmacokinetics; optical imaging; human prediction; monoclonal antibody; NONMEM"	"POPULATION PHARMACOKINETICS; PBPK MODEL; BIODISTRIBUTION; TOMOGRAPHY; ANTIBODIES"	"In the present study, we evaluated the pharmacokinetics (PK) of trastuzumab and sought to predict human PK based on animal studies, through the use of optical imaging and a whole-body physiologically based pharmacokinetic (WB-PBPK) modeling approach. The PK study was conducted in 24 mice, where serial blood samples were withdrawn and major organs were isolated after the last blood withdrawal. The drug concentrations in blood and major organs were measured via optical imaging. The WB-PBPK model was constructed using known physiological values including the volumes of major organs and blood/lymphatic flow. The NONMEM software (version 7.3) was used to determine tissue partition coefficients. Using the WB-PBPK model, a clinical trial simulation was performed with reference to human physiological values acquired from the literature. The simulated human PK was then compared with the actual PK observed in the previous study in which healthy male subjects received 6 mg/kg trastuzumab (Herceptin (R)) via intravenous route. The ratio of the simulated versus observed area under the concentration-time curve was 1.02 and that of maximal concentration was 0.72. The current study describes the potential synergistic applications of WB-PBPK and optical imaging in human PK prediction based on preclinical data obtained in early-stage drug development. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved."	"[Bae, Dong-Jun; Kim, Sang-Yeob; Bae, Sang Mun] ASAN Inst Life Sci, ASAN Med Ctr, Seoul, South Korea; [Kim, Sang-Yeob] Univ Ulsan, Coll Med, Dept Convergence Med, Seoul, South Korea; [Hwang, Ae-Kyung] Asan Med Ctr, Clin Res Ctr, Pharmacokinet & Pharmacogenet Lab, Seoul, South Korea; [Pak, Kwan Cheol; Yoon, SeokKyu; Lim, Hyeong-Seok] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Clin Pharmacol & Therapeut, Seoul, South Korea"	"Lim, HS (corresponding author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Clin Pharmacol & Therapeut, Seoul, South Korea."	"mdhslim@gmail.com"	"NA"	"NA"	"Ministry of Food and Drug SafetyMinistry of Food & Drug Safety (MFDS) [16182MFDS441]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health & Welfare, Republic of Korea [HI14C1090]"	"This research was supported by a grant (16182MFDS441) from the Ministry of Food and Drug Safety in 2016 and by a grant (HI14C1090) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea."	34	0	1	3	6	"ELSEVIER SCIENCE INC"	"NEW YORK"	"STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA"	"0022-3549"	"1520-6017"	"NA"	"J PHARM SCI-US"	"J. Pharm. Sci."	"JUN"	2019	108	6	2180	2190	"NA"	"10.1016/j.xphs.2019.01.024"	11	"Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Pharmacology & Pharmacy; Chemistry"	"IM1MA"	"WOS:000477752600028"	30716331	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Shah, NR; Bulitta, JB; Kinzig, M; Landersdorfer, CB; Jiao, YY; Sutaria, DS; Tao, X; Hohl, R; Holzgrabe, U; Kees, F; Stephan, U; Sorgel, F"	"Shah, Nirav R.; Bulitta, Jurgen B.; Kinzig, Martina; Landersdorfer, Cornelia B.; Jiao, Yuanyuan; Sutaria, Dhruvitkumar S.; Tao, Xun; Hoehl, Rainer; Holzgrabe, Ulrike; Kees, Frieder; Stephan, Ulrich; Soergel, Fritz"	"NA"	"A"	"Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding"	"PHARMACEUTICS"	"English"	"Article"	"cystic fibrosis patients; healthy volunteers; cefotiam; beta-lactam antibiotics; population pharmacokinetics; protein binding; allometric scaling; body size; body composition; S-ADAPT"	"GLOMERULAR-FILTRATION-RATE; RENAL CLEARANCE; PHARMACODYNAMIC BREAKPOINTS; NONLINEAR PHARMACOKINETICS; ANTIBIOTIC-PROPHYLAXIS; CEFOTIAM; DISPOSITION; PLASMA; PIPERACILLIN; SERUM"	"The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound beta -lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for beta -lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 � 5.4kg) and six healthy volunteers (LBM: 53.1 � 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding."	"[Shah, Nirav R.; Bulitta, Jurgen B.; Jiao, Yuanyuan; Sutaria, Dhruvitkumar S.; Tao, Xun] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Orlando, FL 32827 USA; [Kinzig, Martina; Stephan, Ulrich; Soergel, Fritz] IBMP Inst Biomed & Pharmaceut Res, D-90562 Nurnberg, Germany; [Landersdorfer, Cornelia B.] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia; [Hoehl, Rainer] Paracelsus Med Univ, Klinikum Nurnberg, Inst Clin Hyg Med Microbiol & Infectiol, D-90419 Nurnberg, Germany; [Holzgrabe, Ulrike] Univ Wurzburg, Inst Pharm & Food Chem, D-97074 Wurzburg, Germany; [Kees, Frieder] Univ Regensburg, Dept Pharmacol, D-93053 Regensburg, Germany; [Stephan, Ulrich; Soergel, Fritz] Univ Duisburg, Dept Pharmacol, D-47057 Essen, Germany"	"Bulitta, JB (corresponding author), Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Orlando, FL 32827 USA.; Sorgel, F (corresponding author), IBMP Inst Biomed & Pharmaceut Res, D-90562 Nurnberg, Germany.; Sorgel, F (corresponding author), Univ Duisburg, Dept Pharmacol, D-47057 Essen, Germany."	"shah.nirav@cop.ufl.edu; jbulitta@cop.ufl.edu; Martina.Kinzig@gtf-online.de; cornelia.landersdorfer@monash.edu; yyjiao@cop.ufl.edu; DSutaria@cop.ufl.edu; tealingsxun@ufl.edu; rai.hoehl@googlemail.com; ulrike.holzgrabe@uni-wuerzburg.de; frieder.kees@chemie.uni-regensburg.de; Fritz.Soergel@ibmp.net"	"Bulitta, Jurgen B/P-3355-2018; Sutaria, Dhruvitkumar/I-2321-2019"	"Bulitta, Jurgen B/0000-0001-7352-3097; Sutaria, Dhruvitkumar/0000-0001-8149-3481; Landersdorfer, Cornelia/0000-0003-0928-4743"	"NA"	"NA"	67	1	1	0	1	"MDPI"	"BASEL"	"ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND"	"1999-4923"	"NA"	"NA"	"PHARMACEUTICS"	"Pharmaceutics"	"JUN"	2019	11	6	"NA"	"NA"	"NA"	"10.3390/pharmaceutics11060286"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"II6VD"	"WOS:000475330500038"	31216743	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Arshad, U; Chasseloup, E; Nordgren, R; Karlsson, MO"	"Arshad, Usman; Chasseloup, Estelle; Nordgren, Rikard; Karlsson, Mats O."	"NA"	"M"	"Development of visual predictive checks accounting for multimodal parameter distributions in mixture models"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Visual predictive checks; Mixture models; Multimodal parameter distributions; Pharmacokinetics; Pharmacodynamics"	"POPULATION PHARMACOKINETICS; IRINOTECAN; METRICS"	"The assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Mixture model analysis provides the probability for an individual to belong to a subpopulation (IPmix) and the most likely subpopulation for an individual to belong to (MIXEST). Using simulated data examples, two implementation strategies were followed to split the data into subpopulations for the development of mixture model specific VPCs. The first strategy splits the observed and simulated data according to the MIXEST assignment. A shortcoming of the MIXEST-based allocation strategy was a biased allocation towards the dominating subpopulation. This shortcoming was avoided by splitting observed and simulated data according to the IPmix assignment. For illustration purpose, the approaches were also applied to an irinotecan mixture model demonstrating 36% lower clearance of irinotecan metabolite (SN-38) in individuals with UGT1A1 homo/heterozygote versus wild-type genotype. VPCs with segregated subpopulations were helpful in identifying model misspecifications which were not evident with standard VPCs. The new tool provides an enhanced power of evaluation of mixture models."	"[Arshad, Usman; Chasseloup, Estelle; Nordgren, Rikard; Karlsson, Mats O.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Arshad, Usman] Univ Cologne, Fac Med, Gleueler Str 24, D-50931 Cologne, Germany; [Arshad, Usman] Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Gleueler Str 24, D-50931 Cologne, Germany"	"Arshad, U (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden.; Arshad, U (corresponding author), Univ Cologne, Fac Med, Gleueler Str 24, D-50931 Cologne, Germany.; Arshad, U (corresponding author), Univ Cologne, Univ Hosp Cologne, Ctr Pharmacol, Dept Pharmacol 1, Gleueler Str 24, D-50931 Cologne, Germany."	"usman.arshad@uk-koeln.de"	"NA"	"Arshad, Usman/0000-0002-7003-5300"	"Higher Education Commission (HEC) PakistanHigher Education Commission of Pakistan; German Academic Exchange Service (DAAD)Deutscher Akademischer Austausch Dienst (DAAD)"	"The study was supported by a scholarship grant to Mr. Usman Arshad from the Higher Education Commission (HEC) Pakistan in collaboration with the German Academic Exchange Service (DAAD). We acknowledge Prof. Dr. Uwe Fuhr, University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany for his encouragement and support during the course of study."	39	2	2	0	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2019	46	3	241	250	"NA"	"10.1007/s10928-019-09632-9"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HZ1HH"	"WOS:000468597100003"	30968312	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Xie, FF; Mantzarlis, K; Malliotakis, P; Koulouras, V; Degroote, S; Koulenti, D; Blot, S; Boussery, K; Van Bocxlaer, J; Colin, P; Zakynthinos, E; Georgopoulos, D; Papathanasiou, A; Arvaniti, K; Matamis, D; Spring, A; Bekos, V; Komnos, A; Zafeiridis, T; Vogelaers, D"	"Xie, Feifan; Mantzarlis, Konstantinos; Malliotakis, Polychronis; Koulouras, Vasileios; Degroote, Sophie; Koulenti, Despoina; Blot, Stijn; Boussery, Koen; Van Bocxlaer, Jan; Colin, Pieter; Zakynthinos, Epameinondas; Georgopoulos, Dimitrios; Papathanasiou, Athanasios; Arvaniti, Kostoula; Matamis, Dimitrios; Spring, Anna; Bekos, Vasileios; Komnos, Apostolos; Zafeiridis, Tilemachos; Vogelaers, Dirk"	"LIMOP Study Collaborators"	"A"	"Pharmacokinetic evaluation of linezolid administered intravenously in obese patients with pneumonia"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; MODEL EVALUATION; INFECTIONS; PHARMACODYNAMICS; OXAZOLIDINONE; ANTIBIOTICS; METABOLISM; OVERWEIGHT; METRICS; WEIGHT"	"Objectives Altered linezolid pharmacokinetics (PK) in obese individuals has been hypothesized in previous studies. However, specific dosing recommendations for this population are still lacking. The main goal of this study was to evaluate PK/pharmacodynamic (PKPD) target attainment when using a 600mg intravenous q12h linezolid dose against MRSA in obese patients with pneumonia. Methods Fifteen obese pneumonia patients with a confirmed or suspected MRSA involvement treated with 600mg of intravenous linezolid q12h were studied for 3days. Population PK modelling was used to characterize the PK variability and to screen for influential patient characteristics. Monte Carlo simulations were carried out to investigate the PTA and time to target attainment for linezolid dosing against MRSA. Results A two-compartment model with linear elimination adequately described the data. Body weight and age both have a significant effect on linezolid clearance. Simulations demonstrate that the probability of attaining PKPD targets is low. Moreover, the PTA decreases with weight, and increases with age. Standard linezolid dosing in obese pneumonia patients with MRSA (MICs of 1-4mg/L) leads to unacceptably low (near zero to 60%) PTA for patients <65years old. Conclusions Standard linezolid dosing is likely to provide insufficient target attainment against MRSA in obese patients. Body weight and especially age are important characteristics to be considered when administering linezolid to treat MRSA infections."	"[Xie, Feifan; Boussery, Koen; Van Bocxlaer, Jan; Colin, Pieter] Univ Ghent, Fac Pharmaceut Sci, Lab Med Biochem & Clin Anal, Ottergemsesteenweg 460, B-9000 Ghent, Belgium; [Mantzarlis, Konstantinos] Univ Thessaly, Univ Hosp Larissa, Dept Intens Care, Larisa, Greece; [Malliotakis, Polychronis] Univ Hosp Crete, Dept Intens Care, Iraklion, Greece; [Koulouras, Vasileios] Univ Hosp Ioannina, Dept Intens Care, Ioannina, Greece; [Degroote, Sophie] Ghent Univ Hosp, Gen Internal Med, Infect Dis & Psychosomat Med, B-9000 Ghent, Belgium; [Koulenti, Despoina; Blot, Stijn] Univ Queensland, Clin Res Ctr, Burns Trauma & Crit Care Res Ctr, Fac Med, Brisbane, Qld, Australia; [Koulenti, Despoina] Attikon Univ Hosp, Crit Care Dept 2, Athens, Greece; [Blot, Stijn] Univ Ghent, Dept Internal Med, B-9000 Ghent, Belgium; [Colin, Pieter] Univ Groningen, Univ Med Ctr Groningen, Dept Anesthesiol, Groningen, Netherlands; [Zakynthinos, Epameinondas] Univ Hosp Larissa, Larisa, Greece; [Georgopoulos, Dimitrios] Univ Hosp Crete, Iraklion, Greece; [Papathanasiou, Athanasios] Univ Hosp Ioannina, Ioannina, Greece; [Arvaniti, Kostoula; Matamis, Dimitrios] Gen Hosp Thessaloniki, Papageorgiou, Thessaloniki, Greece; [Spring, Anna; Bekos, Vasileios] Naval Hosp Athens, Athens, Greece; [Komnos, Apostolos; Zafeiridis, Tilemachos] Gen Hosp Larissa, Larisa, Greece; [Vogelaers, Dirk] Ghent Univ Hosp, Ghent, Belgium"	"Xie, FF (corresponding author), Univ Ghent, Fac Pharmaceut Sci, Lab Med Biochem & Clin Anal, Ottergemsesteenweg 460, B-9000 Ghent, Belgium."	"Feifan.Xie@UGent.be"	"Xie, Feifan/J-5117-2019; Colin, Pieter/AAK-3525-2020; Blot, Stijn/H-9015-2013"	"Xie, Feifan/0000-0001-8427-4030; Colin, Pieter/0000-0003-3616-5539; Blot, Stijn/0000-0003-2145-0345; Mantzarlis, Konstantinos/0000-0002-2453-5398"	"Pfizer Investigator-initiated research grant (Europe Aspire 2012 Investigator Awards in MRSA) [WS2278278]"	"The study was supported by Pfizer Investigator-initiated research grant (Europe Aspire 2012 Investigator Awards in MRSA, grant number WS2278278)."	35	3	3	2	6	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"MAR"	2019	74	3	667	674	"NA"	"10.1093/jac/dky500"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"HR0RH"	"WOS:000462835800020"	30535122	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Favie, LMA; Groenendaal, F; van den Broek, MPH; Rademaker, CMA; de Haan, TR; van Straaten, HLM; Dijk, PH; van Heijst, A; Dudink, J; Dijkman, KP; Rijken, M; Zonnenberg, IA; Cools, F; Zecic, A; van der Lee, JH; Nuytemans, DHGM; van Bel, F; Egberts, TCG; Huitema, ADR; Brouwer, MJ; Mulder-de Tollenaer, SM; Jebbink-Akkerman, LJMG; Liem, D; Steiner, K; Simons, SHP; de Jonge, RCJ; Bos, AA; Sonnaert, M; Camfferman, FA"	"Favie, Laurent M. A.; Groenendaal, Floris; van den Broek, Marcel P. H.; Rademaker, Carin M. A.; de Haan, Timo R.; van Straaten, Henrica L. M.; Dijk, Peter H.; van Heijst, Arno; Dudink, Jeroen; Dijkman, Koen P.; Rijken, Monique; Zonnenberg, Inge A.; Cools, Filip; Zecic, Alexandra; van der Lee, Johanna H.; Nuytemans, Debbie H. G. M.; van Bel, Frank; Egberts, Toine C. G.; Huitema, Alwin D. R.; Brouwer, Mieke J.; Mulder-de Tollenaer, S. M.; Jebbink-Akkerman, L. J. M. Groot; Liem, Djien; Steiner, Katerina; Simons, Sinno H. P.; de Jonge, Rogier C. J.; Bos, Annelies A.; Sonnaert, Michel; Camfferman, Fleur Anne"	"PharmaCool Study Grp"	"A"	"Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia"	"PLOS ONE"	"English"	"Article"	"NA"	"HYPOXIC-ISCHEMIC ENCEPHALOPATHY; POPULATION PHARMACOKINETICS; GENTAMICIN PHARMACOKINETICS; ASPHYXIATED NEWBORNS; DRUG-METABOLISM; INFANTS; PRETERM; GLUCURONIDATION; PHARMACODYNAMICS; SAFETY"	"Objective Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population. Study design Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants. Results 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5 degrees C) by 6.89%/degrees C (95% CI 5.37%/degrees C-8.41%/degrees C, p<0.001) and metabolite clearance by 4.91%/degrees C (95% CI 3.53%/degrees C-6.22%/degrees C, p<0.001) compared to normothermia (36.5 degrees C). Simulations showed that a loading dose of 50 mu g/kg followed by continuous infusion of 5 mu g/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 mu g/L) during hypothermia. Conclusions Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect."	"[Favie, Laurent M. A.; van den Broek, Marcel P. H.; Rademaker, Carin M. A.; Egberts, Toine C. G.; Huitema, Alwin D. R.] Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands; [Favie, Laurent M. A.; Groenendaal, Floris; van Bel, Frank] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Neonatol, Utrecht, Netherlands; [Groenendaal, Floris; van Bel, Frank] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands; [van den Broek, Marcel P. H.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands; [de Haan, Timo R.] Emma Childrens Hosp, Acad Med Ctr, Dept Neonatol, Amsterdam, Netherlands; [van Straaten, Henrica L. M.] Isala Clin, Dept Neonatol, Zwolle, Netherlands; [Dijk, Peter H.] Groningen Univ Med Ctr, Dept Neonatol, Groningen, Netherlands; [van Heijst, Arno] Radboud Univ Nijmegen, Med Ctr, Amalia Childrens Hosp, Dept Neonatol, Nijmegen, Netherlands; [van Heijst, Arno] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat, Div Neonatol, Rotterdam, Netherlands; [Dijkman, Koen P.] Maxima Med Ctr Veldhoven, Dept Neonatol, Veldhoven, Netherlands; [Rijken, Monique] Leiden Univ, Med Ctr, Dept Neonatol, Leiden, Netherlands; [Zonnenberg, Inge A.] Vrije Univ Amsterdam Med Ctr, Dept Neonatol, Amsterdam, Netherlands; [Cools, Filip] UZ Brussel Vrije Univ Brussel, Dept Neonatol, Brussels, Belgium; [Zecic, Alexandra] Univ Hosp Gent, Dept Neonatol, Ghent, Belgium; [van der Lee, Johanna H.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Paediat Clin Res Off, Amsterdam, Netherlands; [Nuytemans, Debbie H. G. M.] PharmaCool Study, Amsterdam, Netherlands; [Egberts, Toine C. G.] Univ Utrecht, Fac Sci, Dept Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands; [Huitema, Alwin D. R.] Netherlands Canc Inst, Dept Pharm & Pharmacol, Amsterdam, Netherlands"	"Favie, LMA (corresponding author), Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands.; Favie, LMA (corresponding author), Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Neonatol, Utrecht, Netherlands."	"NA"	"Groenendaal, Floris/P-6872-2019; simons, sinno/AAC-7442-2019; de Jonge, R. C.J./M-9912-2014"	"Groenendaal, Floris/0000-0002-9284-1637; de Jonge, R. C.J./0000-0003-0595-1983; Cools, Filip/0000-0002-6581-7009"	"Netherlands Organization for Health Research and Development (ZonMw) Priority Medicines for Children [40-41500-98-9002]"	"Funding for this study was received from the Netherlands Organization for Health Research and Development (ZonMw) Priority Medicines for Children (grant number: 40-41500-98-9002). The funder did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript."	55	6	6	0	0	"PUBLIC LIBRARY SCIENCE"	"SAN FRANCISCO"	"1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA"	"1932-6203"	"NA"	"NA"	"PLOS ONE"	"PLoS One"	"FEB 14"	2019	14	2	"NA"	"NA"	"e0211910"	"10.1371/journal.pone.0211910"	17	"Multidisciplinary Sciences"	"Science & Technology - Other Topics"	"HL5JX"	"WOS:000458763900029"	30763356	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Valade, E; Kakuda, TN; McClure, MW; Westland, C; Valenzuela, B; Ouwerkerk-Mahadevan, S; Perez-Ruixo, JJ; Ackaert, O"	"Valade, Elodie; Kakuda, Thomas N.; McClure, Matthew W.; Westland, Christopher; Valenzuela, Belen; Ouwerkerk-Mahadevan, Sivi; Perez-Ruixo, Juan Jose; Ackaert, Oliver"	"NA"	"A"	"Population Pharmacokinetics of AL-335 and Its Two Main Metabolites (ALS-022399, ALS-022227) in Monotherapy and in Combination with Odalasvir and/or Simeprevir"	"AAPS JOURNAL"	"English"	"Article"	"direct-acting antiviral (DAA) drugs; hepatitis C virus (HCV); nonlinear mixed effects modeling; pharmacokinetics; uridine nucleoside analog"	"QUANTIFICATION LIMIT; INFECTION; CIRRHOSIS; MODELS"	"The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33.9%) and 1910 L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of V-max,V-ALS-022227 and K-m,K-ALS-022227 estimated to be 84,799 ng/h (14.9%) and 450.2 ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination."	"[Kakuda, Thomas N.; McClure, Matthew W.; Westland, Christopher] Alios BioPharma Inc, San Francisco, CA USA; [Valenzuela, Belen] SGS Exprimo NV, Mechelen, Belgium; [Valade, Elodie; Ouwerkerk-Mahadevan, Sivi; Perez-Ruixo, Juan Jose; Ackaert, Oliver] Janssen Res & Dev, Global Clin Pharmacol, Turnhoutseweg 30, B-2340 Beerse, Belgium; [McClure, Matthew W.] Second Genome, San Francisco, CA USA"	"Ackaert, O (corresponding author), Janssen Res & Dev, Global Clin Pharmacol, Turnhoutseweg 30, B-2340 Beerse, Belgium."	"oackaert@ITS.JNJ.com"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"NA"	"NA"	18	0	0	0	2	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JAN"	2019	21	1	"NA"	"NA"	1	"10.1208/s12248-018-0272-z"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HC5ZF"	"WOS:000451880200001"	30377854	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"de Mello, CPP; Tao, X; Kim, TH; Vicchiarelli, M; Bulitta, JB; Kaushik, A; Brown, AN"	"de Mello, Camilly P. Pires; Tao, Xun; Kim, Tae Hwan; Vicchiarelli, Michael; Bulitta, Juergen B.; Kaushik, Ajeet; Brown, Ashley N."	"NA"	"A"	"Clinical Regimens of Favipiravir Inhibit Zika Virus Replication in the Hollow-Fiber Infection Model"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"mathematical modeling; Zika virus; antiviral therapy; favipiravir; hollow-fiber infection model; pharmacodynamics; pharmacokinetics"	"IN-VIVO ACTIVITIES; POPULATION PHARMACOKINETICS; VITRO; SYSTEM; TRANSMISSION; T-705"	"Zika virus (ZIKV) infection is associated with serious, long-term neurological manifestations. There are currently no approved therapies for the treatment or prevention of ZIKV infection. Favipiravir (FAV) is a viral polymerase inhibitor with broad-spectrum activity. Our prior studies used static FAV concentrations and demonstrated promising activity. However, the anti-ZIKV activity of dynamic FAV concentrations has never been evaluated in a human cell line. Here we employed the hollow-fiber infection model (HFIM) to simulate the human pharmacokinetic (PK) profiles associated with the clinically utilized FAV dosage regimens against influenza and Ebola viruses and assessed the viral burden profiles. Clinically achievable FAV concentrations inhibited ZIKV replication in HUH-7 cells in a dose-dependent fashion (50% effective concentration = 236.5 mu M). The viral burden profiles under dynamic FAV concentrations were predicted by use of a mechanism-based mathematical model (MBM) and subsequently successfully validated in the HFIM. This validated, translational MBM can now be used to predict the anti-ZIKV activity of other FAV dosage regimens in the presence of between-patient variability in pharmacokinetics. This approach can be extended to rationally optimize FAV combination dosage regimens which hold promise to treat ZIKV infections in nonpregnant patients."	"[de Mello, Camilly P. Pires; Vicchiarelli, Michael; Brown, Ashley N.] Univ Florida, Coll Med, Dept Med, Inst Therapeut Innovat, Orlando, FL 32827 USA; [Tao, Xun; Kim, Tae Hwan; Bulitta, Juergen B.] Univ Florida, Coll Pharm, Dept Pharmaceut, Ctr Pharmacometr & Syst Pharmacol, Orlando, FL USA; [Kaushik, Ajeet] Florida Int Univ, Herbert Wertheim Coll Med, Inst Neuroimmune Pharmacol, Ctr Personalized Nanomed,Dept Immunol, Miami, FL 33199 USA"	"Brown, AN (corresponding author), Univ Florida, Coll Med, Dept Med, Inst Therapeut Innovat, Orlando, FL 32827 USA."	"Ashley.Brown@medicine.ufl.edu"	"Kaushik, Ajeet/K-1289-2018; Bulitta, Jurgen B/P-3355-2018"	"Kaushik, Ajeet/0000-0003-4206-1541; Bulitta, Jurgen B/0000-0001-7352-3097"	"Florida Department of Health Biomedical Research Program [7ZK30]"	"This work was supported by grant 7ZK30 from the Florida Department of Health Biomedical Research Program."	29	6	6	2	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"SEP"	2018	62	9	"NA"	"NA"	"e00967-18"	"10.1128/AAC.00967-18"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"GR6NN"	"WOS:000442771200067"	29967017	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Simon, N; Moirand, R; Dematteis, M; Bordet, R; Deplanque, D; Rolland, B"	"Simon, Nicolas; Moirand, Romain; Dematteis, Maurice; Bordet, Regis; Deplanque, Dominique; Rolland, Benjamin"	"NA"	"A"	"Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder"	"FRONTIERS IN PSYCHIATRY"	"English"	"Article"	"baclofen; alcohol use disorder; pharmacokinetics; human; clinical trial"	"PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; DEPENDENT PATIENTS; INTRAVENOUS BACLOFEN; SAFETY; EFFICACY; RECOMMENDATIONS; VOLUNTEERS; ABSTINENCE"	"Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: < 60 mg/d; 2: 60-120 mg/d; 3: > 120 mg/d-180 mg/d; and 4: > 180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34-2), clearance (Cl/F) 11.6 L/h (10.8-12.3) and volume of distribution (Vd/F) 72.8 L (66.5-80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19-65), 21% (16-27), and 22% (11-36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21-26). No serious adverse event was reported."	"[Simon, Nicolas] Aix Marseille Univ, Hop St Marguerite, AP HM, INSERM,IRD,SESSTIM,Serv Pharmacol Clin,CAP TV, Marseille, France; [Moirand, Romain] Univ Rennes, CHU Rennes, Inst NUMECAN Nutr Metab & Canc, INSERM,INRA,CIC 1414,Unite Addictol, Rennes, France; [Dematteis, Maurice] Univ Grenoble Alpes, UFR Med, Grenoble, France; [Dematteis, Maurice] CHU Grenoble Alpes, Serv Addictol, Grenoble, France; [Bordet, Regis; Deplanque, Dominique] Univ Lille, Inserm U1171, Lille, France; [Deplanque, Dominique] Univ Lille, CHU Lille, Inserm CIC1403, Lille, France; [Rolland, Benjamin] CH Le VInatier, SUAL, Pole MOPHA, Bron, France; [Rolland, Benjamin] Univ Lyon, Inserm U1028, CNRS UMR5292, UCBL,CRNL, Bron, France"	"Rolland, B (corresponding author), CH Le VInatier, SUAL, Pole MOPHA, Bron, France.; Rolland, B (corresponding author), Univ Lyon, Inserm U1028, CNRS UMR5292, UCBL,CRNL, Bron, France."	"benjrolland@gmail.com"	"ROLLAND, Benjamin/E-7374-2013; Simon, Nicolas/B-1235-2016; Deplanque, Dominique/E-4901-2015; ROLLAND, Benjamin/H-6625-2019"	"ROLLAND, Benjamin/0000-0002-8666-3635; Simon, Nicolas/0000-0003-4393-2257; Deplanque, Dominique/0000-0002-4995-584X; ROLLAND, Benjamin/0000-0002-8666-3635"	"Ethypharm"	"The study was funded by Ethypharm."	37	4	4	0	4	"FRONTIERS MEDIA SA"	"LAUSANNE"	"AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND"	"1664-0640"	"NA"	"NA"	"FRONT PSYCHIATRY"	"Front. Psychiatry"	"AUG 23"	2018	9	"NA"	"NA"	"NA"	385	"10.3389/fpsyt.2018.00385"	9	"Psychiatry"	"Psychiatry"	"GR3TL"	"WOS:000442518300001"	30190685	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Peigne, S; Chhun, S; Tod, M; Rey, E; Rodrigues, C; Chiron, C; Pons, G; Jullien, V"	"Peigne, Sophie; Chhun, Stephanie; Tod, Michel; Rey, Elisabeth; Rodrigues, Christelle; Chiron, Catherine; Pons, Gerard; Jullien, Vincent"	"NA"	"A"	"Population Pharmacokinetics of Stiripentol in Paediatric Patients with Dravet Syndrome Treated with Stiripentol, Valproate and Clobazam Combination Therapy"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"SEVERE MYOCLONIC EPILEPSY; JAPANESE PATIENTS; CHILDREN; MODEL; AGE; CLEARANCE; TRIAL; COMEDICATION; VARIABILITY; PARAMETERS"	"The aim of this study was to describe the pharmacokinetics of stiripentol in children with Dravet syndrome and to determine the concentrations of stiripentol achieved in this population for the usual 25 mg/kg twice-daily dose. Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using MONOLIX software). Four blood samples were drawn per patient. Stiripentol area under the plasma concentration-time curve (AUC) values and trough concentrations were simulated for 7000 theoretical children weighing between 10 and 70 kg for the 25 mg/kg twice-daily dose. The pharmacokinetics of stiripentol was described using a one-compartment model with zero-order absorption and first-order elimination. The apparent clearance (CL/F) and apparent volume of distribution (V (d)/F) of stiripentol were related to body weight by allometric equations. A dose-dependent non-linearity was also observed with an allometric model relating CL/F to the weight-normalised dose. Mean population estimates (% inter-individual variability) were 4.2 L/h (21%) for CL/F and 82 L (25%) for V (d)/F. The AUC of stiripentol increased by 300% when body weight increased from 10 to 70 kg. This population pharmacokinetic model of stiripentol in children with Dravet syndrome confirmed the dose-dependent non-linearity that has been evidenced in adults. It also supported that a 25 mg/kg twice-daily dose might lead to excessive exposure in children > 30 kg, suggesting an eventual dose adjustment during adolescence. This study is part of the STIPOP study (EUDRACT number: 2007-001784-30)."	"[Peigne, Sophie; Chhun, Stephanie; Rey, Elisabeth; Rodrigues, Christelle; Chiron, Catherine; Pons, Gerard; Jullien, Vincent] INSERM, U1129, Paris, France; [Peigne, Sophie; Chhun, Stephanie; Rey, Elisabeth; Rodrigues, Christelle; Chiron, Catherine; Pons, Gerard; Jullien, Vincent] Paris Descartes Univ, PRES Sorbonne Paris Cite, Paris, France; [Peigne, Sophie; Chhun, Stephanie; Rey, Elisabeth; Rodrigues, Christelle; Chiron, Catherine; Pons, Gerard; Jullien, Vincent] CEA, Gif Sur Yvette, France; [Tod, Michel] Univ Lyon 1, Fac Pharm, Dept Physiol Pharmacol Toxicol, Lyon, France; [Tod, Michel] Hosp Civils Lyon, Hop Croix Rousse, Lyon, France; [Jullien, Vincent] Hop Europeen Georges Pompidou, Serv Pharmacol, 20 Rue Leblanc, F-75015 Paris, France; [Jullien, Vincent] AP HP, Paris, France"	"Jullien, V (corresponding author), INSERM, U1129, Paris, France.; Jullien, V (corresponding author), Paris Descartes Univ, PRES Sorbonne Paris Cite, Paris, France.; Jullien, V (corresponding author), CEA, Gif Sur Yvette, France.; Jullien, V (corresponding author), Hop Europeen Georges Pompidou, Serv Pharmacol, 20 Rue Leblanc, F-75015 Paris, France.; Jullien, V (corresponding author), AP HP, Paris, France."	"vincent.jullien@aphp.fr"	"Chiron, Catherine/E-8506-2016"	"Chiron, Catherine/0000-0002-9096-1694; jullien, vincent/0000-0002-5971-6316; Rodrigues, Christelle/0000-0001-6681-5542"	"Biocodex"	"This study was conducted with the financial support of Biocodex."	42	10	10	0	5	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUN"	2018	57	6	739	748	"NA"	"10.1007/s40262-017-0592-7"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GH6ND"	"WOS:000433560200008"	28819726	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Zhao, W; Leroux, S; Biran, V; Jacqz-Aigrain, E"	"Zhao, Wei; Leroux, Stephanie; Biran, Valerie; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Developmental pharmacogenetics of CYP2C19 in neonates and young infants: omeprazole as a probe drug"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"ABCB1; CYP2C19; neonates; ontogeny; pharmacogenetics; pharmacokinetics"	"PROTON PUMP INHIBITORS; POPULATION PHARMACOKINETICS; P-GLYCOPROTEIN; CONCISE GUIDE; CHILDREN; METABOLISM; PHARMACOLOGY; PANTOPRAZOLE; MODEL; AGE"	"AimsAlthough substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug. MethodsPharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM. ResultsData fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CLOMZ-M1) increases with postnatal age. In CYP2C19 poor and intermediate metabolizers, model-predicted CLOMZ-M1 are 12.5% (5-95% percentile: 3-14.9%) and 44.9% (5-95% percentile: 29.9-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant of omeprazole is 6.93 (5-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients. ConclusionsDevelopmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semiphysiological developmental pharmacokinetic modelling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation."	"[Zhao, Wei] Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China; [Zhao, Wei] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Pharm, Jinan, Shandong, Peoples R China; [Zhao, Wei; Leroux, Stephanie; Jacqz-Aigrain, Evelyne] Robert Debre Univ Hosp, AP HP, Dept Paediat Pharmacol & Pharmacogenet, Paris, France; [Leroux, Stephanie] Rennes Univ Hosp, Dept Neonatol, Rennes, France; [Biran, Valerie] Robert Debre Univ Hosp, AP HP, Dept Neonatol, Paris, France; [Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC1426, Paris, France; [Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, EA7323, Paris, France"	"Zhao, W (corresponding author), Shandong Univ, Sch Pharmaceut Sci, Dept Clin Pharm, Jinan, Shandong, Peoples R China.; Jacqz-Aigrain, E (corresponding author), Robert Debre Univ Hosp, Dept Paediat Pharmacol & Pharmacogenet, F-75019 Paris, France."	"zhao4wei2@hotmail.com; evelyne.jacqzaigrain@gmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"National Science and Technology Major Projects for Major New Drugs Innovation and Development [2017ZX09304029-002]; Young Taishan Scholars Program; Young Scholars Program of Shandong University; Global Research in Paediatrics Network of Excellence (GRIP, EU) [261060]; French Ministry of Health [AOM05123]"	"This work is supported by National Science and Technology Major Projects for Major New Drugs Innovation and Development (2017ZX09304029-002), Young Taishan Scholars Program, Young Scholars Program of Shandong University, Global Research in Paediatrics Network of Excellence (GRIP, EU-funded FP7 project, Grant Agreement number 261060) and a grant from the French Ministry of Health (AOM05123)."	33	3	3	2	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAY"	2018	84	5	997	1005	"NA"	"10.1111/bcp.13526"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GD0CQ"	"WOS:000430167400017"	29377228	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Boucher, M; Bennetts, M"	"Boucher, Martin; Bennetts, Meg"	"NA"	"M"	"Many Flavors of Model-Based Meta-Analysis: Part II - Modeling Summary Level Longitudinal Responses"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"MISSING VARIANCE DATA; NETWORK METAANALYSIS; FRACTIONAL POLYNOMIALS; RHEUMATOID-ARTHRITIS; CONTROLLED-TRIAL; EFFICACY; WEIGHT; BENEFIT; NONMEM; PAIN"	"Meta-analyses typically assess comparative treatment response for an end point at specific timepoints across studies. However, during drug development, it is often of interest to understand the response time-course of competitor compounds for a variety of purposes. Examples of such application include informing study design and characterizing the onset, maintenance, and offset of action. This tutorial acts as a points for consideration document, reviews relevant literature, and fits a longitudinal model to an example dataset."	"[Boucher, Martin; Bennetts, Meg] Pfizer Ltd, Dept Pharmacometr, Sandwich, Kent, England"	"Boucher, M (corresponding author), Pfizer Ltd, Dept Pharmacometr, Sandwich, Kent, England."	"martin.boucher@pfizer.com"	"NA"	"NA"	"NA"	"NA"	33	4	4	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"MAY"	2018	7	5	288	297	"NA"	"10.1002/psp4.12299"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GI0UR"	"WOS:000434085800002"	29569841	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Bijleveld, YA; de Haan, TR; van der Lee, JH; Groenendaal, F; Dijk, PH; van Heijst, A; de Jonge, RCJ; Dijkman, KP; van Straaten, HLM; Rijken, M; Zonnenberg, IA; Cools, F; Zecic, A; Nuytemans, DHGM; van Kaam, AH; Mathot, RAA"	"Bijleveld, Yuma A.; de Haan, Timo R.; van der Lee, Johanna H.; Groenendaal, Floris; Dijk, Peter H.; van Heijst, Arno; de Jonge, Rogier C. J.; Dijkman, Koen P.; van Straaten, Henrica L. M.; Rijken, Monique; Zonnenberg, Inge A.; Cools, Filip; Zecic, Alexandra; Nuytemans, Debbie H. G. M.; van Kaam, Anton H.; Mathot, Ron A. A."	"PharmaCool Study Grp"	"A"	"Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"benzylpenicillin; moderate hypothermia; neonate; perinatal asphyxia; population pharmacokinetics"	"HYPOXIC-ISCHEMIC ENCEPHALOPATHY; PERINATAL ASPHYXIA; PENICILLIN-G; POPULATION PHARMACOKINETICS; INFANTS; DRUGS; MODEL; BIRTH; SEIZURES; NEUROTOXICITY"	"The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5 degrees C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and >= 42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development."	"[Bijleveld, Yuma A.; Mathot, Ron A. A.] Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands; [de Haan, Timo R.; Nuytemans, Debbie H. G. M.; van Kaam, Anton H.] Acad Med Ctr, Emma Childrens Hosp, Dept Neonatol, Amsterdam, Netherlands; [van der Lee, Johanna H.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Paediat Clin Res Off, Amsterdam, Netherlands; [Groenendaal, Floris] Wilhelmina Childrens Hosp, Dept Neonatol, Utrecht, Netherlands; [Groenendaal, Floris] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands; [Dijk, Peter H.] Univ Groningen, Dept Neonatol, Groningen, Netherlands; [van Heijst, Arno] Radboud Univ Nijmegen, Dept Neonatol, Med Ctr, Nijmegen, Netherlands; [de Jonge, Rogier C. J.] Erasmus MC Sophia Childrens Hosp, Div Neonatol, Dept Pediat, Rotterdam, Netherlands; [Dijkman, Koen P.; van Kaam, Anton H.] Maxima Med Ctr Veldhoven, Dept Neonatol, Veldhoven, Netherlands; [van Straaten, Henrica L. M.] Isala Clin, Dept Neonatol, Zwolle, Netherlands; [Rijken, Monique] Leiden Univ, Dept Neonatol, Med Ctr, Leiden, Netherlands; [Zonnenberg, Inge A.] Vrije Univ Amsterdam Med Ctr, Dept Neonatol, Amsterdam, Netherlands; [Cools, Filip] Vrije Univ Brussel, Dept Neonatol, Brussels, Belgium; [Zecic, Alexandra] Univ Hosp Gent, Dept Neonatol, Ghent, Belgium"	"Bijleveld, YA (corresponding author), Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands."	"y.a.bijleveld@amc.nl"	"Groenendaal, Floris/P-6872-2019; de Jonge, R. C.J./M-9912-2014; van Heijst, Arno/P-8527-2014"	"Groenendaal, Floris/0000-0002-9284-1637; de Jonge, R. C.J./0000-0003-0595-1983; van Heijst, Arno/0000-0003-2276-0177; Cools, Filip/0000-0002-6581-7009; Simons, Sinno/0000-0001-5219-5696"	"Dutch government (ZonMw) [40-41500-98-9002]"	"This study was funded by the Dutch government (ZonMw grant number 40-41500-98-9002)."	49	5	5	0	2	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2018	62	4	"NA"	"NA"	"e02311-17"	"10.1128/AAC.02311-17"	13	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"GA5RU"	"WOS:000428392100064"	29378710	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Maksoud, E; Koehl, B; Facchin, A; Ha, P; Zhao, W; Kaguelidou, F; Benkerrou, M; Mariani, P; Faye, A; Lorrot, M; Jacqz-Aigrain, E"	"Maksoud, Elsa; Koehl, Berengere; Facchin, Aude; Phuong Ha; Zhao, Wei; Kaguelidou, Florentia; Benkerrou, Malika; Mariani, Patricia; Faye, Albert; Lorrot, Mathie; Jacqz-Aigrain, Evelyne"	"NA"	"A"	"Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"Monte Carlo simulation; cefotaxime; dosage adaptation; pediatrics; population pharmacokinetics; sickle cell disease"	"NEWER CEPHALOSPORINS; FEBRILE CHILDREN; IN-VITRO; DESACETYLCEFOTAXIME; INFECTIONS; METABOLISM; SUSCEPTIBILITY; VOLUNTEERS; PREDICTORS; MANAGEMENT"	"The pharmacokinetic profile of most drugs is dependent on the patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in pediatric patients with sickle cell disease (SCD), characterized by vaso-occlusive complications, chronic hemolytic anemia, and a defective immunological function predisposing the individual to severe infection. Data on the impact of the disease on the disposition of cefotaxime are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed to children with SCD for suspected or proven bacterial infection, identify significant covariates, and perform Monte Carlo simulations to optimize the drug dosage. Cefotaxime serum concentrations were measured in 78 pediatric SCD patients receiving cefotaxime intravenously at a daily dose of 200 mg/kg of body weight in three or four divided doses over 30 min. A total of 107 concentrations were available for pharmacokinetic analysis. A population pharmacokinetic model was developed with NONMEM software and used for Monte Carlo simulations. Cefotaxime concentrations ranged from 0.05 to 103.7 mg/liter. Cefotaxime pharmacokinetics were best described by a one-compartment model: the median estimated weight-normalized volume of distribution and clearance were 0.42 liter/kg (range, 0.2 to 1.1 liter/kg) and 0.38 liter/h/kg (range, 0.1 to 1.2 liter/h/kg). Cefotaxime clearance increased by 22% in patients with acute chest syndrome. Dosing optimization, performed using EUCAST MIC susceptibility breakpoints, showed that a dose of 100 mg/kg/6 h should be used, depending on the patient's characteristics and clinical presentation, in order to reach a value of the percentage of time that the drug concentration exceeded the MIC under steady-state pharmacokinetic conditions of 80% in 80% of the patients when targeting sensitive Gram-positive cocci and Gram-negative bacilli with MICs of 1 mg/liter or below."	"[Maksoud, Elsa; Facchin, Aude; Phuong Ha; Zhao, Wei; Kaguelidou, Florentia; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France; [Koehl, Berengere; Benkerrou, Malika] Hop Robert Debre, AP HP, Reference Ctr Sickle Cell Dis, Dept Hematol, Paris, France; [Koehl, Berengere; Faye, Albert; Lorrot, Mathie] Hop Robert Debre, AP HP, Dept Pediat, Paris, France; [Kaguelidou, Florentia; Jacqz-Aigrain, Evelyne] Hop Robert Debre, AP HP, Clin Invest Ctr CIC1426, Paris, France; [Mariani, Patricia] Hop Robert Debre, AP HP, Dept Microbiol, Paris, France; [Kaguelidou, Florentia; Faye, Albert; Lorrot, Mathie; Jacqz-Aigrain, Evelyne] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France; [Lorrot, Mathie] Hop Trousseau, AP HP, Dept Pediat, Paris, France"	"Jacqz-Aigrain, E (corresponding author), Hop Robert Debre, AP HP, Dept Pediat Pharmacol & Pharmacogenet, Paris, France."	"evelyne.jacqzaigrain@gmail.com"	"Zhao, Wei/D-3322-2011"	"Zhao, Wei/0000-0002-1830-338X"	"NA"	"NA"	41	5	5	0	6	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2018	62	4	"NA"	"NA"	"e00637-17"	"10.1128/AAC.00637-17"	12	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"GA5RU"	"WOS:000428392100008"	29378711	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Candelaria, M; Gonzalez, D; Gomez, FJF; Paravisini, A; Garcia, AD; Perez, L; Miguel-Lillo, B; Millan, S"	"Candelaria, Myrna; Gonzalez, Derlis; Fernandez Gomez, Francisco Javier; Paravisini, Alexandra; Del Campo Garcia, Ana; Perez, Luis; Miguel-Lillo, Bernardo; Millan, Susana"	"NA"	"A"	"Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83 (TM), a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Rituximab; RTXM83; Population pharmacokinetics; Biosimilar; Diffuse large B-cell lymphoma; Pharmacodynamics; ADA assessment"	"ANTI-CD20 MONOCLONAL-ANTIBODY; CHOP CHEMOTHERAPY; ELDERLY-PATIENTS"	"The main objective was to quantify any potential differences in pharmacokinetic (PK) parameters (AUC and C (max)) between RTXM83, a proposed rituximab biosimilar, and its reference product, using a population PK model approach. Rituximab PK and PD data were obtained from a randomized, double-blind, phase III clinical study (RTXM83-AC-01-11) in patients with diffuse large B-cell lymphoma (DLBCL) that received 375 mg/m(2) intravenous RTXM83 or its reference product with CHOP regimen, every 3 weeks, for six cycles. Rituximab levels were quantified by Meso Scale Discovery assay. PK analysis was performed using NONMEM 7.3.0. The effect of disease and patient covariates on RXTM83 PK was investigated. Model was evaluated using visual predictive check and non-parametric bootstrap. In total, 251 DLBCL patients (127 and 124 in RXTM83-CHOP and rituximab-CHOP arms, respectively) and 5341 serum concentrations (2703 for RXTM83 and 2638 for rituximab, respectively) were available for the population PK analysis. The volume of distribution of the central compartment (V (1)) and clearance of RXTM83 were estimated at 3.19 L and 12.5 mL/h, respectively. Body surface area allowed to explain the interindividual variability for V (1). A statistical analysis showed that systemic exposure (AUC and C (max)) of RTXM83 was similar to rituximab. The 90% confidence intervals for all pairwise comparisons were within the predefined bioequivalence interval of 0.80-1.25. PD similarity of B-cell depletion and recovery was also observed. The time course of RTXM83 was well characterized by the model developed. The systemic exposure of RTXM83 and its associated variability were similar to those for rituximab reference in DLBCL patients, demonstrating PK similarity. The PD similarity of RTXM83 and rituximab reference product was also demonstrated."	"[Candelaria, Myrna] Inst Nacl Cancerol, Ave San Fernando 22,Secc 16, Mexico City, DF, Mexico; [Gonzalez, Derlis] IPHIC, Mariano Roque Alonso 1450, Asuncion, Paraguay; [Fernandez Gomez, Francisco Javier; Paravisini, Alexandra; Del Campo Garcia, Ana; Perez, Luis; Millan, Susana] mAbxience Res SL, Manuel Pombo Angulo 28, Madrid 28050, Spain; [Miguel-Lillo, Bernardo] SGS Exprimo NV, Mechelen, Belgium"	"Gomez, FJF (corresponding author), mAbxience Res SL, Manuel Pombo Angulo 28, Madrid 28050, Spain."	"javierfergo@outlook.com"	"NA"	"NA"	"Mabxience Research SL"	"This study was supported by Mabxience Research SL."	32	17	16	0	4	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"MAR"	2018	81	3	515	527	"NA"	"10.1007/s00280-018-3524-9"	13	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"FX4PJ"	"WOS:000426060100009"	29362903	"Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Bijleveld, YA; Mathot, RAA; van der Lee, JH; Groenendaal, F; Dijk, PH; van Heijst, A; Simons, SHP; Dijkman, KP; van Straaten, HLM; Rijken, M; Zonnenberg, IA; Cools, F; Zecic, A; Nuytemans, DHGM; van Kaam, AH; de Haan, TR"	"Bijleveld, Y. A.; Mathot, R. A. A.; van der Lee, J. H.; Groenendaal, F.; Dijk, P. H.; van Heijst, A.; Simons, S. H. P.; Dijkman, K. P.; van Straaten, H. L. M.; Rijken, M.; Zonnenberg, I. A.; Cools, F.; Zecic, A.; Nuytemans, D. H. G. M.; van Kaam, A. H.; de Haan, T. R."	"PharmaCool Study Grp"	"A"	"Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"HYPOXIC-ISCHEMIC ENCEPHALOPATHY; INFANTS; NEWBORNS"	"The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW3,000 g, 2 days PNA (i.e., TEMP 33.5 degrees C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.0 degrees C. The respective contributions of both covariates were 23% and 27%. Based onMonte Carlo simulations we recommend 50 and 75mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively."	"[Bijleveld, Y. A.; Mathot, R. A. A.] Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands; [van Kaam, A. H.; de Haan, T. R.] Acad Med Ctr, Emma Childrens Hosp, Dept Neonatol, Amsterdam, Netherlands; [van der Lee, J. H.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Paediat Clin Res Off, Amsterdam, Netherlands; [Groenendaal, F.] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Neonatol, Utrecht, Netherlands; [Dijk, P. H.] Univ Groningen, Univ Med Ctr Groningen, Dept Neonatol, Groningen, Netherlands; [van Heijst, A.] Radboud Univ Nijmegen, Med Ctr, Dept Neonatol, Nijmegen, Netherlands; [Simons, S. H. P.] Sophia Childrens Univ Hosp, Erasmus MC, Div Neonatol, Dept Pediat, Rotterdam, Netherlands; [Dijkman, K. P.] Maxima Med Ctr Veldhoven, Dept Neonatol, Veldhoven, Netherlands; [van Straaten, H. L. M.] Isala Clin, Dept Neonatol, Zwolle, Netherlands; [Rijken, M.] Leiden Univ, Med Ctr, Dept Neonatol, Leiden, Netherlands; [Zonnenberg, I. A.] Vrije Univ Amsterdam, Med Unit, Dept Neonatol, Amsterdam, Netherlands; [Cools, F.] Vrije Univ Brussel, Dept Neonatol, Brussels, Belgium; [Zecic, A.] Acad Med Ctr, Dept Neonatol, Ghent, Belgium; [Nuytemans, D. H. G. M.] PharmaCool Study, Amsterdam, Netherlands"	"Bijleveld, YA (corresponding author), Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands."	"y.a.bijleveld@amc.nl"	"simons, sinno/AAC-7442-2019; van Heijst, Arno/P-8527-2014; Groenendaal, Floris/P-6872-2019"	"van Heijst, Arno/0000-0003-2276-0177; Groenendaal, Floris/0000-0002-9284-1637; Simons, Sinno/0000-0001-5219-5696; Cools, Filip/0000-0002-6581-7009"	"Dutch Government (ZonMw Grant) [40-41500-98-9002]; Dutch Government (ZonMw Grant) [40-41500-98-9002]"	"Collaborators of the PharmaCool study group are: Mieke J. Brouwer<SUP>4</SUP>, Marcel P. van den Broek<SUP>4</SUP>, Carin M. A. Rademaker<SUP>4</SUP>, Djien Liem<SUP>6</SUP>, Katerina Steiner<SUP>6</SUP>, Rogier C.J. de Jonge<SUP>7</SUP>, Annelies A. Bos<SUP>7</SUP>, S. M. Mulder-de Tollenaer<SUP>9</SUP>, L.J.M. Groot Jebbink-Akkerman<SUP>9</SUP>, Michel Sonnaert<SUP>12</SUP>, Fleur Anne Camfferman. <SUP>12</SUP> Funding for this study was received from the Dutch Government (ZonMw Grant number: 40-41500-98-9002). The authors thank Irmgard Corten of the Clinical Research Unit (CRU) of the Academic Medical Center (CRU) for contributions with regard to data management."	40	9	9	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"MAR"	2018	103	3	458	467	"NA"	"10.1002/cpt.748"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FV4CB"	"WOS:000424520000026"	28555724	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Sharma, VD; Combes, FP; Vakilynejad, M; Lahu, G; Lesko, LJ; Trame, MN"	"Sharma, Vishnu D.; Combes, Francois P.; Vakilynejad, Majid; Lahu, Gezim; Lesko, Lawrence J.; Trame, Mirjam N."	"NA"	"A"	"Model-Based Approach to Predict Adherence to Protocol During Antiobesity Trials"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Nonlinear Mixed-Effect Models; Population Pharmacodynamics; NONMEM; Obesity; Markov Model; Contrave (R); Clinical Trials"	"NALTREXONE SR/BUPROPION SR; MIXED EFFECT MODELS; BODY-MASS INDEX; POPULATION PHARMACOKINETICS; DRUG DEVELOPMENT; OBESITY; WEIGHT; PARAMETERS; COMBINATION; PREVALENCE"	"Development of antiobesity drugs is continuously challenged by high dropout rates during clinical trials. The objective was to develop a population pharmacodynamic model that describes the temporal changes in body weight, considering disease progression, lifestyle intervention, and drug effects. Markov modeling (MM) was applied for quantification and characterization of responder and nonresponder as key drivers of dropout rates, to ultimately support the clinical trial simulations and the outcome in terms of trial adherence. Subjects (n = 4591) from 6 Contrave((R)) trials were included in this analysis. An indirect-response model developed by van Wart et al was used as a starting point. Inclusion of drug effect was dose driven using a population dose- and time-dependent pharmacodynamic (DTPD) model. Additionally, a population-pharmacokinetic parameter- and data (PPPD)-driven model was developed using the final DTPD model structure and final parameter estimates from a previously developed population pharmacokinetic model based on available Contrave((R)) pharmacokinetic concentrations. Last, MM was developed to predict transition rate probabilities among responder, nonresponder, and dropout states driven by the pharmacodynamic effect resulting from the DTPD or PPPD model. Covariates included in the models and parameters were diabetes mellitus and race. The linked DTPD-MM and PPPD-MM was able to predict transition rates among responder, nonresponder, and dropout states well. The analysis concluded that body-weight change is an important factor influencing dropout rates, and the MM depicted that overall a DTPD model-driven approach provides a reasonable prediction of clinical trial outcome probabilities similar to a pharmacokinetic-driven approach."	"[Sharma, Vishnu D.; Combes, Francois P.; Lesko, Lawrence J.; Trame, Mirjam N.] Univ Florida, Dept Pharmaceut, Coll Pharm, Ctr Pharmacometr & Syst Pharmacol, Orlando, FL USA; [Vakilynejad, Majid] Takeda Pharmaceut Res Div, Pharmacometr, Deerfield, IL USA; [Lahu, Gezim] Takeda Pharmaceut Res Div, Pharmacometr, Zurich, Switzerland"	"Trame, MN (corresponding author), Coll Pharm, Dept Pharmaceut, Ctr Pharmacometr & Syst Pharmacol, 6550 Sanger Rd, Orlando, FL 32827 USA."	"mtrame@cop.ufl.edu"	"Combes, Francoise/F-6046-2011"	"Combes, Francoise/0000-0003-2658-7893; combes, francois/0000-0002-8637-7372"	"Takeda Pharmaceuticals Research Division, Pharmacometrics, Deerfield, IL, USA"	"This work was supported by Takeda Pharmaceuticals Research Division, Pharmacometrics, Deerfield, IL, USA."	37	2	2	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"FEB"	2018	58	2	240	253	"NA"	"10.1002/jcph.994"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FS4JC"	"WOS:000419755500013"	28858397	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Flint, RB; Brouwer, CNM; Kranzlin, ASC; Lie-A-Huen, L; Bos, AP; Mathot, RAA"	"Flint, Robert B.; Brouwer, Carole N. M.; Kranzlin, Anne S. C.; Lie-A-Huen, Loraine; Bos, Albert P.; Mathot, Ron A. A."	"NA"	"A"	"Pharmacokinetics of S-ketamine during prolonged sedation at the pediatric intensive care unit"	"PEDIATRIC ANESTHESIA"	"English"	"Article"	"children; long-term; pharmacokinetics; sedation; S-ketamine; S-norketamine"	"LIVER MICROSOMAL PREPARATIONS; POPULATION PHARMACOKINETICS; COMPARATIVE PHARMACOLOGY; HEALTHY-VOLUNTEERS; CHILDREN; MODEL; NORKETAMINE; NONMEM; PAIN; RAT"	"BackgroundS-ketamine is the S()-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation. AimsThe aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18years during long-term sedation. Twenty-five children (median age: 0.42years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the power model. ResultsA total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CLS-KETAMINE=112L/h/70kg, V1(S-KETAMINE)=7.7L/70kg, V2(S-KETAMINE)=545L/70kg, Q(S-kETAMINE)=196L/h/70kg, and CLS-NORKETAMINE=53L/h/70kg. Interpatient variability of CLS-KETAMINE and CLS-NORKETAMINE was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. ConclusionSubstantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation."	"[Flint, Robert B.; Lie-A-Huen, Loraine; Mathot, Ron A. A.] Acad Med Ctr, Dept Hosp Pharm, Amsterdam, Netherlands; [Brouwer, Carole N. M.; Kranzlin, Anne S. C.; Bos, Albert P.] Acad Med Ctr, Pediat Intens Care, Amsterdam, Netherlands; [Kranzlin, Anne S. C.] Acad Med Ctr, Dept Anesthesiol, Amsterdam, Netherlands"	"Mathot, RAA (corresponding author), Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands."	"r.mathot@amc.uva.nl"	"Flint, Robert B/A-1862-2016"	"Flint, Robert B/0000-0002-3658-594X"	"NA"	"NA"	36	0	0	0	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1155-5645"	"1460-9592"	"NA"	"PEDIATR ANESTH"	"Pediatr. Anesth."	"NOV"	2017	27	11	1098	1107	"NA"	"10.1111/pan.13239"	10	"Anesthesiology; Pediatrics"	"Anesthesiology; Pediatrics"	"FJ7IX"	"WOS:000412931600005"	29030928	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bulitta, JB; Paik, SH; Chi, YH; Kim, TH; Shin, S; Landersdorfer, CB; Jiao, YY; Yadav, R; Shin, BS"	"Bulitta, Jurgen B.; Paik, Soo Heui; Chi, Yong Ha; Kim, Tae Hwan; Shin, Soyoung; Landersdorfer, Cornelia B.; Jiao, Yuanyuan; Yadav, Rajbharan; Shin, Beom Soo"	"NA"	"A"	"Characterizing the time-course of antihypertensive activity and optimal dose range of fimasartan via mechanism-based population modeling"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Angiotensin II receptor blocker; Hypertension cardiovascular activity; Enterohepatic recirculation; Population pharmacokinetics pharmacodynamics; Mechanism-based modeling; Circadian rhythm"	"TO-MODERATE HYPERTENSION; II RECEPTOR ANTAGONIST; BLOOD-PRESSURE; DOUBLE-BLIND; KOREAN PATIENTS; HEALTHY-SUBJECTS; CANCER-PATIENTS; CONSCIOUS RATS; CARDIAC-OUTPUT; PARALLEL-GROUP"	"Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan via a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180 mg fimasartan every 24 h for 28 days and healthy volunteers received placebo or 20 to 480 mg as a single oral dose or as seven doses every 24 h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1 � 7.5 (12.6 � 9.2; mean � SD) mmHg for 20 mg, 14.2 � 7.0 (15.1 � 9.3) mmHg for 60 mg, and 15.9 � 6.8 (11.5 � 9.9) mmHg for 180 mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23 ng/mL fimasartan for diastolic and 12 ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60 mg oral fimasartan given once daily was predicted as optimal dose range."	"[Bulitta, Jurgen B.; Kim, Tae Hwan; Jiao, Yuanyuan] Univ Florida, Coll Pharm, Dept Pharmaceut, Ctr Pharmacometr & Syst Pharmacol, 6550 Sanger Rd, Orlando, FL 32827 USA; [Paik, Soo Heui] Sunchon Natl Univ, Coll Pharm, Sunchon, Jeollanam Do, South Korea; [Chi, Yong Ha] Boryung Pharm Co Ltd, Cent Res Inst, Seoul, South Korea; [Kim, Tae Hwan; Shin, Beom Soo] Sungkyunkwan Univ, Sch Pharm, 300 Cheoncheon Dong, Suwon 440746, Gyeonggi Do, South Korea; [Shin, Soyoung] Wonkwang Univ, Dept Pharm, Coll Pharm, Iksan, South Korea; [Landersdorfer, Cornelia B.; Yadav, Rajbharan] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville Campus, Parkville, Vic, Australia"	"Bulitta, JB (corresponding author), Univ Florida, Coll Pharm, Dept Pharmaceut, Ctr Pharmacometr & Syst Pharmacol, 6550 Sanger Rd, Orlando, FL 32827 USA.; Shin, BS (corresponding author), Sungkyunkwan Univ, Sch Pharm, 300 Cheoncheon Dong, Suwon 440746, Gyeonggi Do, South Korea."	"jbulitta@cop.ufl.edu; bsshin@skku.edu"	"Bulitta, Jurgen B/P-3355-2018; Landersdorfer, Cornelia/I-4103-2019"	"Bulitta, Jurgen B/0000-0001-7352-3097; Landersdorfer, Cornelia/0000-0003-0928-4743; Yadav, Rajbharan/0000-0002-4608-8744"	"Korean Health Technology R & D Project, Ministry of Health & Welfare, Republic of Korea [HI13C1130]; Ministry of Food and Drug Safety (Korea)Ministry of Food & Drug Safety (MFDS) [16173MFDS542]; Australian National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [1062509, 1084163]"	"This study was supported by a research grant of the Korean Health Technology R & D Project, Ministry of Health & Welfare, Republic of Korea (HI13C1130) and partially supported by grant 16173MFDS542 from the Ministry of Food and Drug Safety (Korea). CBL and JBB are the recipients of Career Development Fellowships by the Australian National Health and Medical Research Council (NHMRC, fellowship: 1062509 to CBL and 1084163 to JBB). Parts of this work have been presented as a poster (abstract W-057) at the Sixth American Conference on Pharmacometrics (ACoP6) in Crystal City, VA (October 5-8, 2015), and as a poster (Abstract: R6294) at the AAPS 2015 Annual Meetings and Exposition in Orlando, FL (October 25-29, 2015). We thank Mr. Ingo Menhard for support with professional graphical editing."	41	4	4	0	4	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"SEP 30"	2017	107	"NA"	32	44	"NA"	"10.1016/j.ejps.2017.06.008"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FD9IT"	"WOS:000407836700004"	28599987	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kim, TH; Shin, S; Shin, JC; Bulitta, JB; Weon, KY; Yoo, SD; Park, GY; Jeong, SW; Kwon, DR; Min, BS; Woo, MH; Shin, BS"	"Kim, Tae Hwan; Shin, Soyoung; Shin, Jeong Cheol; Bulitta, Jurgen B.; Weon, Kwon-Yeon; Yoo, Sun Dong; Park, Gi-Young; Jeong, Seok Won; Kwon, Dong Rak; Min, Byung Sun; Woo, Mi Hee; Shin, Beom Soo"	"NA"	"A"	"Effect of Sipjeondaebo- Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling"	"MOLECULES"	"English"	"Article"	"herbal medicine; drug-drug interaction; pharmacokinetics; 5-FU; gimeracil; Sipjeondaebo-tang"	"JUZEN-TAIHO-TO; GASTRIC-CANCER; HERBAL MEDICINE; PHASE-II; CYTOCHROME-P450 2A6; 5-FLUOROURACIL; TEGAFUR; PHARMACODYNAMICS; BIOACTIVATION; GROWTH"	"S-1 (TS-1 (R)) is an oral fluoropyrimidine anticancer agent containing tegafur, oteracil, and gimeracil. Sipjeondaebo-tang (SDT) is a traditional oriental herbal medicine that has potential to alleviate chemotherapy-related adverse effects. The aim of the present study was to evaluate the effect of SDT on the pharmacokinetics of S-1. Sprague-Dawley rats were pretreated with a single dose or repeated doses of SDT for seven consecutive days (1200 mg/kg/day). After the completion of pretreatment with SDT, S-1 was orally administered and plasma concentrations of tegafur, its active metabolite 5-FU, and gimeracil were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). A population pharmacokinetic model was developed to evaluate the effect of SDT on pharmacokinetics of tegafur and 5-FU. Although a single dose of SDT did not have any significant effect, the absorption rate of tegafur decreased, and the plasma levels of 5-FU reduced significantly in rats pretreated with SDT for seven days in parallel to the decreased gimeracil concentrations. Population pharmacokinetic modeling also showed the enhanced elimination of 5-FU in the SDT-pretreated group. Repeated doses of SDT may inhibit the absorption of gimeracil, an inhibitor of 5-FU metabolism, resulting in enhanced elimination of 5-FU and decrease its plasma level."	"[Kim, Tae Hwan; Bulitta, Jurgen B.] Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Coll Pharm, Orlando, FL 32827 USA; [Shin, Soyoung] Wonkwang Univ, Coll Pharm, Iksan 54538, Jeonbuk, South Korea; [Shin, Jeong Cheol; Weon, Kwon-Yeon; Jeong, Seok Won; Min, Byung Sun; Woo, Mi Hee] Catholic Univ Daegu, Coll Pharm, 13-13 Hayang Ro, Gyongsan 38430, Gyeongbuk, South Korea; [Yoo, Sun Dong; Shin, Beom Soo] Sungkyunkwan Univ, Sch Pharm, Suwon 16419, Gyeonggi Do, South Korea; [Park, Gi-Young; Kwon, Dong Rak] Catholic Univ Daegu, Sch Med, Dept Rehabil Med, Daegu 42472, South Korea"	"Shin, BS (corresponding author), Sungkyunkwan Univ, Sch Pharm, Suwon 16419, Gyeonggi Do, South Korea."	"taehwan.kim@cop.ufl.edu; shins@wku.ac.kr; sjc0211@gmail.com; JBulitta@cop.ufl.edu; weonky@cu.ac.kr; sdyoo@skku.ac.kr; parkgy@cu.ac.kr; jswpia@gmail.com; coolkwon@cu.ac.kr; bsmin@cu.ac.kr; woomh@cu.ac.kr; bsshin@skku.edu"	"Bulitta, Jurgen B/P-3355-2018"	"Bulitta, Jurgen B/0000-0001-7352-3097; Kim, Tae Hwan/0000-0003-1234-1681; Shin, Soyoung/0000-0001-8328-1087"	"Comprehensive and Interactive Medicine Institute (CIMI); National Research Foundation of Korea (NRF)National Research Foundation of Korea [2015R1D1A1A09059248, 2017R1D1A1A02018615]"	"This work was supported by the Comprehensive and Interactive Medicine Institute (CIMI) and the National Research Foundation of Korea (NRF) Grant nos. 2015R1D1A1A09059248 and 2017R1D1A1A02018615."	36	1	1	0	1	"MDPI"	"BASEL"	"ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND"	"1420-3049"	"NA"	"NA"	"MOLECULES"	"Molecules"	"SEP"	2017	22	9	"NA"	"NA"	1488	"10.3390/molecules22091488"	12	"Biochemistry & Molecular Biology; Chemistry, Multidisciplinary"	"Biochemistry & Molecular Biology; Chemistry"	"FH9AV"	"WOS:000411499400083"	28880240	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Jawien, W; Wilimowska, J; Klys, M; Piekoszewski, W"	"Jawien, Wojciech; Wilimowska, Jolanta; Klys, Malgorzata; Piekoszewski, Wojciech"	"NA"	"A"	"Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning"	"PHARMACOLOGICAL REPORTS"	"English"	"Article"	"Valproic acid; Population pharmacokinetics; Acute poisoning; Metabolic pathway; Monolix"	"ACTIVATED-CHARCOAL; EPILEPTIC PATIENTS; TOXICITY; HEMOPERFUSION; DISPOSITION; MANAGEMENT; CLEARANCE; DRUG"	"Background: Valproic acid (VPA) is a first-line antiepileptic drug. It is used in the treatment of many different types of partial and generalized epileptic seizures. Though the clinical pharmacokinetics of VPA has been well defined, information about pharmacokinetics after overdoses is rare. The aim of this study was to try to build a population pharmacokinetic model that would describe the time course of VPA and its selected metabolites when the drug is ingested in an overdose situation. Methods: Blood samples were collected during admission to the hospital and several times during treatment for poisoning (10 men and 10 women). The concentration of VPA and its metabolites were determined by liquid chromatography coupled with mass spectrometry. For population pharmacokinetic evaluation of VPA and its metabolites, the two-compartment-model was applied. Results: The estimated doses of VPA taken ranged from 6 to 65 g, while the time after ingestion ranged from 1 to 30 h. Results showed that the beta-oxidation process exhibited Michaelis-Menten kinetics becoming saturated during acute intoxication. The same could not be said for the desaturation route. VPA therapy increased the Vmax for beta-oxidation by 59% while decontamination appeared to be of moderate efficacy lowering the F value by 34% on the average. Conclusions: None of the models perfectly described the experimental data. Important factors like the variable degree of protein binding by VPA could not be included in the models. The small number of subjects used in the study made the analysis of more covariates impossible. (C) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved."	"[Jawien, Wojciech] Jagiellonian Univ, Dept Pharmaceut Biophys, Krakow, Poland; [Wilimowska, Jolanta] Univ Hosp Krakow, Dept Diagnost, Krakow, Poland; [Klys, Malgorzata] Jagiellonian Univ, Chair & Dept Forens Med, Krakow, Poland; [Piekoszewski, Wojciech] Jagiellonian Univ, Dept Analyt Chem, Fac Chem, Krakow, Poland; [Piekoszewski, Wojciech] Far Eastern Fed Univ, Sch Biomed, Vladivostok, Russia"	"Piekoszewski, W (corresponding author), Jagiellonian Univ, Dept Analyt Chem, Fac Chem, Krakow, Poland.; Piekoszewski, W (corresponding author), Far Eastern Fed Univ, Sch Biomed, Vladivostok, Russia."	"wpiekosz@tlen.pl"	"Piekoszewski, Wojciech/AAV-5051-2020; Jawien, Wojciech/AAR-9855-2020"	"Jawien, Wojciech/0000-0002-1741-490X"	"NA"	"NA"	31	7	7	0	8	"POLISH ACAD SCIENCES INST PHARMACOLOGY"	"KRAKOW"	"SMETNA 12, 31-343 KRAKOW, POLAND"	"1734-1140"	"NA"	"NA"	"PHARMACOL REP"	"Pharmacol. Rep."	"APR"	2017	69	2	340	349	"NA"	"10.1016/j.pharep.2016.12.003"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"EQ3SK"	"WOS:000397992700019"	28187395	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Cojutti, PG; Ramos-Martin, V; Schiavon, I; Rossi, P; Baraldo, M; Hope, W; Pea, F"	"Cojutti, Pier Giorgio; Ramos-Martin, Virginia; Schiavon, Isabella; Rossi, Paolo; Baraldo, Massimo; Hope, William; Pea, Federico"	"NA"	"A"	"Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"fluoroquinolones; personalized therapy; safety; efficacy; population pharmacokinetics"	"RESPIRATORY-TRACT INFECTIONS; COMMUNITY-ACQUIRED PNEUMONIA; INTRAVENOUS LEVOFLOXACIN; STREPTOCOCCUS-PNEUMONIAE; HEALTHY-VOLUNTEERS; ELDERLY-PATIENTS; 500 MG; FLUOROQUINOLONES; 750-MILLIGRAM; REGIMENS"	"A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399  0.051 x CrCLCKD-EPI [creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC(24)/MIC ratio (>= 95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (> 80%) against Escherichia coli and Haemophilus influenzae, borderline against Staphylococcus aureus, and suboptimal against Pseudomonas aeruginosa. The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of <= 0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens."	"[Cojutti, Pier Giorgio; Baraldo, Massimo; Pea, Federico] Santa Maria della Misericordia Univ Hosp Udine, Inst Clin Pharmacol, Udine, Italy; [Cojutti, Pier Giorgio; Baraldo, Massimo; Pea, Federico] Univ Udine, Dept Expt & Clin Med Sci, Udine, Italy; [Ramos-Martin, Virginia; Hope, William] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Antimicrobial Pharmacodynam & Therapeut, Liverpool, Merseyside, England; [Schiavon, Isabella; Rossi, Paolo] Santa Maria della Misericordia Univ Hosp Udine, Div Internal Med 1, Udine, Italy"	"Pea, F (corresponding author), Santa Maria della Misericordia Univ Hosp Udine, Inst Clin Pharmacol, Udine, Italy.; Pea, F (corresponding author), Univ Udine, Dept Expt & Clin Med Sci, Udine, Italy."	"federico.pea@asuiud.sanita.fvg.it"	"Pea, Federico/O-3636-2019"	"Pea, Federico/0000-0002-6966-7167; Hope, William/0000-0001-6187-878X"	"NA"	"NA"	27	4	4	0	7	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"MAR"	2017	61	3	"NA"	"NA"	"e02134-16"	"10.1128/AAC.02134-16"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"EL4QM"	"WOS:000394605900010"	28031199	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Bijleveld, YA; van den Heuvel, ME; Hodiamont, CJ; Mathot, RAA; de Haan, TR"	"Bijleveld, Yuma A.; van den Heuvel, Maria E.; Hodiamont, Caspar J.; Mathot, Ron A. A.; de Haan, Timo R."	"NA"	"A"	"Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"gentamicin; neonates; pharmacokinetics; MIC"	"GLOMERULAR-FILTRATION-RATE; DOSE DOPAMINE INFUSION; BIRTH-WEIGHT INFANTS; AMIKACIN CLEARANCE; NEONATAL SEPSIS; PREMATURE; PRETERM; AMINOGLYCOSIDES; TOBRAMYCIN; MATURATION"	"The aim of this study was to describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven Gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial MICs found in this population. Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care Unit (NICU) at the Academic Medical Center (AMC), Amsterdam, The Netherlands. A single nonlinear mixed-effects regression analysis (NONMEM) was performed to describe the population PK of gentamicin. Dosage regimens based upon gestational age (GA) were generated using Monte Carlo simulations with the final model. Target values were based on the MIC distribution in our patient population. In total, 136 gentamicin concentrations from 65 (pre) term neonates were included. The PK was best described by an allometric 2-compartment model with postmenstrual age (PMA) as a covariate on clearance (Cl). The MIC distribution (median, 0.75 [range, 0.5 to 1.5] mg/liter) justified a gentamicin target peak concentration of 8 to 12 mg/liter. This study describes the PK of gentamicin in (pre) term neonates. Dosage regimens of 5 mg/kg of body weight every 48 h, 5 mg/kg every 36 h, and 5 mg/kg every 24 h for patients with GAs of <37 weeks, 37 to 40 weeks, and >= 40 weeks, respectively, are recommended."	"[Bijleveld, Yuma A.; Mathot, Ron A. A.] Univ Amsterdam, Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands; [van den Heuvel, Maria E.; de Haan, Timo R.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Dept Neonatol, Amsterdam, Netherlands; [Hodiamont, Caspar J.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, Amsterdam, Netherlands"	"Bijleveld, YA (corresponding author), Univ Amsterdam, Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands."	"y.a.bijleveld@amc.nl"	"NA"	"NA"	"NA"	"NA"	29	7	7	0	1	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JAN"	2017	61	1	"NA"	"NA"	"e01304-16"	"10.1128/AAC.01304-16"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"EK7HC"	"WOS:000394095800018"	27795373	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"de Charry, F; Colomban, O; You, B; Ruffion, A; Paparel, P; Wilbaux, M; Tod, M; Freyer, G; Perrin, P"	"de Charry, Felicite; Colomban, Olivier; You, Benoit; Ruffion, Alain; Paparel, Philippe; Wilbaux, Melanie; Tod, Michel; Freyer, Gilles; Perrin, Paul"	"NA"	"A"	"Identification of Most Aggressive Carcinoma Among Patients Diagnosed With Prostate Cancer Using Mathematical Modeling of Prostate-Specific Antigen Increases"	"CLINICAL GENITOURINARY CANCER"	"English"	"Article"	"Decision support techniques; Models; Prostrate neoplasms; PSA kinetics; Theoretical"	"RADICAL PROSTATECTOMY; BIOMARKERS; GUIDELINES; STANDARD; VELOCITY; SURVIVAL; RISK"	"Mathematical models of prostate-specific antigen (PSA) longitudinal growth can help differentiate aggressive and indolent prostate cancer at diagnosis. The PSA kinetics of 62 patients with benign prostatic hyperplasia and 149 patients with prostate cancer were modeled. A modeled PSA growth rate kinetic parameter (RHO1) was associated with the probability of the D'Amico high-risk group and lower relapse-free survival. Background: Tools for differentiating aggressive and indolent prostate carcinoma (PCa) are needed. Mathematical modeling is a promising approach for longitudinal analysis of tumor marker kinetics. Patients and Methods: The prostate-specific antigen (PSA) increases from patients with PCa and those with benign prostatic hyperplasia (BPH) were retrospectively analyzed using a mathematical model. Using the NONMEM program, individual PSA kinetics were fit to the following equation: [d(PSA)/dt = (PROD.K x exp [RHO1 x t]) x (1 - BPH) - PROD.NK x exp (RHO2 x t) - KELIM x (PSA)], where RHO1 is the PSA production increase rate by PCa cells (PROD.K), RHO2 is the PSA production increase rate by non-PCa cells (PROD.NK), and KELIM is the PSA elimination rate. The comparative value of the modeled kinetic parameters, estimated for each patient, for predicting the D'Amico score and relapse-free survival (RFS) were tested using logistic regression analysis and multivariate survival tests. Results: The PSA kinetics from 62 patients with BPH and 149 patients with PCa before radical prostatectomy were successfully modeled. We identified statistically significant relationships between the PSA growth rate related to cancer cells (RHO1) and the probability of D'Amico high-risk group (less than the median RHO1 vs. at the median or greater: odds ratio, 2.15; 95% confidence interval [CI], 1.00-4.77; P = .05). RHO1 was also a significant prognostic factor for RFS on univariate analysis and against other reported prognostic factors using multivariate Cox tests. Three independent prognostic factors of RFS were found: RHO1 (hazard ratio [ HR], 2.71; 95% CI, 1.25-5.84; P = .01), Gleason score (HR, 8.54; 95% CI, 4.19-17.40; P < .01), and positive surgical margins (HR, 2.04; 95% CI, 1.05-3.97; P = .03). Conclusion: Using a few PSA time points analyzed with a mathematical model (easily manageable in routine practice), it could be possible to determine before surgery whether a patient has presented with aggressive PCa. (C) 2015 Elsevier Inc. All rights reserved."	"[de Charry, Felicite; You, Benoit; Tod, Michel; Freyer, Gilles] HCL, IC, Ctr Hosp Lyon Sud, Oncol Med, Lyon, France; [de Charry, Felicite] HIA Desgenettes, Serv Sante Armees, Serv Med Interne & Oncol, Lyon, France; [Colomban, Olivier; You, Benoit; Wilbaux, Melanie; Tod, Michel; Freyer, Gilles] Univ Lyon 1, Fac Med Lyon Sud, EMR UCBL HCL 3738, F-69365 Lyon, France; [Ruffion, Alain; Paparel, Philippe; Perrin, Paul] Hosp Civils Lyon, Ctr Hosp Lyon Sud, Dept Urol, Lyon, France"	"You, B (corresponding author), Ctr Hosp Lyon Sud, Hosp Civils Lyon, Oncol Med, Chemin Grand Revoyet, F-69495 Lyon, France."	"benoit.you@chu-lyon.fr"	"You, Benoit/M-4558-2014"	"COLOMBAN, OLIVIER/0000-0003-1671-3470"	"NA"	"NA"	33	1	1	0	3	"CIG MEDIA GROUP, LP"	"DALLAS"	"3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA"	"1558-7673"	"1938-0682"	"NA"	"CLIN GENITOURIN CANC"	"Clin. Genitourin. Cancer"	"JUN"	2016	14	3	210	"U117"	"NA"	"10.1016/j.clgc.2015.12.006"	9	"Oncology; Urology & Nephrology"	"Oncology; Urology & Nephrology"	"DN9OR"	"WOS:000377409600009"	26804605	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bijleveld, YA; de Haan, TR; van der Lee, HJH; Groenendaal, F; Dijk, PH; van Heijst, A; de Jonge, RCJ; Dijkman, KP; van Straaten, HLM; Rijken, M; Zonnenberg, IA; Cools, F; Zecic, A; Nuytemans, DHGM; van Kaam, AH; Mathot, RAA"	"Bijleveld, Yuma A.; de Haan, Timo R.; van der Lee, Hanneke J. H.; Groenendaal, Floris; Dijk, Peter H.; van Heijst, Arno; de Jonge, Rogier C. J.; Dijkman, Koen P.; van Straaten, Henrica L. M.; Rijken, Monique; Zonnenberg, Inge A.; Cools, Filip; Zecic, Alexandra; Nuytemans, Debbie H. G. M.; van Kaam, Anton H.; Mathot, Ron A. A."	"PharmaCool Study Grp"	"A"	"Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"controlled hypothermia; gentamicin; neonates; population pharmacokinetics"	"HYPOXIC-ISCHEMIC ENCEPHALOPATHY; THERAPEUTIC HYPOTHERMIA; POPULATION PHARMACOKINETICS; RECEIVING HYPOTHERMIA; GLOMERULAR-FILTRATION; MODEL; CLEARANCE; AMIKACIN; STANDARD; PRETERM"	"AIM(S) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic-ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. METHODS Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the 'PharmaCool Study') were collected. A non-linear mixed-effects regression analysis (NONMEM (R)) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg(-1) h(-1) (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (V-c) was 0.46 l kg(-1) (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg(-1) every 36 h or every 24 h for patients with GA 36-40 weeks and GA 42 weeks, respectively. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Little is known of the pharmacokinetic (PK) properties of gentamicin in neonates receiving controlled hypothermia. Only a few retrospective studies have been performed to evaluate these properties. For example, conflicting data exist with regard to the changes in clearance (CL) of gentamicin in this population. WHAT THIS STUDY ADDS A description of the PK properties of gentamicin in this patient population based on prospectively gathered data was obtained. We found a 29% higher CL during normothermia compared with the hypothermic and rewarming periods. We suggest a new dosing regimen with which adequate peak and trough levels will be acquired."	"[Bijleveld, Yuma A.; Mathot, Ron A. A.] Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands; [de Haan, Timo R.; van Kaam, Anton H.] Emma Childrens Hosp, Acad Med Ctr, Dept Neonatol, Amsterdam, Netherlands; [van der Lee, Hanneke J. H.] Univ Amsterdam, Acad Med Ctr, Div Woman Child, Pediat Clin Res Off, Amsterdam, Netherlands; [Groenendaal, Floris] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Neonatol, Utrecht, Netherlands; [Dijk, Peter H.] Univ Groningen, Univ Med Ctr Groningen, Dept Neonatol, Groningen, Netherlands; [van Heijst, Arno] Radboud Univ Nijmegen, Dept Neonatol, Med Ctr, Nijmegen, Netherlands; [de Jonge, Rogier C. J.] Sophia Childrens Univ Hosp, Erasmus MC, Div Neonatol, Dept Pediat, Rotterdam, Netherlands; [Dijkman, Koen P.] Maxima Med Ctr Veldhoven, Dept Neonatol, Veldhoven, Netherlands; [van Straaten, Henrica L. M.] Isala Clin, Dept Neonatol, Zwolle, Netherlands; [Rijken, Monique] Leiden Univ, Dept Neonatol, Med Ctr, Leiden, Netherlands; [Zonnenberg, Inge A.] Vrije Univ Amsterdam, Dept Neonatol, Med Ctr, Amsterdam, Netherlands; [Cools, Filip] Vrije Univ Brussel, Dept Neonatol, Brussels, Belgium; [Zecic, Alexandra] Acad Med Ctr, Dept Neonatol, Ghent, Belgium; [Nuytemans, Debbie H. G. M.] Clin Res Coordinator PharmaCool Study, Ghent, Belgium"	"Bijleveld, YA (corresponding author), Acad Med Ctr, Dept Pharm, Amsterdam, Netherlands."	"y.a.bijleveld@amc.nl"	"Groenendaal, Floris/P-6872-2019; van Heijst, Arno/P-8527-2014; de Jonge, R. C.J./M-9912-2014"	"Groenendaal, Floris/0000-0002-9284-1637; van Heijst, Arno/0000-0003-2276-0177; de Jonge, R. C.J./0000-0003-0595-1983; Cools, Filip/0000-0002-6581-7009"	"Dutch Government (ZonMw) [40-41 500-98-9002]"	"Funding for this study has been received by the Dutch Government (ZonMw Grant number: 40-41 500-98-9002). The authors thank Irmgard Corten of the Clinical Research Unit Academic medical Centre (CRU) for her contributions with regard to the data management."	31	20	20	1	3	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JUN"	2016	81	6	1067	1077	"NA"	"10.1111/bcp.12883"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DU9AL"	"WOS:000382508500008"	26763684	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Ly, NS; Bulman, ZP; Bulitta, JB; Baron, C; Rao, GG; Holden, PN; Li, J; Sutton, MD; Tsuji, BT"	"Ly, Neang S.; Bulman, Zackery P.; Bulitta, Juergen B.; Baron, Christopher; Rao, Gauri G.; Holden, Patricia N.; Li, Jian; Sutton, Mark D.; Tsuji, Brian T."	"NA"	"A"	"Optimization of Polymyxin B in Combination with Doripenem To Combat Mutator Pseudomonas aeruginosa"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"CRITICALLY-ILL PATIENTS; NEGATIVE BACTERIAL-INFECTIONS; 2-COMPONENT REGULATORY SYSTEM; IN-VITRO ACTIVITY; MULTIDRUG-RESISTANT; CYSTIC-FIBROSIS; POPULATION PHARMACOKINETICS; PHARMACODYNAMIC MODEL; LUNG INFECTION; ANTIMICROBIAL RESISTANCE"	"Development of spontaneous mutations in Pseudomonas aeruginosa has been associated with antibiotic failure, leading to high rates of morbidity and mortality. Our objective was to evaluate the pharmacodynamics of polymyxin B combinations against rapidly evolving P. aeruginosa mutator strains and to characterize the time course of bacterial killing and resistance via mechanism-based mathematical models. Polymyxin B or doripenem alone and in combination were evaluated against six P. aeruginosa strains: wild-type PAO1, mismatch repair (MMR)-deficient (mutS and mutL) strains, and 7,8-dihydro-8-oxo-deoxyguanosine system (GO) base excision repair (BER)-deficient (mutM, mutT, and mutY) strains over 48 h. Pharmacodynamic modeling was performed using S-ADAPT and facilitated by SADAPT-TRAN. Mutator strains displayed higher mutation frequencies than the wild type (>600-fold). Exposure to monotherapy was followed by regrowth, even at high polymyxin B concentrations of up to 16 mg/liter. Polymyxin B and doripenem combinations displayed enhanced killing activity against all strains where complete eradication was achieved for polymyxin B concentrations of >4 mg/liter and doripenem concentrations of 8 mg/liter. Modeling suggested that the proportion of preexisting polymyxin B-resistant subpopulations influenced the pharmacodynamic profiles for each strain uniquely (fraction of resistance values are -8.81 log(10) for the wild type, -4.71 for the mutS mutant, and -7.40 log(10) for the mutM mutant). Our findings provide insight into the optimization of polymyxin B and doripenem combinations against P. aeruginosa mutator strains."	"[Ly, Neang S.; Bulman, Zackery P.; Rao, Gauri G.; Holden, Patricia N.; Tsuji, Brian T.] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Lab Antimicrobial Pharmacodynam, Buffalo, NY USA; [Ly, Neang S.; Bulman, Zackery P.; Rao, Gauri G.; Holden, Patricia N.; Tsuji, Brian T.] SUNY Buffalo, New York State Ctr Excellence Bioinformat & Life, Buffalo, NY USA; [Baron, Christopher; Sutton, Mark D.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Biochem, Buffalo, NY USA; [Li, Jian] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic, Australia; [Bulitta, Juergen B.] Univ Florida, Coll Pharm, Dept Pharmaceut, Orlando, FL USA; [Ly, Neang S.] MedImmune LLC, Clin Pharmacol & DMPK, Mountain View, CA USA"	"Tsuji, BT (corresponding author), SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Lab Antimicrobial Pharmacodynam, Buffalo, NY USA.; Tsuji, BT (corresponding author), SUNY Buffalo, New York State Ctr Excellence Bioinformat & Life, Buffalo, NY USA."	"btsuji@buffalo.edu"	"Li, Jian/I-5538-2016; Bulitta, Jurgen B/P-3355-2018"	"Li, Jian/0000-0001-7953-8230; Bulitta, Jurgen B/0000-0001-7352-3097; Bulman, Zackery/0000-0002-5396-911X; Ly, Neang/0000-0002-5571-0347"	"HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01AI111990]"	"HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Brian T. Tsuji under grant number R01AI111990."	65	9	9	0	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"MAY"	2016	60	5	2870	2880	"NA"	"10.1128/AAC.02377-15"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"DN4NX"	"WOS:000377045600032"	26926641	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Simon, N; Viallet, F; Boulamery, A; Eusebio, A; Gayraud, D; Azulay, JP"	"Simon, N.; Viallet, F.; Boulamery, A.; Eusebio, A.; Gayraud, D.; Azulay, J-P."	"NA"	"A"	"A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"NONMEM; Population pharmacokinetics; Pharmacodynamics; Levodopa; Parkinson's dyskinesia"	"10-YEAR FOLLOW-UP; POPULATION PHARMACOKINETICS; COMPLICATIONS; THERAPY"	"Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 mu g/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 mu g/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 mu g/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia."	"[Simon, N.; Boulamery, A.] Hop St Marguerite, AP HM, CAP TV, Serv Pharmacol Clin, F-13274 Marseille, France; [Simon, N.] Aix Marseille Univ, SESSTIM, IRD, INSERM UMR S 912, F-13385 Marseille, France; [Viallet, F.; Gayraud, D.] Ctr Hosp Intercommunal Aix Pertuis, Serv Neurol, F-13613 Aix En Provence, France; [Viallet, F.] Aix Marseille Univ, Lab Parole & Langage, UMR CNRS 7309, F-13003 Marseille, France; [Eusebio, A.; Azulay, J-P.] CHU Timone, Serv Neurol, Marseille, France"	"Simon, N (corresponding author), Hop St Marguerite, AP HM, CAP TV, Serv Pharmacol Clin, F-13274 Marseille, France.; Simon, N (corresponding author), Aix Marseille Univ, SESSTIM, IRD, INSERM UMR S 912, F-13385 Marseille, France."	"nicolas.Simon@ap-hm.fr"	"Simon, Nicolas/B-1235-2016"	"Simon, Nicolas/0000-0003-4393-2257"	"NA"	"NA"	25	6	6	0	8	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"APR"	2016	72	4	423	430	"NA"	"10.1007/s00228-016-2034-0"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DG6DK"	"WOS:000372172200004"	26936272	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Petit, C; Jullien, V; Samson, A; Guedj, J; Kiechel, JR; Zohar, S; Comets, E"	"Petit, Caroline; Jullien, Vincent; Samson, Adeline; Guedj, Jeremie; Kiechel, Jean-Rene; Zohar, Sarah; Comets, Emmanuelle"	"NA"	"M"	"Designing a Pediatric Study for an Antimalarial Drug by Using Information from Adults"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"PLASMODIUM-FALCIPARUM MALARIA; MIXED EFFECTS MODELS; POPULATION PHARMACOKINETICS; MEFLOQUINE; CHILDREN; CLEARANCE; PREDICTION; SIZE; OPTIMIZATION; ARTEMISININ"	"The objectives of this study were to design a pharmacokinetic (PK) study by using information about adults and evaluate the robustness of the recommended design through a case study of mefloquine. PK data about adults and children were available from two different randomized studies of the treatment of malaria with the same artesunate-mefloquine combination regimen. A recommended design for pediatric studies of mefloquine was optimized on the basis of an extrapolated model built from adult data through the following approach. (i) An adult PK model was built, and parameters were estimated by using the stochastic approximation expectation-maximization algorithm. (ii) Pediatric PK parameters were then obtained by adding allometry and maturation to the adult model. (iii) A D-optimal design for children was obtained with PFIM by assuming the extrapolated design. Finally, the robustness of the recommended design was evaluated in terms of the relative bias and relative standard errors (RSE) of the parameters in a simulation study with four different models and was compared to the empirical design used for the pediatric study. Combining PK modeling, extrapolation, and design optimization led to a design for children with five sampling times. PK parameters were well estimated by this design with few RSE. Although the extrapolated model did not predict the observed mefloquine concentrations in children very accurately, it allowed precise and unbiased estimates across various model assumptions, contrary to the empirical design. Using information from adult studies combined with allometry and maturation can help provide robust designs for pediatric studies."	"[Petit, Caroline; Zohar, Sarah] Univ Paris 06, INSERM, Univ Paris 05, CRC,Team 22,UMRS 1138, Paris, France; [Jullien, Vincent] Univ Paris 05, Dept Pharmacol, Sorbonne Paris Cite, Inserm U1129,HEGP, Paris, France; [Samson, Adeline] Univ Grenoble 1, UMR CNRS 5224, LJK, Grenoble, France; [Guedj, Jeremie; Comets, Emmanuelle] Univ Paris Diderot, INSERM, IAME, UMR 1137 Sorbonne Paris Cite, Paris, France; [Kiechel, Jean-Rene] Drugs Neglected Dis Initiat, Geneva, Switzerland; [Comets, Emmanuelle] Univ Rennes 1, INSERM, CIC 1414, Rennes, France"	"Petit, C (corresponding author), Univ Paris 06, INSERM, Univ Paris 05, CRC,Team 22,UMRS 1138, Paris, France."	"caroline.petit@crc.jussieu.fr"	"Comets, Emmanuelle/C-9328-2017; Zohar, Sarah/A-5026-2016; Guedj, Jeremie/A-6842-2017"	"Guedj, Jeremie/0000-0002-5534-5482; Zohar, Sarah/0000-0002-8429-2340"	"IDEX Paris Cite Sorbonne [24]; InSPiRe [FP HEALTH 2013-602144]"	"IDEX Paris Cite Sorbonne provided funding for this project under grant number 24. InSPiRe provided funding to Sarah Zohar and Emmanuelle Comets under grant agreement FP HEALTH 2013-602144."	40	4	6	0	8	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"MAR"	2016	60	3	1481	1491	"NA"	"10.1128/AAC.01125-15"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"DM6VM"	"WOS:000376490800038"	26711749	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Peigne, S; Fouliard, S; Decourcelle, S; Chenel, M"	"Peigne, Sophie; Fouliard, Sylvain; Decourcelle, Sophie; Chenel, Marylore"	"NA"	"A"	"Model-based approaches for ivabradine development in paediatric population, part II: PK and PK/PD assessment"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Ivabradine; Paediatric; Population pharmacokinetic modelling; Allometric scaling; Maturation function; Pharmacokinetic/pharmacodynamic relationship"	"PHARMACOKINETIC PARAMETERS; HEALTHY-VOLUNTEERS; HEART-RATE; CHILDREN; MIDAZOLAM; SIZE; METABOLITE; PREDICTION; CLEARANCE"	"The objectives of this work were first to describe the pharmacokinetic (PK) of ivabradine and its active metabolite in a paediatric patient population after repeated oral administration of ivabradine using a population PK approach, and secondly to assess whether the blood/plasma ratio and the pharmacokinetic/pharmacodynamic (PK/PD) relationship are preserved in the paediatric population in comparison to adult. PK data for 70 patients were obtained after blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. In order to describe ivabradine and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects on PK parameters. Plasma PK exposure parameters were calculated in children using plasma PK profiles. In order to assess the PK/PD relationship in children, an adult PK/PD model was used. The relationship between blood and plasma concentrations was described using linear mixed effect models. Two and one compartment models best described parent and metabolite dispositions. Weight effects were fixed to the allometric values of 3/4 on clearance (CL) and 1 on volume. A maturation function was added on metabolite formation clearance (CLPM) reflecting enzyme maturation. Plasma exposure comparison indicated that higher dose/kg were necessary to achieve a similar exposure between younger and older children. No differences between age classes were observed in terms of range of exposure at the maintenance dose. The PK/PD relationship in adult patients is conserved in children."	"[Peigne, Sophie; Fouliard, Sylvain; Chenel, Marylore] Inst Rech Int Servier, Clin Pharmacokinet & Pharmacometr Dept, Suresnes, France; [Decourcelle, Sophie] Inst Rech Int Servier, Pole Innovat Cardiol, Suresnes, France"	"Peigne, S (corresponding author), Inst Rech Int Servier, Clin Pharmacokinet & Pharmacometr Dept, Suresnes, France."	"sophie.peigne@servier.com"	"NA"	"NA"	"NA"	"NA"	40	3	3	1	3	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"FEB"	2016	43	1	29	43	"NA"	"10.1007/s10928-015-9452-y"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DK1VV"	"WOS:000374704000003"	26578442	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gonzalez-Sales, M; Barriere, O; Tremblay, PO; Nekka, F; Desrochers, J; Tanguay, M"	"Gonzalez-Sales, Mario; Barriere, Olivier; Tremblay, Pierre-Olivier; Nekka, Fahima; Desrochers, Julie; Tanguay, Mario"	"NA"	"A"	"Modeling Testosterone Circadian Rhythm in Hypogonadal Males: Effect of Age and Circannual Variations"	"AAPS JOURNAL"	"English"	"Article"	"circadian rhythm; NONMEM (R); stretched cosine function; testosterone"	"SEASONAL-VARIATION; HEALTHY-MEN"	"The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysis. The circadian rhythm of the testosterone was described by a stretched cosine function. Model parameters were estimated using NONMEM (R) 7.3. The effect of different covariates on the testosterone levels was investigated. Model evaluation was performed using non-parametric bootstrap and predictive checks. A stretched cosine function deeply improved the data goodness of fit compared to the standard trigonometric function (p<0.001; Delta OFV=-204). The effect of the age and the semester, defined as winter and spring versus summer and fall, were significantly associated with the baseline levels of testosterone (p<0.001, Delta OFV=-15.6, and p<0.001, Delta OFV=-47.0). Model evaluation procedures such as diagnostic plots, visual predictive check, and non-parametric bootstrap evidenced that the proposed stretched cosine function was able to model the time course of the diurnal testosterone levels in hypogonadal males with accuracy and precision. The circadian rhythm of the testosterone levels was better predicted by the proposed stretched cosine function than a standard cosine function. Testosterone levels decreased by 5.74 ng/dL (2.4%) every 10 years and were 19.3 ng/dL (8.1%) higher during winter and spring compared to summer and fall."	"[Gonzalez-Sales, Mario; Nekka, Fahima] Univ Montreal, Montreal, PQ, Canada; [Gonzalez-Sales, Mario; Barriere, Olivier; Tremblay, Pierre-Olivier; Desrochers, Julie; Tanguay, Mario] inVentiv Hlth Clin, Montreal, PQ H3X 2H9, Canada"	"Barriere, O (corresponding author), inVentiv Hlth Clin, 5160 Decarie, Montreal, PQ H3X 2H9, Canada."	"olivier.barriere@inventivhealth.com"	"NA"	"Tanguay, Mario/0000-0001-5352-2871"	"Mitacs ELEVATE; inVentiv Health"	"This work was supported by Mitacs ELEVATE in partnership with inVentiv Health."	25	7	7	0	1	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JAN"	2016	18	1	217	227	"NA"	"10.1208/s12248-015-9841-6"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DA1AY"	"WOS:000367529900019"	26553482	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Perez-Ruixo, C; Valenzuela, B; Peris, JE; Bretcha-Boix, P; Escudero-Ortiz, V; Farre-Alegre, J; Perez-Ruixo, JJ"	"Perez-Ruixo, Carlos; Valenzuela, Belen; Esteban Peris, Jose; Bretcha-Boix, Pedro; Escudero-Ortiz, Vanesa; Farre-Alegre, Jose; Perez-Ruixo, Juan Jose"	"NA"	"A"	"Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin"	"AAPS JOURNAL"	"English"	"Article"	"cytoreductive surgery; hyperthermic intraperitoneal chemotherapy (HIPEC); oxaliplatin; peritoneal carcinomatosis; population pharmacokinetic pharmacodynamic modeling; thrombocytopenia; thrombocytosis"	"HEALTHY-SUBJECTS; POPULATION PHARMACOKINETICS; SURGICAL STRESS; LIFE-SPAN; CHEMOTHERAPY; MODEL; THROMBOCYTOPENIA; CANCER; HIPEC; THROMBOPOIETIN"	"The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N=18) or CRS and HIO (N=62) were used to estimate the baseline platelet count (PLT0), rate constants for platelet maturation (k(tr)) and platelet random destruction (k(s)), feedback on progenitor cell proliferation (gamma), and the drug-specific model parameters (alpha, beta). Plasma oxaliplatin concentrations, C-p, reduced the proliferation rate of progenitor cells (k(prol)) according to a power function alpha xC(p)(beta). The surgery effect on k(prol) and k(s) was explored. The typical values (between subject variability) of the PLT0, k(tr), k(s), gamma, alpha, and beta were estimated to be 237x10(9) cells/L (32.9%), 7.09x10(-3) h(-1) (47.1%), 8.86x10(-3) h(-1) (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k(prol) that was attenuated with a half-life of 8.42 days. Splenectomy decreased k(s) by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity."	"[Perez-Ruixo, Carlos; Esteban Peris, Jose] Univ Valencia, Pharm & Pharmaceut Technol Dept, Valencia, Spain; [Valenzuela, Belen; Bretcha-Boix, Pedro; Farre-Alegre, Jose] Hosp Quiron Torrevieja, Platform Oncol, Torreviejaalicante 03184, Spain; [Valenzuela, Belen; Bretcha-Boix, Pedro; Farre-Alegre, Jose] UCAM Catholic Univ San Antonio, Cathedra Multidisciplinary Oncol, Murcia, Spain; [Escudero-Ortiz, Vanesa] Univ CEU Cardenal Herrera, Pharm & Clin Nutr Grp, Elchealicante, Spain; [Perez-Ruixo, Juan Jose] Janssen Res & Dev, Clin Pharmacol & Pharmacometr, Beerse, Belgium"	"Valenzuela, B (corresponding author), Hosp Quiron Torrevieja, Platform Oncol, Partida Loma S-N, Torreviejaalicante 03184, Spain."	"belen.valenzuela@quiron.es"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"Conselleria de Sanidad of Comunidad Valenciana [GE-079/11]"	"The authors would like to thank the patients and medical, nursing, and laboratory staff of the Hospital Quiron Torrevieja who participated in the present study. This work was supported by Conselleria de Sanidad of Comunidad Valenciana (Grant GE-079/11)."	55	4	4	0	3	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JAN"	2016	18	1	239	250	"NA"	"10.1208/s12248-015-9839-0"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"DA1AY"	"WOS:000367529900021"	26577587	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"You, B; Deng, W; Henin, E; Oza, A; Osborne, R"	"You, Benoit; Deng, Wei; Henin, Emilie; Oza, Amit; Osborne, Raymond"	"NA"	"A"	"Validation of the Predictive Value of Modeled Human Chorionic Gonadotrophin Residual Production in Low-Risk Gestational Trophoblastic Neoplasia Patients Treated in NRG Oncology/Gynecologic Oncology Group-174 Phase III Trial"	"INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER"	"English"	"Article"	"Chorionic gonadotropin; Dactinomycin; Drug resistance; Gestational trophoblastic neoplasia; Methotrexate; Prognosis"	"SINGLE-AGENT METHOTREXATE; RESISTANCE; QUANTIFICATION; CHEMOTHERAPY; TUMORS"	"Objectives In low-risk gestational trophoblastic neoplasia, chemotherapy effect is monitored and adjusted with serum human chorionic gonadotrophin (hCG) levels. Mathematical modeling of hCG kinetics may allow prediction of methotrexate (MTX) resistance, with production parameter hCGres. This approach was evaluated using the GOG-174 (NRG Oncology/Gynecologic Oncology Group-174) trial database, in which weekly MTX (arm 1) was compared with dactinomycin (arm 2). Methods Database (210 patients, including 78 with resistance) was split into 2 sets. A 126-patient training set was initially used to estimate model parameters. Patient hCG kinetics from days 7 to 45 were fit to: [hCG(time)] = hCG7 * exp(-k * time)  hCGres, where hCGres is residual hCG tumor production, hCG7 is the initial hCG level, and k is the elimination rate constant. Receiver operating characteristic (ROC) analyses defined putative hCGRes predictor of resistance. An 84-patient test set was used to assess prediction validity. Results The hCGres was predictive of outcome in both arms, with no impact of treatment arm on unexplained variability of kinetic parameter estimates. The best hCGres cutoffs to discriminate resistant versus sensitive patients were 7.7 and 74.0 IU/L in arms 1 and 2, respectively. By combining them, 2 predictive groups were defined (ROC area under the curve, 0.82; sensitivity, 93.8%; specificity, 70.5%). The predictive value of hCGres-based groups regarding resistance was reproducible in test set (ROC area under the curve, 0.81; sensitivity, 88.9%; specificity, 73.1%). Both hCGres and treatment arm were associated with resistance by logistic regression analysis. Conclusions The early predictive value of the modeled kinetic parameter hCGres regarding resistance seems promising in the GOG-174 study. This is the second positive evaluation of this approach. Prospective validation is warranted."	"[You, Benoit; Henin, Emilie] Univ Lyon 1, Inst Cancerol, Hosp Civils Lyon IC HCL, Hosp Civils Lyon,Ctr Reference Malad Trophoblast, F-69365 Lyon, France; [Deng, Wei] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA; [Oza, Amit] Toronto Sunnybrook Reg Canc Ctr, Dept Oncol, Princess Margaret Hosp, Toronto, ON, Canada; [Osborne, Raymond] Toronto Sunnybrook Reg Canc Ctr, Dept Gynecol Oncol, Toronto, ON, Canada"	"You, B (corresponding author), Ctr Hosp Lyon Sud, Hosp Civils Lyon, Med Oncol Serv, 165 Chemin Grand Revoyet, F-69495 Pierre Benite, France."	"benoit.you@chu-lyon.fr"	"You, Benoit/M-4558-2014"	"Oza, Amit/0000-0002-9510-8641"	"National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA27469]; Gynecologic Oncology Group Statistics and Data Center [CA37517]; NRG Oncology [1 U10CA180822.]"	"This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469), the Gynecologic Oncology Group Statistics and Data Center (CA37517), and the NRG Oncology 1 U10CA180822."	27	4	7	0	4	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"1048-891X"	"1525-1438"	"NA"	"INT J GYNECOL CANCER"	"Int. J. Gynecol. Cancer"	"JAN"	2016	26	1	208	215	"NA"	"10.1097/IGC.0000000000000581"	8	"Oncology; Obstetrics & Gynecology"	"Oncology; Obstetrics & Gynecology"	"DA1DU"	"WOS:000367537300028"	26569059	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Vandenberghe, F; Guidi, M; Choong, E; von Gunten, A; Conus, P; Csajka, C; Eap, CB"	"Vandenberghe, Frederik; Guidi, Monia; Choong, Eva; von Gunten, Armin; Conus, Philippe; Csajka, Chantal; Eap, Chin B."	"NA"	"A"	"Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"PALIPERIDONE EXTENDED-RELEASE; PREGNANE-X-RECEPTOR; KOREAN SCHIZOPHRENIC-PATIENTS; DRUG-DRUG INTERACTIONS; PLASMA-CONCENTRATIONS; CYTOCHROME-P450 2D6; 9-HYDROXY METABOLITE; HEALTHY-VOLUNTEERS; CLINICAL-RESPONSE; CYP2D6 GENOTYPES"	"Background High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. Objective Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. Methods Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPAR alpha, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEMA (R)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. Results The cytochrome P450 (CYP) 2D6 phenotype explained 52 % of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28 % higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26 % with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration > 40 ng/mL should be targeted only in cases of insufficient, or absence of, response. Conclusions Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment."	"[Vandenberghe, Frederik; Choong, Eva] Univ Lausanne Hosp, Unit Pharmacogenet & Clin Psychopharmacol, Ctr Psychiat Neurosci, Dept Psychiat,Hosp Cery, CH-1008 Prilly, Switzerland; [Guidi, Monia; Csajka, Chantal] Univ Lausanne Hosp, Dept Labs, Div Clin Pharmacol, Lausanne, Switzerland; [von Gunten, Armin] Univ Lausanne Hosp, Dept Psychiat, Serv Old Age Psychiat, CH-1008 Prilly, Switzerland; [Conus, Philippe] Univ Lausanne Hosp, Dept Psychiat, Serv Gen Psychiat, CH-1008 Prilly, Switzerland; [Guidi, Monia; Csajka, Chantal; Eap, Chin B.] Univ Lausanne, Univ Geneva, Sch Pharmaceut Sci, Geneva, Switzerland"	"Eap, CB (corresponding author), Univ Lausanne Hosp, Unit Pharmacogenet & Clin Psychopharmacol, Ctr Psychiat Neurosci, Dept Psychiat,Hosp Cery, CH-1008 Prilly, Switzerland."	"chin.eap@chuv.ch"	"Choong, Eva/F-1570-2019"	"Choong, Eva/0000-0001-6776-4978; Guidi, Monia/0000-0002-6419-9317; Csajka, Chantal/0000-0002-0660-082X; Eap, Chin/0000-0002-5439-0230; Vandenberghe, Frederik/0000-0002-8964-2047; von Gunten, Armin/0000-0001-7852-3803"	"Swiss National Research FoundationSwiss National Science Foundation (SNSF) [320030-120686, 324730-144064]"	"This work has been funded in part by the Swiss National Research Foundation (CBE and PC: 320030-120686 and 324730-144064)."	73	19	21	0	8	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2015	54	12	1259	1272	"NA"	"10.1007/s40262-015-0289-8"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CX5BU"	"WOS:000365716700006"	26129906	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Brill, MJ; van Rongen, A; van Dongen, EP; van Ramshorst, B; Hazebroek, EJ; Darwich, AS; Rostami-Hodjegan, A; Knibbe, CA"	"Brill, Margreke J.; van Rongen, Anne; van Dongen, Eric P.; van Ramshorst, Bert; Hazebroek, Eric J.; Darwich, Adam S.; Rostami-Hodjegan, Amin; Knibbe, Catherijne A."	"NA"	"A"	"The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients Before and One Year After Bariatric Surgery"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"bariatric surgery; midazolam; pharmacokinetics; CYP3A"	"DRUG-METABOLIZING-ENZYMES; CARDIOVASCULAR RISK; HEALTHY-VOLUNTEERS; HEPATIC STEATOSIS; INFLAMMATION; LIVER; MODEL; TRANSPORTERS; METAANALYSIS; ABSORPTION"	"Bariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m(2)). As information about the effects of this procedure on a drug's pharmacokinetics is limited, we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients that was studied before and 1 year post bariatric surgery. Twenty morbidly obese patients (aged 26-58 years) undergoing bariatric surgery participated in the study of which 18 patients returned 1 year after surgery. At both occasions, patients received 7.5 mg oral and 5 mg intravenous midazolam separated by 160 � 48 min. Per patient and occasion, a mean of 22 blood samples were collected. Midazolam concentrations were analyzed using population pharmacokinetic modeling. One year after bariatric surgery, systemic clearance of midazolam was higher [0.65 (7%) versus 0.39 (11%) L/min, mean � RSE (P < 0.01), respectively] and mean oral transit time (MTT) was faster [23 (20%) versus 51 (15%) minutes (P < 0.01)], while oral bioavailability was unchanged (0.54 (9%)). Central and peripheral volumes of distribution were overall lower (P < 0.05). In this cohort study in morbidly obese patients, systemic clearance was 1.7 times higher 1 year after bariatric surgery, which may potentially result from an increase in hepatic CYP3A activity per unit of liver weight. Although MTT was found to be faster, oral bioavailability remained unchanged, which considering the increased systemic clearance implies an increase in the fraction escaping intestinal first pass metabolism."	"[Brill, Margreke J.; van Rongen, Anne; Knibbe, Catherijne A.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Brill, Margreke J.; van Rongen, Anne; Knibbe, Catherijne A.] St Antonius Hosp, Dept Clin Pharm, NL-3435 CM Nieuwegein, Netherlands; [van Dongen, Eric P.] St Antonius Hosp, Dept Anaesthesiol & Intens Care, NL-3435 CM Nieuwegein, Netherlands; [van Ramshorst, Bert; Hazebroek, Eric J.] St Antonius Hosp, Dept Surg, NL-3435 CM Nieuwegein, Netherlands; [Darwich, Adam S.; Rostami-Hodjegan, Amin] Univ Manchester, Manchester Pharm Sch, Manchester, Lancs, England"	"Knibbe, CA (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"NA"	"Rostami-Hodjegan, Amin/0000-0003-3917-844X"	"ZonMW (The Netherlands Organisation for Health Research and Development)Netherlands Organization for Health Research and Development [836011008]"	"This study was sponsored by ZonMW (The Netherlands Organisation for Health Research and Development), project number: 836011008. The authors declare no conflicts of interest."	50	27	27	0	5	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"DEC"	2015	32	12	3927	3936	"NA"	"10.1007/s11095-015-1752-9"	10	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"CV0QK"	"WOS:000363955900012"	26202517	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Largajolli, A; Bertoldo, A; Campioni, M; Cobelli, C"	"Largajolli, Anna; Bertoldo, Alessandra; Campioni, Marco; Cobelli, Claudio"	"NA"	"M"	"Visual Predictive Check in Models with Time-Varying Input Function"	"AAPS JOURNAL"	"English"	"Article"	"mixed-effect modeling; model diagnostic; models using input function; visual predictive check"	"GLUCOSE MINIMAL MODEL; INSULIN SENSITIVITY; SECRETION; PHARMACOKINETICS; WARFARIN"	"The nonlinear mixed effects models are commonly used modeling techniques in the pharmaceutical research as they enable the characterization of the individual profiles together with the population to which the individuals belong. To ensure a correct use of them is fundamental to provide powerful diagnostic tools that are able to evaluate the predictive performance of the models. The visual predictive check (VPC) is a commonly used tool that helps the user to check by visual inspection if the model is able to reproduce the variability and the main trend of the observed data. However, the simulation from the model is not always trivial, for example, when using models with time-varying input function (IF). In this class of models, there is a potential mismatch between each set of simulated parameters and the associated individual IF which can cause an incorrect profile simulation. We introduce a refinement of the VPC by taking in consideration a correlation term (the Mahalanobis or normalized Euclidean distance) that helps the association of the correct IF with the individual set of simulated parameters. We investigate and compare its performance with the standard VPC in models of the glucose and insulin system applied on real and simulated data and in a simulated pharmacokinetic/pharmacodynamic (PK/PD) example. The newly proposed VPC performance appears to be better with respect to the standard VPC especially for the models with big variability in the IF where the probability of simulating incorrect profiles is higher."	"[Largajolli, Anna; Bertoldo, Alessandra; Cobelli, Claudio] Univ Padua, Dept Informat Engn, I-35131 Padua, Italy; [Campioni, Marco] Merck KGaA, Exploratory Med, Darmstadt, Germany"	"Bertoldo, A (corresponding author), Univ Padua, Dept Informat Engn, Via G Gradenigo 6-B, I-35131 Padua, Italy."	"bertoldo@dei.unipd.it"	"NA"	"NA"	"NA"	"NA"	22	1	1	0	3	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"NOV"	2015	17	6	1455	1463	"NA"	"10.1208/s12248-015-9808-7"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CV2RJ"	"WOS:000364104100014"	26265094	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"You, B; Salles, G; Bachy, E; Casasnovas, O; Tilly, H; Ribrag, V; Sebban, C; Henin, E; Guitton, J; Tod, M; Freyer, G"	"You, Benoit; Salles, Gilles; Bachy, Emmanuel; Casasnovas, Olivier; Tilly, Herve; Ribrag, Vincent; Sebban, Catherine; Henin, Emilie; Guitton, Jeome; Tod, Michel; Freyer, Gilles"	"NA"	"A"	"Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA)"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Etoposide; Lymphoma; Non-Hodgkin; Pharmacokinetics; Survival; Stem cell transplantations"	"STEM-CELL TRANSPLANTATION; NON-HODGKINS-LYMPHOMA; POPULATION PHARMACOKINETICS; RANDOMIZED-TRIAL; LUNG-CANCER; CHEMOTHERAPY; DISEASE; CONSOLIDATION; SURVIVAL"	"Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients. The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEMA (R) program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses. A total of 91 patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL): 79; Hodgkin's lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC (min), categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC (min) was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS. This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment."	"[You, Benoit; Henin, Emilie; Guitton, Jeome; Tod, Michel; Freyer, Gilles] Univ Lyon 1, Fac Med Lyon Sud, EMR UCBL, HCL 3738, F-69365 Lyon, France; [You, Benoit; Henin, Emilie; Guitton, Jeome; Tod, Michel; Freyer, Gilles] Ctr Hosp Lyon Sud, Hosp Civils Lyon, Med Oncol Serv, CITOHL, F-69495 Pierre Benite, France; [Salles, Gilles; Bachy, Emmanuel] Ctr Hosp Lyon Sud, Serv Hematol, Inst Cancerol, Hosp Civils Lyon, Pierre Benite, France; [Salles, Gilles; Bachy, Emmanuel] Univ Lyon 1, F-69365 Lyon, France; [Casasnovas, Olivier] Ctr Hosp Univ Dijon, Serv Hematol, CITOHL, F-21034 Dijon, France; [Tilly, Herve] Ctr Henri Becquerel, F-76038 Rouen, France; [Ribrag, Vincent] Inst Gustave Roussy, F-94805 Villejuif, France; [Sebban, Catherine] Ctr Leon Berard, F-69008 Lyon, France"	"You, B (corresponding author), Univ Lyon 1, Fac Med Lyon Sud, EMR UCBL, HCL 3738, F-69365 Lyon, France."	"benoit.you@chu-lyon.fr"	"Salles, Gilles/Z-2336-2019; Bachy, Emmanuel/M-4678-2014; You, Benoit/M-4558-2014"	"Bachy, Emmanuel/0000-0003-2694-7510; Casasnovas, Rene-Olivier/0000-0002-1156-8983; Guitton, Jerome/0000-0001-6180-5708"	"French Programme Hospitalier de Recherche Clinique (PHRC)"	"The study was supported by a French Programme Hospitalier de Recherche Clinique (PHRC) obtained in 2001."	28	6	7	0	3	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"NOV"	2015	76	5	939	948	"NA"	"10.1007/s00280-015-2866-9"	10	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"CU0YR"	"WOS:000363245800007"	26391155	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Fauchet, F; Treluyer, JM; Illamola, SM; Pressiat, C; Lui, G; Valade, E; Mandelbrot, L; Lechedanec, J; Delmas, S; Blanche, S; Warszawski, J; Urien, S; Tubiana, R; Hirt, D"	"Fauchet, Floris; Treluyer, Jean-Marc; Illamola, Silvia M.; Pressiat, Claire; Lui, Gabrielle; Valade, Elodie; Mandelbrot, Laurent; Lechedanec, Jerome; Delmas, Sandrine; Blanche, Stephane; Warszawski, Josiane; Urien, Saik; Tubiana, Roland; Hirt, Deborah"	"ANRS 135 Primeva Study Grp"	"A"	"Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"PLASMA-CONCENTRATIONS; PROTEASE INHIBITORS; MITOCHONDRIAL DYSFUNCTION; ANTIRETROVIRAL DRUGS; UNINFECTED CHILDREN; NUCLEOSIDE ANALOGS; EXPOSURE; RITONAVIR; BINDING; LOPINAVIR/RITONAVIR"	"The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy."	"[Fauchet, Floris; Treluyer, Jean-Marc; Illamola, Silvia M.; Pressiat, Claire; Lui, Gabrielle; Valade, Elodie; Blanche, Stephane; Urien, Saik; Hirt, Deborah] Univ Paris 05, EA 08, Sorbonne Paris Cite, Paris, France; [Fauchet, Floris; Treluyer, Jean-Marc; Illamola, Silvia M.; Pressiat, Claire; Lui, Gabrielle; Valade, Elodie; Urien, Saik] Hop Tarnier, AP HP, Unite Rech Clin, Paris, France; [Treluyer, Jean-Marc; Hirt, Deborah] Grp Hosp Pris Ctr, AP HP, Serv Pharmacol Clin, Paris, France; [Treluyer, Jean-Marc; Urien, Saik] INSERM, CIC 0901, Paris, France; [Mandelbrot, Laurent; Lechedanec, Jerome; Delmas, Sandrine; Warszawski, Josiane] Equipe VIH & IST, Ctr Res Epidemiol & Populat Hlth, INSERM, U1018, Le Kremlin Bicetre, France; [Mandelbrot, Laurent] HUPNVS, Hop Louis Mourier, AP HP, Serv Gynecol & Obstet, Colombes, France; [Mandelbrot, Laurent] Univ Paris 07, Paris, France; [Delmas, Sandrine; Warszawski, Josiane] Hop Bicetre, AP HP, Serv Epidemiol & Sante Publ, Le Kremlin Bicetre, France; [Blanche, Stephane] Hop Necker Enfants Malad, AP HP, Unite Immunol Hematol Pediat, Paris, France; [Tubiana, Roland] Univ Paris 06, Sorbonne Univ, Pierre Louis Inst Epidemiol & Publ Hlth, INSERM,UMRS 943, Paris, France; [Tubiana, Roland] GH Pitie Salpetriere, AP HP, Malad Infect, Paris, France"	"Fauchet, F (corresponding author), Univ Paris 05, EA 08, Sorbonne Paris Cite, Paris, France."	"florisfauchet@gmail.com"	"Urien, Saik/G-3240-2013; Mandelbrot, Laurent/AAD-3554-2019; treluyer, Jean-Marc/F-8036-2010; Foix-L'Helias, Laurence/AAH-4933-2019"	"Foix-L'Helias, Laurence/0000-0002-5699-4839; Mandelbrot, Laurent/0000-0002-5883-7597"	"French National Agency for Research on AIDS and Viral Hepatitis (ANRS)ANRSFrench National Research Agency (ANR)"	"This study was sponsored by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). LPV/r tablets used in the study were kindly donated by Abbvie (Rungis, France), but the firm had no role in study design, data collection, or analysis and interpretation, or in writing the report."	39	6	6	0	4	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"SEP"	2015	59	9	5727	5735	"NA"	"10.1128/AAC.00863-15"	9	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"CV5XD"	"WOS:000364343900078"	26149996	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Imbert, B; Alvarez, JC; Simon, N"	"Imbert, Bruce; Alvarez, Jean-Claude; Simon, Nicolas"	"NA"	"A"	"Anticraving Effect of Baclofen in Alcohol-Dependent Patients"	"ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH"	"English"	"Article"	"Baclofen; Alcohol; Craving; Obsessive-Compulsive Drinking Scale; NONMEM; Population Approach; Modeling"	"DOUBLE-BLIND; POPULATION PHARMACOKINETICS; GLOBAL BURDEN; EFFICACY; SAFETY; RECEPTOR; DISEASE; INJURY; MODELS"	"BackgroundBaclofen is a GABA-B receptor agonist currently used in the treatment of spasticity. In recent years, baclofen has been used to reduce craving, voluntary alcohol intake and withdrawal syndrome of alcoholic patients. To date, there are no data available to estimate the relationship between baclofen exposure and the variation of craving. The first objective of this study was to investigate the variation of craving as a function of exposure, and the second was to explore the possible existence of baclofen responders and nonresponders. MethodsSixty-seven outpatients, 43 men/24 women (weight: 73kg [42 to 128]; age: 49years old [29 to 68]) followed in the addictology unit, were studied during 3months after treatment initiation. Baclofen was administered by oral route. Therapeutic drug monitoring enabled the measurement of plasma concentrations. Craving level was assessed by the Obsessive-Compulsive Drinking Scale (OCDS). A population pharmacokinetic (PK)-pharmacodynamic analysis of the OCDS variation following baclofen administration was performed. Demographic data, biological data, and tobacco consumption were tested for their influence on the parameters. ResultsData were modeled with a 1-compartment model with first-order absorption and elimination. PK analysis confirms the results of our previous study. An E-max model best-described the exposure-OCDS relationship. None of the covariates tested was able to improve the fit or decrease intersubject variability. However, 2 subpopulations were defined for the exposure corresponding to half the maximal effect (BE50). The proportion of patients being classified as responders was 38% (95% confidence interval [CI] 7 to 76), the maximal decrease in OCDS (E-max) was 72% (95% CI 25 to 85), and the BE50 was 12.6 (95% CI 0.02 to 74.3) or 4,390 (95% CI 20.4 to 31,800) hmg/l for responders and nonresponders, respectively. ConclusionsWe defined the relationship between baclofen exposure and craving in patients with alcohol use disorder. Baclofen treatment decreased craving in all patients. However, we drew up the hypothesis of 2 subpopulations of patients differentiated by their speed of response. A wide interindividual variability in response was depicted, making it currently impossible to predict which group a patient will belong to."	"[Imbert, Bruce] Allauch Hosp Ctr, Dept Addictol, Allauch, France; [Imbert, Bruce] Aix Marseille Univ, INSERM SESSTIM U912, Marseille, France; [Alvarez, Jean-Claude] Hop Raymond Poincare, Lab Pharmacol Toxicol, Garches, France; [Alvarez, Jean-Claude] Univ Versailles St Quentin, UFR Sci Sante Simone Veil, Montigny Le Bretonneux, France; [Simon, Nicolas] Hop St Marguerite, Serv Addictol, F-13274 Marseille, France; [Simon, Nicolas] Aix Marseille Univ, INSERM SESSTIM U912, Marseille, France"	"Simon, N (corresponding author), Hop St Marguerite, Dept Clin Pharmacol, CAP TV, APHM, 279 Bd St Marguerite, F-13274 Marseille, France."	"nicolas.simon@ap-hm.fr"	"Simon, Nicolas/B-1235-2016; Imbert, Bruce/L-3145-2016"	"Simon, Nicolas/0000-0003-4393-2257; Imbert, Bruce/0000-0002-0359-6255; ALVAREZ, jean claude/0000-0001-5344-9475"	"NA"	"NA"	28	26	26	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0145-6008"	"1530-0277"	"NA"	"ALCOHOL CLIN EXP RES"	"Alcoholism (NY)"	"SEP"	2015	39	9	1602	1608	"NA"	"10.1111/acer.12823"	7	"Substance Abuse"	"Substance Abuse"	"CQ7ZB"	"WOS:000360824300005"	26207768	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kim, TH; Shin, S; Landersdorfer, CB; Chi, YH; Paik, SH; Myung, J; Yadav, R; Horkovics-Kovats, S; Bulitta, JB; Shin, BS"	"Kim, Tae Hwan; Shin, Soyoung; Landersdorfer, Cornelia B.; Chi, Yong Ha; Paik, Soo Heui; Myung, Jayhyuk; Yadav, Rajbharan; Horkovics-Kovats, Stefan; Bulitta, Jurgen B.; Shin, Beom Soo"	"NA"	"A"	"Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans"	"AAPS JOURNAL"	"English"	"Article"	"animal to human scaling; enterohepatic recirculation; fimasartan; population pharmacokinetics; S-ADAPT"	"RENAL-TRANSPLANT RECIPIENTS; II AII ANTAGONIST; MYCOPHENOLIC-ACID; HEALTHY-VOLUNTEERS; ANTIHYPERTENSIVE AGENT; PHARMACODYNAMICS PD; CIRCULATION MODEL; DRUG-INTERACTIONS; MULTIPLE-PEAKS; ABSORPTION"	"Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3-3 mg/kg; oral doses, 1-10 mg/kg), 34 dogs (intravenous doses, 0.3-1mg/kg; oral doses, 1-10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20-480mg) were determined via liquid chromatography-tandemmass spectrometry (LCMS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9-88.7%) in rats, 33.3% (24.0-45.9%) in dogs, and 65.6% (56.5-72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85-8.85) as high in rats, 1.50-fold (1.32-1.85) in dogs, and 2.91-fold (2.30-3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0-59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1%(15.1-43.9%) under fasting and 18.2% (12.2-31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng.h/mL for 60 mg fimasartan compared with 424 � 63 ng.h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans."	"[Kim, Tae Hwan] Sungkyunkwan Univ, Sch Pharm, Suwon, Gyeonggi Do, South Korea; [Shin, Soyoung] Wonkwang Univ, Coll Pharm, Dept Pharm, Iksan, Jeonbuk, South Korea; [Landersdorfer, Cornelia B.; Yadav, Rajbharan; Bulitta, Jurgen B.] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia; [Landersdorfer, Cornelia B.] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Buffalo, NY USA; [Chi, Yong Ha; Paik, Soo Heui; Myung, Jayhyuk] Boryung Pharm Co Ltd, Cent Res Inst, Seoul, South Korea; [Horkovics-Kovats, Stefan] Sandoz GmbH, Kundl, Austria; [Shin, Beom Soo] Catholic Univ Daegu, Coll Pharm, Gyongsan, Gyeongbuk, South Korea"	"Shin, BS (corresponding author), Catholic Univ Daegu, Coll Pharm, Gyongsan, Gyeongbuk, South Korea."	"j@bulitta.com; bsshin@cu.ac.kr"	"Bulitta, Jurgen B/P-3355-2018; Landersdorfer, Cornelia/I-4103-2019"	"Bulitta, Jurgen B/0000-0001-7352-3097; Landersdorfer, Cornelia/0000-0003-0928-4743; Yadav, Rajbharan/0000-0002-4608-8744"	"Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [HI13C1130]; Australian National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [1062509, 1084163]"	"This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI13C1130). CBL and JBB are the recipients of Career Development Fellowships by the Australian National Health and Medical Research Council (NHMRC, fellowship: 1062509 to CBL and 1084163 to JBB)."	70	10	10	0	9	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"SEP"	2015	17	5	1210	1223	"NA"	"10.1208/s12248-015-9764-2"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CQ1NN"	"WOS:000360364500016"	25990964	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Simon, N; Finzi, J; Cayla, G; Montalescot, G; Collet, JP; Hulot, JS"	"Simon, Nicolas; Finzi, Jonathan; Cayla, Guillaume; Montalescot, Gilles; Collet, Jean-Philippe; Hulot, Jean-Sebastien"	"NA"	"A"	"Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Clopidogrel; Proton-pump inhibitors; Pharmacokinetic; Pharmacogenetic; Drug interaction; Nonmem; Modelling"	"PROTON-PUMP INHIBITORS; DUAL ANTIPLATELET THERAPY; ST-SEGMENT ELEVATION; DRUG-ELUTING STENTS; HEALTHY-SUBJECTS; MYOCARDIAL-INFARCTION; INTERVENTION; LANSOPRAZOLE; RISK; RESPONSIVENESS"	"Proton-pump Inhibitors use and CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses and increased cardiovascular events. Post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 41) or homozygous (*2/*2, n = 7) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel loading dose. A PK/PD model was defined using the variation of the P2Y(12) reaction unit relative to baseline. Carriage of CYP2C19*2 allele and the use of omeprazole/esomeprazole were associated with the inter-individual variability in the active metabolite clearance. The relationship between inhibition of platelet aggregation (IPA, %) and the active metabolite AUC (h*mu g/L) was described by a sigmoid function (Emax 56 � 5%; E-AUC50 15.9 � 0.8 h*mu g/L) with a gamma exponent (7.04 � 2.26). This on/off shape explains that a small variation of exposure may have a clinical relevance."	"[Simon, Nicolas] Aix Marseille Univ, INSERM, SESSTIM UMR912, F-13003 Marseille, France; [Simon, Nicolas] Hop St Marguerite, Ctr Anti Poison, AP HM, Serv Pharmacol Clin, F-13274 Marseille, France; [Finzi, Jonathan; Cayla, Guillaume; Montalescot, Gilles; Collet, Jean-Philippe; Hulot, Jean-Sebastien] Univ Paris 06, Sorbonne Univ, Fac Med, Inst Cardiometab & Nutr,UMRS ICAN 1166, F-75013 Paris, France; [Finzi, Jonathan; Cayla, Guillaume; Montalescot, Gilles; Collet, Jean-Philippe; Hulot, Jean-Sebastien] Hop La Pitie Salpetriere, AP HP, Cardiol Inst, F-75013 Paris, France; [Finzi, Jonathan; Cayla, Guillaume; Montalescot, Gilles; Collet, Jean-Philippe; Hulot, Jean-Sebastien] INSERM, UMRS ICAN 1166, F-75013 Paris, France; [Simon, Nicolas] Fac Med, Serv Pharmacol Clin, F-13385 Marseille, France"	"Simon, N (corresponding author), Aix Marseille Univ, INSERM, SESSTIM UMR912, F-13003 Marseille, France."	"nicolas.simon@ap-hm.fr"	"Hulot, Jean-Sebastien/AAM-6490-2020; Hulot, Jean-Sebastien/A-2278-2016; Simon, Nicolas/B-1235-2016"	"Hulot, Jean-Sebastien/0000-0001-5463-6117; Hulot, Jean-Sebastien/0000-0001-5463-6117; Simon, Nicolas/0000-0003-4393-2257"	"NA"	"NA"	38	14	15	0	9	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"SEP"	2015	71	9	1059	1066	"NA"	"10.1007/s00228-015-1882-3"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CO8UM"	"WOS:000359447600004"	26071277	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Miguel-Lillo, B; Valenzuela, B; Peris-Ribera, J; Soto-Matos, A; Perez-Ruixo, J"	"Miguel-Lillo, Bernardo; Valenzuela, Belen; Peris-Ribera, Jose Esteban; Soto-Matos, Arturo; Perez-Ruixo, Juan Jose"	"NA"	"A"	"Population pharmacokinetics of kahalalide F in advanced cancer patients"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Cancer patients; Clinical trials; Population pharmacokinetics; NONMEM (TM); Kahalalide F"	"ADVANCED SOLID TUMORS; CHAIN MONTE-CARLO; PHASE-I; QUANTIFICATION LIMIT; ANTICANCER AGENT; HANDLING DATA; DEPSIPEPTIDE; PERFORMANCE; COMPOUND; MODEL"	"In this study, we characterize the population pharmacokinetics of kahalalide F (KF), a novel marine anticancer drug, after intravenous (i.v.) administration in advanced cancer patients. Data from 240 patients included in three Phase I and three Phase II trials receiving i.v. weekly and every 3 weeks infusions of KF, at doses ranging 266-6650 A mu g/m(2), were analyzed using NONMEM (TM) VII. The effect of demographics and/or pathophysiologically relevant factors on KF pharmacokinetic parameters was evaluated. Model evaluation was conducted using nonparametric bootstrap and visual predictive check (in both internal and external datasets). An open two-compartment model with linear distribution and elimination from central compartment was suitable to describe the data. Volume of distribution at steady state and its between-subject variability (CV%) was estimated to be 6.56 L (28 %). Plasma clearance was estimated to be 6.25 L/h (43 %). Within the range of covariates evaluated, age, weight, body surface area, gender, ECOG performance status, presence of liver metastases, creatinine clearance, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein and serum albumin did not contribute to explain KF pharmacokinetic variability to a significant extent. The developed model was deemed appropriate to describe the time course of KF plasma concentrations and its variability in advanced cancer patients. The integration of pharmacokinetic data from six clinical studies demonstrated KF linear elimination from plasma, dose-proportional exposure and time-independent pharmacokinetics. Based on analyzed data, no clinically relevant covariates were identified as predictors of KF pharmacokinetics."	"[Miguel-Lillo, Bernardo; Soto-Matos, Arturo] Pharma Mar, Clin Pharmacol, Madrid, Spain; [Valenzuela, Belen] Hosp Quiron Torrevieja, Platform Oncol, Torrevieja, Spain; [Valenzuela, Belen] UCAM Catholic Univ San Antonio, Cathedra Multidisciplinary Oncol, Murcia, Spain; [Peris-Ribera, Jose Esteban] Univ Valencia, Pharm & Pharmaceut Technol Dept, Valencia, Spain; [Soto-Matos, Arturo] Pharma Mar, Clin Dev, Madrid, Spain; [Perez-Ruixo, Juan Jose] Janssen Res & Dev, Model Based Drug Dev, Beerse, Belgium; [Miguel-Lillo, Bernardo] Pharma Mar, Clin Res & Dev, Dept Clin Pharmacol, Madrid 28770, Spain"	"Miguel-Lillo, B (corresponding author), Pharma Mar, Clin Pharmacol, Madrid, Spain."	"bmlillo@gmail.com"	"Ruixo, Juan Jose Perez/AAL-2987-2020; Ruixo, Juan Jose Perez/AAF-3160-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"NA"	"NA"	44	13	13	0	7	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"AUG"	2015	76	2	365	374	"NA"	"10.1007/s00280-015-2800-1"	10	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"CN6ZA"	"WOS:000358581900016"	26093949	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Li, HQ; Xu, JY; Jin, L; Xin, JL"	"Li, Han Qing; Xu, Jia Yin; Jin, Liang; Xin, Ji Le"	"NA"	"A"	"Utilization of model-based meta-analysis to delineate the net efficacy of taspoglutide from the response of placebo in clinical trials"	"SAUDI PHARMACEUTICAL JOURNAL"	"English"	"Article"	"PPG; HbA1c; Taspoglutide; Glucagon-like peptide-1; Pharmacodynamics; Meta-analysis"	"GLUCAGON-LIKE PEPTIDE-1; DOUBLE-BLIND; POPULATION PHARMACOKINETICS; DIABETIC-PATIENTS; GLYCEMIC CONTROL; BODY-WEIGHT; TYPE-2; METFORMIN; ANALOG; PIOGLITAZONE"	"The objective of this study was to develop quantitative models to delineate the net efficacy of taspoglutide on fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) from the response of placebo in type 2 diabetes patients, and further find pharmacodynamic potency of taspoglutide and FPG for half of maximum reduction responses of FPG and HbA1c, respectively. Several PD data about taspoglutide treatments for type 2 diabetes patients were digitalized from the published papers related with the clinical development of taspoglutide. The model based meta-analysis (MBMA) studies for FPG and HbA1c were performed with Monolix 4.2 software. The MBMA successfully described the effects of placebo and taspoglutide on pharmacological indexes of FPG and HbA1c through mono and multiple combination therapies in clinical trials. The pharmacodynamic potency (25.3 pmo1/1) produced 50% of maximum responses of FPG (-2.39 mmo1/1) from the responses of placebo for FPG (-0.371 mmo1/1); the response change of FPG (-1.81 mmo1/1) affected 50% of maximum response change (-1.74%) for HbA1c from the response of placebo (-0.253%). The leveraging prior knowledge from the longitudinal MBMA will be utilized to guide clinical development of taspoglutide and further support study designs including optimization of dose and duration of therapy. (C) 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University."	"[Li, Han Qing; Jin, Liang; Xin, Ji Le] Int Mongolian Hosp Inner Mongolia, State Clin Trial Inst New Drugs, Hohhot 010065, Inner Mongolia, Peoples R China; [Xu, Jia Yin] Int Mongolian Hosp Inner Mongolia, Mongolian Pharmaceut Preparat Ctr, Hohhot 010065, Inner Mongolia, Peoples R China"	"Li, HQ (corresponding author), Int Mongolian Hosp Inner Mongolia, State Clin Trial Inst New Drugs, 83 Da Xue East Rd, Sai Han Dist 010065, Hohhot, Peoples R China."	"hqltcm@163.com"	"NA"	"NA"	"NA"	"NA"	28	2	2	0	6	"ELSEVIER"	"AMSTERDAM"	"RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS"	"1319-0164"	"2213-7475"	"NA"	"SAUDI PHARM J"	"Saudi Pharm. J."	"JUL"	2015	23	3	241	249	"NA"	"10.1016/j.jsps.2014.11.008"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CL0QP"	"WOS:000356647600005"	26106272	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Doshi, S; Gisleskog, PO; Zhang, YL; Zhu, M; Oliner, KS; Loh, E; Ruixo, JJP"	"Doshi, Sameer; Gisleskog, Per Olsson; Zhang, Yilong; Zhu, Min; Oliner, Kelly S.; Loh, Elwyn; Ruixo, Juan Jose Perez"	"NA"	"A"	"Rilotumumab Exposure-Response Relationship in Patients with Advanced or Metastatic Gastric Cancer"	"CLINICAL CANCER RESEARCH"	"English"	"Article"	"NA"	"HEPATOCYTE GROWTH-FACTOR; HUMAN MONOCLONAL-ANTIBODY; AMG 102; POPULATION PHARMACOKINETICS; MODELING FRAMEWORK; TUMOR-SIZE; C-MET; MOTESANIB; COMBINATION; SURVIVAL"	"Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab. Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors. Simulations were undertaken to predict the relationship between rilotumumab dose and OS. Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. MET-positive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18-0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W. Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET1; NCT01697072). (C) 2015 AACR."	"[Doshi, Sameer; Zhang, Yilong; Zhu, Min; Oliner, Kelly S.; Ruixo, Juan Jose Perez] Amgen Inc, Thousand Oaks, CA 91320 USA; [Gisleskog, Per Olsson] SGS Exprimo NV, Mechelen, Belgium; [Loh, Elwyn] Amgen Inc, San Francisco, CA USA"	"Doshi, S (corresponding author), Amgen Inc, 1 Amgen Ctr Dr,MS 28-3-B, Thousand Oaks, CA 91320 USA."	"sdoshi@amgen.com"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"Olsson Gisleskog, Per/0000-0002-0706-8783; PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X; Zhu, Min/0000-0002-5669-9602"	"Amgen Inc.Amgen"	"This work was sponsored by Amgen Inc., which was involved in the study design, data collection, analysis, interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication."	35	22	23	0	0	"AMER ASSOC CANCER RESEARCH"	"PHILADELPHIA"	"615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA"	"1078-0432"	"1557-3265"	"NA"	"CLIN CANCER RES"	"Clin. Cancer Res."	"JUN 1"	2015	21	11	2453	2461	"NA"	"10.1158/1078-0432.CCR-14-1661"	9	"Oncology"	"Oncology"	"CL9YT"	"WOS:000357335800008"	25712685	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Chen, P; Melhem, M; Xiao, J; Kuchimanchi, M; Ruixo, JJP"	"Chen, Ping; Melhem, Murad; Xiao, Jim; Kuchimanchi, Mita; Ruixo, Juan Jose Perez"	"NA"	"A"	"Population Pharmacokinetics Analysis of AMG 416, an Allosteric Activator of the Calcium-Sensing Receptor, in Subjects With Secondary Hyperparathyroidism Receiving Hemodialysis"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"AMG 416; calcium-sensing receptor; secondary hyperparathyroidism; NONMEM; pharmacokinetics"	"PEPTIDE AGONIST; MODEL; VELCALCETIDE; PHARMACOLOGY; CINACALCET; STABILITY"	"This study characterizes the population pharmacokinetics of AMG 416, an allosteric activator of the calcium-sensing receptor, in subjects with secondary hyperparathyroidism receiving hemodialysis. AMG 416 doses ranging from 2.5 to 60 mg were administered intravenously as single or multiple thrice weekly (TIW) doses at the end of hemodialysis during rinseback. The influence of demographics, concomitant medications, and other disease-related biomarkers on pharmacokinetic parameters was explored. The predictability of the final model was evaluated using bootstrapping and visual predictive checks. A 3-compartment linear pharmacokinetic model that accounts for the hemodialysis clearance best described the data. Plasma clearance (interindividual variability) was 0.564 L/h (14.0% CV). The hemodialysis clearance was 22.2 L/h. The volume of distribution at steady-state was approximately 624 L (82% CV). The mean time to achieve 90% steady-state predialysis concentrations with 3-and 6-hour hemodialysis TIW was 46 and 32 days, respectively. No statistically significant (P < .01) covariates effect was found on pharmacokinetic parameters. Bootstrapping and predictive checks supported model predictive ability. AMG 416 exhibits linear and stationary pharmacokinetics within the range of doses evaluated. Within the range of covariate values investigated, pharmacokinetically driven adjustments of AMG416 dosing on the basis of these covariates were not warranted."	"[Chen, Ping; Melhem, Murad; Xiao, Jim; Kuchimanchi, Mita; Ruixo, Juan Jose Perez] Amgen Inc, Thousand Oaks, CA 91320 USA"	"Chen, P (corresponding author), One Amgen Ctr Dr, Thousand Oaks, CA 91360 USA."	"pingc@amgen.com"	"Ruixo, Juan Jose Perez/AAL-2987-2020; Ruixo, Juan Jose Perez/AAF-3160-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"Amgen Inc.Amgen"	"This study was sponsored by Amgen Inc., which was involved in the study design, data collection, analysis, interpretation, writing the manuscript, and the decision to submit the manuscript for publication."	20	19	20	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JUN"	2015	55	6	620	628	"NA"	"10.1002/jcph.460"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CK0BO"	"WOS:000355869100002"	25581635	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gonzalez-Sales, M; Barriere, O; Tremblay, PO; Nekka, F; Mamputu, JC; Boudreault, S; Tanguay, M"	"Gonzalez-Sales, Mario; Barriere, Olivier; Tremblay, Pierre Olivier; Nekka, Fahima; Mamputu, Jean-Claude; Boudreault, Sylvie; Tanguay, Mario"	"NA"	"A"	"Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Phase I; Clinical trial; Population pharmacokinetics and pharmacodynamics; Indirect response; NONMEM"	"GROWTH-HORMONE; FACTOR ANALOG; MANAGEMENT; MODELS; TH9507; MEN"	"The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an episodic manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data."	"[Gonzalez-Sales, Mario; Nekka, Fahima] Univ Montreal, Montreal, PQ, Canada; [Gonzalez-Sales, Mario; Barriere, Olivier; Tremblay, Pierre Olivier; Boudreault, Sylvie; Tanguay, Mario] InVentiv Hlth Clin, Montreal, PQ, Canada; [Mamputu, Jean-Claude] Theratechnologies Inc, Montreal, PQ, Canada"	"Nekka, F (corresponding author), Univ Montreal, Montreal, PQ, Canada."	"fahima.nekka@umontreal.ca"	"NA"	"Tanguay, Mario/0000-0001-5352-2871"	"Mitacs ELEVATE; inVentiv Health; NSERC-Industrial Chair in Pharmacometrics; FRQNT"	"This work was supported by Mitacs ELEVATE, in partnership with inVentiv Health, NSERC-Industrial Chair in Pharmacometrics and FRQNT. The authors would like to thank the reviewers of this manuscript for their careful reading and suggestions."	19	2	2	1	8	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2015	42	3	287	299	"NA"	"10.1007/s10928-015-9416-2"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CI1GW"	"WOS:000354492800008"	25895899	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Bulitta, JB; Ly, NS; Landersdorfer, CB; Wanigaratne, NA; Velkov, T; Yadav, R; Oliver, A; Martin, L; Shin, BS; Forrest, A; Tsuji, BT"	"Bulitta, Juergen B.; Ly, Neang S.; Landersdorfer, Cornelia B.; Wanigaratne, Nicholin A.; Velkov, Tony; Yadav, Rajbharan; Oliver, Antonio; Martin, Lisandra; Shin, Beom Soo; Forrest, Alan; Tsuji, Brian T."	"NA"	"A"	"Two Mechanisms of Killing of Pseudomonas aeruginosa by Tobramycin Assessed at Multiple Inocula via Mechanism-Based Modeling"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"COMBINATION ANTIMICROBIAL THERAPY; 2-COMPONENT REGULATORY SYSTEM; ADAPTIVE RESISTANCE; OUTER-MEMBRANE; EFFLUX PUMP; POPULATION PHARMACOKINETICS; POLYCATIONIC ANTIBIOTICS; QUANTITATIVE ASSESSMENT; PHARMACODYNAMIC MODEL; STAPHYLOCOCCUS-AUREUS"	"Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three Pseudomonas aeruginosa strains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (>= 8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 108.9 CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5-to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens."	"[Bulitta, Juergen B.; Landersdorfer, Cornelia B.; Wanigaratne, Nicholin A.; Velkov, Tony; Yadav, Rajbharan] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic, Australia; [Bulitta, Juergen B.; Ly, Neang S.; Landersdorfer, Cornelia B.; Forrest, Alan; Tsuji, Brian T.] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Buffalo, NY 14260 USA; [Oliver, Antonio] Hosp Univ Son Espases, Microbiol Serv, Palma De Mallorca, Spain; [Martin, Lisandra] Monash Univ, Sch Chem, Clayton, Vic, Australia; [Shin, Beom Soo] Catholic Univ Daegu, Coll Pharm, Gyongsan, Gyeongbuk, South Korea"	"Bulitta, JB (corresponding author), Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville Campus, Parkville, Vic, Australia."	"jurgen.bulitta@monash.edu"	"Landersdorfer, Cornelia/I-4103-2019; Martin, Lisandra L/E-4482-2010; Oliver, Antonio/E-4048-2012; Bulitta, Jurgen B/P-3355-2018; Oliver, Antonio/V-5541-2019"	"Landersdorfer, Cornelia/0000-0003-0928-4743; Martin, Lisandra L/0000-0003-0486-5813; Oliver, Antonio/0000-0001-9327-1894; Bulitta, Jurgen B/0000-0001-7352-3097; Ly, Neang/0000-0002-5571-0347; velkov, tony/0000-0002-0017-7952; Yadav, Rajbharan/0000-0002-4608-8744"	"Australian National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [1045105];  [DE120103084];  [1062509];  [1003836]"	"J.B.B. is an Australian Research Council DECRA Fellow (DE120103084). C.B.L. is a National Health and Medical Research Council (NHMRC) Career Development Fellow (1062509). T.V is an NHMRC Career Development Industry Fellow (1003836). This research was in part supported by the Australian National Health and Medical Research Council (NHMRC; project grant 1045105 to J.B.B.)."	64	43	44	0	26	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2015	59	4	2315	2327	"NA"	"10.1128/AAC.04099-14"	13	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"CI8BY"	"WOS:000354993700058"	25645838	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Ramon-Lopez, A; Allen, JM; Thomson, AH; Dheansa, BS; James, SE; Hanlon, GW; Stewart, B; Davies, JG"	"Ramon-Lopez, Amelia; Allen, Jane M.; Thomson, Alison H.; Dheansa, Bajlit S.; James, S. Elizabeth; Hanlon, Geoff W.; Stewart, Bruce; Davies, J. Graham"	"NA"	"A"	"Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"pharmacodynamics; carbapenems; antibiotics; intensive care; PK"	"FEBRILE NEUTROPENIC PATIENTS; PSEUDOMONAS-AERUGINOSA; CONTINUOUS-INFUSION; MODEL; INFECTION; PHARMACODYNAMICS; COMBINATION; RESISTANCE; THERAPY; PATIENT"	"Objectives: To develop a population model to describe the pharmacokinetics (PK) of intravenous meropenem in adult patients with severe burns and investigate potential relationships between dosage regimens and antimicrobial efficacy. Patients and methods: A dose of 1 g every 8 h was administered to adult patients with total body surface area burns of >= 15%. Doses for subsequent courses were determined using results from the initial course and the patient's clinical condition. Five plasma meropenem concentrations were typically measured over the dosage interval on one to four occasions. An open, two-compartment PK model was fitted to the meropenem concentrations using NONMEM and the effect of covariates on meropenem PKwas investigated. Monte Carlo simulations investigated dosage regimens to achieve a target T->MIC for >= 40%, >= 60% or >= 80% of the dose interval. Results: Data comprised 113 meropenem concentration measurements from 20 dosage intervals in 12 patients. The parameters were CL (L/h) = 0.196 L/h/kgx[1-0.023x(age-46)] x[1-0.049x(albumin-15)], V-1 = 0.273 L/kg x [1-0.049x(albumin-15)], Q = 0.199 L/h/kg and V-2 = 0.309 L/kgx[1-0.049x(albumin-15)]. For a target of >= 80% T->MIC, the breakpoint was 8 mg/L for doses of 1 g every 4 h and 2 g every 8 h given over 3 h, but only 4 mg/L if given over 5 min. Conclusions: Although 1 g 8 hourly should be effective against Escherichia coli and CoNS, higher doses, ideally with a longer infusion time, would be more appropriate for empirical therapy, mixed infections and bacteria with MIC values >= 4 mg/L."	"[Ramon-Lopez, Amelia; Thomson, Alison H.] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark, Scotland; [Ramon-Lopez, Amelia] Miguel Hernandez Univ, Dept Engn, Div Pharm & Pharmaceut, Alicante, Spain; [Allen, Jane M.] Queen Victoria Hosp NHS Fdn Trust, Dept Pharm, E Grinstead, W Sussex, England; [Thomson, Alison H.] Univ Glasgow, Western Infirm, Dept Pharm, Glasgow G11 6NT, Lanark, Scotland; [Dheansa, Bajlit S.] Queen Victoria Hosp NHS Fdn Trust, Burns Ctr, E Grinstead, W Sussex, England; [James, S. Elizabeth; Hanlon, Geoff W.] Univ Brighton, Sch Pharm & Biomol Sci, Brighton, E Sussex, England; [Stewart, Bruce] Surrey & Sussex Healthcare NHS Trust, Dept Microbiol, Redhill, Surrey, England; [Davies, J. Graham] Kings Coll London, Inst Pharmaceut Sci, London WC2R 2LS, England"	"Allen, JM (corresponding author), Surrey & Sussex Healthcare NHS Trust, East Surrey Hosp, Dept Pharm, Canada Ave, Redhill RH1 5RH, Surrey, England."	"jane.allen4@nhs.net"	"Thomson, Alison H H/H-9743-2016"	"Thomson, Alison H H/0000-0002-2354-6116; Ramon-Lopez, Amelia/0000-0002-2848-4743; Dheansa, Baljit/0000-0003-1418-9986"	"Royal Pharmaceutical Society; PfizerPfizer; Forest Laboratories"	"This work was supported by the Galen Award 2008 awarded by the Royal Pharmaceutical Society. The cost of meropenem assays were met by AstraZeneca. Unconditional educational grants were received from Pfizer and Forest Laboratories to purchase equipment and to support courier costs."	43	16	16	0	7	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"MAR"	2015	70	3	882	890	"NA"	"10.1093/jac/dku429"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"CC2ZV"	"WOS:000350214700034"	25362574	"Green Accepted, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Chan, LJ; Bulitta, JB; Ascher, DB; Haynes, JM; McLeod, VM; Porter, CJH; Williams, CC; Kaminskas, LM"	"Chan, Linda J.; Bulitta, Juergen B.; Ascher, David B.; Haynes, John M.; McLeod, Victoria M.; Porter, Christopher J. H.; Williams, Charlotte C.; Kaminskas, Lisa M."	"NA"	"A"	"PEGylation Does Not Significantly Change the Initial Intravenous or Subcutaneous Pharmacokinetics or Lymphatic Exposure of Trastuzumab in Rats but Increases Plasma Clearance after Subcutaneous Administration"	"MOLECULAR PHARMACEUTICS"	"English"	"Article"	"PEGylation; trastuzumab; lymphatic; pharmacokinetics; monoclonal antibody; HER2; population modeling; S-ADAPT"	"METASTATIC BREAST-CANCER; POLYETHYLENE-GLYCOL; POPULATION PHARMACOKINETICS; SENTINEL LYMPHADENECTOMY; POLY(ETHYLENE GLYCOL); ANTIBODY THERAPEUTICS; SYSTEMIC AVAILABILITY; ABSORPTION; TRANSPORT; PROTEINS"	"The lymphatic system plays a major role in the metastatic dissemination of cancer and has an integral role in immunity. PEGylation enhances drainage and lymphatic uptake following subcutaneous (sc) administration of proteins and protein-like polymers, but the impact of PEGylation of very large proteins (such as antibodies) on subcutaneous and lymphatic pharmacokinetics is unknown. This study therefore aimed to evaluate the impact of PEGylation on the sc absorption and lymphatic disposition of the anti-HER2 antibody trastuzumab in rats. PEG-trastuzumab was generated via the conjugation of a single 40 kDa PEG-NHS ester to trastuzumab. PEG-trastuzumab showed a 5-fold reduction in HER2 binding affinity, however the in vitro growth inhibitory effects were preserved as a result of changes in cellular trafficking when compared to native trastuzumab. The lymphatic pharmacokinetics of PEG-trastuzumab was evaluated in thoracic lymph duct cannulated rats after iv and sc administration and compared to the pharmacokinetics of native trastuzumab. The iv pharmacokinetics and lymphatic exposure of PEG-trastuzumab was similar when compared to trastuzumab. After sc administration, initial plasma pharmacokinetics and lymphatic exposure were also similar between PEG-trastuzumab and trastuzumab, but the absolute bioavailability of PEG-trastuzumab was 100% when compared to 86.1% bioavailability for trastuzumab. In contrast to trastuzumab, PEG-trastuzumab showed accelerated plasma clearance beginning approximately 7 days after sc, but not iv, administration, presumably as a result of the generation of anti-PEG IgM. This work suggests that PEGylation does not significantly alter the lymphatic disposition of very large proteins, and further suggests that it is unlikely to benefit therapy with monoclonal antibodies."	"[Chan, Linda J.; Bulitta, Juergen B.; McLeod, Victoria M.; Porter, Christopher J. H.; Kaminskas, Lisa M.] Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia; [Ascher, David B.] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England; [Haynes, John M.] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia; [Williams, Charlotte C.] CSIRO Mat Sci & Engn, Parkville, Vic 3052, Australia"	"Kaminskas, LM (corresponding author), Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, 381 Royal Parade, Parkville, Vic 3052, Australia."	"lisa.kaminskas@monash.edu"	"Williams, Charlotte C/G-5077-2013; Porter, Christopher JH/C-6333-2011; Bulitta, Jurgen B/P-3355-2018"	"Williams, Charlotte C/0000-0003-0807-3864; Porter, Christopher JH/0000-0003-3474-7551; Bulitta, Jurgen B/0000-0001-7352-3097; , john/0000-0003-3075-1553; Kaminskas, Lisa/0000-0003-4821-4262; Ascher, David/0000-0003-2948-2413"	"NHMRCNational Health and Medical Research Council of Australia [APP1022732, APP1072476, APP1044802]; Australian Research CouncilAustralian Research Council [DE120103084]"	"We thank Dr. Mark Waltham from St Vincent's Hospital for his generous gift of the BT474 and T47D breast cancer cells; Dr. David Shackleford for his assistance with the analysis of the HUVEC permeability assays; and Dr. Judith Scoble and John Bentley from CSIRO (Parkville) for their assistance with protein purification. L.M.K. was supported by an NHMRC Career Development fellowship (APP1022732). D.B.A. was supported by an NHMRC CJ Martin fellowship (APP1072476). J.B.B. is the recipient of an Australian Research Council Discovery Early Career Research Award (DE120103084). This work was supported by an NHMRC project funding grant (APP1044802)."	66	19	19	1	24	"AMER CHEMICAL SOC"	"WASHINGTON"	"1155 16TH ST, NW, WASHINGTON, DC 20036 USA"	"1543-8384"	"NA"	"NA"	"MOL PHARMACEUT"	"Mol. Pharm."	"MAR"	2015	12	3	794	809	"NA"	"10.1021/mp5006189"	16	"Medicine, Research & Experimental; Pharmacology & Pharmacy"	"Research & Experimental Medicine; Pharmacology & Pharmacy"	"CC5HY"	"WOS:000350390900013"	25644368	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gonzalez-Sales, M; Barriere, O; Tremblay, PO; Nekka, F; Mamputu, JC; Boudreault, S; Tanguay, M"	"Gonzalez-Sales, Mario; Barriere, Olivier; Tremblay, Pierre Olivier; Nekka, Fahima; Mamputu, Jean-Claude; Boudreault, Sylvie; Tanguay, Mario"	"NA"	"A"	"Population Pharmacokinetic Analysis of Tesamorelin in HIV-Infected Patients and Healthy Subjects"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"GROWTH-HORMONE; LIPODYSTROPHY; MODELS; ANALOG"	"Background Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequently, the aim of this study was to characterize the population pharmacokinetics of tesamorelin in HIV-infected patients and healthy subjects. Methods A total of 38 HIV-infected patients and healthy subjects receiving subcutaneous tesamorelin doses of 1 or 2 mg administered daily during 14 consecutive days were included in the analysis. An open one-compartment model with first- and zero-order absorption and first-order elimination was developed to best describe the data using NONMEMA (R) VII. The effect of different covariates on tesamorelin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. Results Plasma clearance and its interindividual variability [% coefficient of variation (CV)] was estimated to be 1,060 L/h (33.6 %). Volume of distribution was calculated to be 200 L (17.7 %). Age, body size measures, race and health status were not related to tesamorelin pharmacokinetic parameters within the range of covariates studied. The fraction of tesamorelin absorbed by a first-order process is 13.1 % higher on day 14 compared with day 1. Predictive checks and non-parametric bootstrap demonstrated that the model is appropriate in describing the time course of tesamorelin plasma concentrations in both HIV-infected patients and healthy subjects. Conclusions An open one-compartment model with first and zero order absorption processes and linear elimination is suitable to characterize the pharmacokinetics of tesamorelin. The fraction of tesamorelin absorbed by a first-order process evolves with time. No clinically relevant covariates were identified as predictors of tesamorelin pharmacokinetics."	"[Gonzalez-Sales, Mario; Nekka, Fahima; Tanguay, Mario] Univ Montreal, Fac Pharm, Montreal, PQ, Canada; [Gonzalez-Sales, Mario; Barriere, Olivier; Tremblay, Pierre Olivier; Boudreault, Sylvie; Tanguay, Mario] InVentiv Hlth Clin, Montreal, PQ, Canada; [Mamputu, Jean-Claude] Theratechnol Inc, Montreal, PQ, Canada"	"Nekka, F (corresponding author), Univ Montreal, Fac Pharm, CP 6128,Succ Ctr Ville, Montreal, PQ, Canada."	"fahima.nekka@umontreal.ca"	"NA"	"Mamputu, Jean-Claude/0000-0001-8493-959X; Tanguay, Mario/0000-0001-5352-2871"	"Mitacs ELEVATE; NSERC-Industrial Chair in Pharmacometrics; FRQNT; Theratechnologies Inc."	"This work was supported by Mitacs ELEVATE, in partnership with in Ventiv Health Canada, NSERC-Industrial Chair in Pharmacometrics and FRQNT. The authors would like to thank the patients, investigators, and their medical, nursing and laboratory staff who participated in the clinical trials included in the present study. Jean-Claude Mamputu is an employee of Theratechnologies Inc., which supported this study. Other authors declare no conflicts of interest."	15	4	4	1	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAR"	2015	54	3	285	294	"NA"	"10.1007/s40262-014-0202-x"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CC1MD"	"WOS:000350103900006"	25358450	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Li, HQ; Xu, JY; Fan, XH"	"Li, Hanqing; Xu, Jiayin; Fan, Xiaohong"	"NA"	"A"	"Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus"	"JOURNAL OF PHARMACOLOGICAL SCIENCES"	"English"	"Article"	"Exenatide extended-release; Model based meta-analysis; Pharmacokinetics; Pharmacodynamics; Dosing regimens"	"POPULATION PHARMACOKINETICS; PHARMACODYNAMIC MODEL; JAPANESE PATIENTS; DRUG DISPOSITION; SAFETY; RATS; TOLERABILITY; MICROSPHERES; EXENDIN-4; SINGLE"	"A hybrid pharmacokinetic/pharmacodynamic (PK/PD) model with extended-release (ER) process and target mediated drug disposition (TMDD) was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R)-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM) were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PM profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol. (C) 2015 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society."	"[Li, Hanqing; Fan, Xiaohong] Int Mongolian Hosp Inner Mongolia, State Clin Trial Inst New Drugs, Hohhot 010065, Peoples R China; [Xu, Jiayin] Int Mongolian Hosp Inner Mongolia, Mongolian Pharmaceut Preparat Ctr, Hohhot 010065, Peoples R China"	"Li, HQ (corresponding author), Int Mongolian Hosp Inner Mongolia, State Clin Trial Inst New Drugs, 83 Da Xue East Rd, Hohhot 010065, Peoples R China."	"hqltcm@163.com"	"NA"	"NA"	"NA"	"NA"	37	8	8	0	10	"JAPANESE PHARMACOLOGICAL SOC"	"KYOTO"	"EDITORIAL OFF, KANTOHYA BLDG GOKOMACHI-EBISUGAWA NAKAGYO-KU, KYOTO, 604, JAPAN"	"1347-8613"	"1347-8648"	"NA"	"J PHARMACOL SCI"	"J. Pharmacol. Sci."	"FEB"	2015	127	2	170	180	"NA"	"10.1016/j.jphs.2014.12.004"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"CD9NH"	"WOS:000351424500003"	25727954	"DOAJ Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Li, HQ; Xu, JY; Jin, L; Xin, JL"	"Li, Han-Qing; Xu, Jia-Yin; Jin, Liang; Xin, Ji-Le"	"NA"	"A"	"The efficacy of placebo-adjusted taspoglutide on body weight reduction in clinical trials"	"PHARMAZIE"	"English"	"Article"	"NA"	"DOUBLE-BLIND; POPULATION PHARMACOKINETICS; ANALOG TASPOGLUTIDE; DIABETIC-PATIENTS; PEPTIDE-1 ANALOG; GLYCEMIC CONTROL; GLP-1 ANALOG; METFORMIN; METAANALYSIS; SAFETY"	"Taspoglutide has elicited a long-lasting glycemic control effect with favorable body weight loss. The objective of this study was to develop a quantitative model to delineate the net efficacy of taspoglutide on body weight (WT) loss from the response of placebo in type 2 diabetes patients, and further find pharmacodynamic potency of taspoglutide for half of maximum reduction response of WT. Several PD data about taspoglutide treatments for type 2 diabetes patients were digitalized from the published papers. The model based meta-analysis (MBMA) study for WT loss was performed with Monolix 4.3 software. The MBMA successfully described the effects of placebo and taspoglutide on the pharmacological index of WT loss in clinical trials. The pharmacodynamic potency (41.7 pmol/l) produced 50% of maximum response of WT (-1.85 kg) from the responses of placebo (-1.33 kg). The longitudinal MBMA could be utilized to quantitatively describe the efficacy of taspoglutide on body weight loss and may lead to a clinical guideline for treatment of type 2 diabetes patients in the future."	"[Li, Han-Qing; Jin, Liang; Xin, Ji-Le] Int Mongolian Hosp Inner Mongolia, State Clin Trial Inst New Drugs, Inner Mongolia, Hohhot, Peoples R China; [Xu, Jia-Yin] Int Mongolian Hosp Inner Mongolia, Mongolian Pharmaceut Preparat Ctr, Inner Mongolia, Hohhot, Peoples R China"	"Li, HQ (corresponding author), Int Mongolian Hosp Inner Mongolia, State Clin Trial Inst New Drugs, 83 Da Xue East Rd, Sai Han Dist 010065, Hohhot, Peoples R China."	"hqltcm@163.com"	"NA"	"NA"	"NA"	"NA"	26	1	1	0	8	"GOVI-VERLAG  PHARMAZEUTISCHER VERLAG GMBH"	"ESCHBORN"	"PHARMAZEUTISCCARL MANNICH STR 26, D-65760 ESCHBORN, GERMANY"	"0031-7144"	"NA"	"NA"	"PHARMAZIE"	"Pharmazie"	"FEB"	2015	70	2	110	116	"NA"	"10.1691/ph.2015.4716"	7	"Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Pharmacology & Pharmacy; Chemistry"	"CA6VP"	"WOS:000349054200008"	25997251	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Guidi, M; Foletti, G; McLaren, P; Cavassini, M; Rauch, A; Tarr, PE; Lamy, O; Panchaud, A; Telenti, A; Csajka, C; Rotger, M"	"Guidi, Monia; Foletti, Giuseppe; McLaren, Paul; Cavassini, Matthias; Rauch, Andri; Tarr, Philip E.; Lamy, Olivier; Panchaud, Alice; Telenti, Amalio; Csajka, Chantal; Rotger, Margalida"	"Swiss HIV Cohort Study"	"A"	"Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry"	"ANTIVIRAL THERAPY"	"English"	"Article"	"NA"	"GENOME-WIDE ASSOCIATION; D DEFICIENCY; ANTIRETROVIRAL THERAPY; OLDER MEN; PREVALENCE; EFAVIRENZ; SMOKING; CYP3A4; PSN"	"Background: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH) D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH) D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. Methods: 1,397 25(OH) D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH) D levels. 25(OH) D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH) D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation. Results: A one-compartment model with linear absorption and elimination was used to describe 25(OH) D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH) D concentrations. 11% of the inter-individual variability in 25(OH) D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year. Conclusions: This analysis allowed identifying factors associated with 25(OH) D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results."	"[Guidi, Monia; Panchaud, Alice; Csajka, Chantal] Univ Lausanne, Sch Pharmaceut Sci, Geneva, Switzerland; [Guidi, Monia; Panchaud, Alice; Csajka, Chantal] Univ Geneva, Geneva, Switzerland; [Guidi, Monia; Panchaud, Alice; Csajka, Chantal] Univ Lausanne Hosp, Div Clin Pharmacol & Toxicol, Lausanne, Switzerland; [Guidi, Monia; Foletti, Giuseppe; McLaren, Paul; Panchaud, Alice; Telenti, Amalio; Csajka, Chantal; Rotger, Margalida] Univ Lausanne, Lausanne, Switzerland; [Foletti, Giuseppe; McLaren, Paul; Telenti, Amalio; Rotger, Margalida] Univ Lausanne Hosp, Inst Microbiol, Lausanne, Switzerland; [Cavassini, Matthias] Univ Lausanne Hosp, Div Infect Dis, Lausanne, Switzerland; [Rauch, Andri] Univ Hosp Bern, Div Infect Dis, CH-3010 Bern, Switzerland; [Tarr, Philip E.] Kantonsspital Basel, Infect Dis Serv, Basel, Switzerland; [Tarr, Philip E.] Univ Basel, Basel, Switzerland; [Lamy, Olivier] Univ Lausanne Hosp, Div Internal Med, Lausanne, Switzerland"	"Rotger, M (corresponding author), Univ Lausanne Hosp, Inst Microbiol, Lausanne, Switzerland."	"Margalida.rotger@chuv.ch"	"Rauch, Andri/E-9948-2017; Panchaud, Alice/S-6535-2019; Pantaleo, Giuseppe/K-6163-2016; cavassini, matthias/F-8987-2017"	"Rauch, Andri/0000-0001-5297-6062; Panchaud, Alice/0000-0001-6086-2401; cavassini, matthias/0000-0003-0933-7833; Csajka, Chantal/0000-0002-0660-082X; Guidi, Monia/0000-0002-6419-9317; McLaren, Paul/0000-0001-6019-7018"	"Swiss National Science Foundation (SNF)Swiss National Science Foundation (SNSF) [134277, 324730_141234]"	"This study has been financed within the framework of the SHCS (number 698) supported by the Swiss National Science Foundation (SNF; grant number 134277) and (grant number 324730_141234). The data are gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians. The authors thank Deolinda Alves and Raquel Martinez for technical help, Yannick Vallet and Yann Manet for assistance and the Vital-IT Center for High-Performance Computing of the Swiss Institute of Bioinformatics for providing the computational resources for the population analyses."	44	2	2	0	11	"INT MEDICAL PRESS LTD"	"LONDON"	"2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND"	"1359-6535"	"NA"	"NA"	"ANTIVIR THER"	"Antivir. Ther."	"NA"	2015	20	3	261	269	"NA"	"10.3851/IMP2823"	9	"Infectious Diseases; Pharmacology & Pharmacy; Virology"	"Infectious Diseases; Pharmacology & Pharmacy; Virology"	"CP5GP"	"WOS:000359909600002"	25032819	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Tylutki, Z; Jawien, W; Ciszowski, K; Wilimowska, J; Anand, JS"	"Tylutki, Zofia; Jawien, Wojciech; Ciszowski, Krzysztof; Wilimowska, Jolanta; Anand, Jacek Sein"	"NA"	"A"	"Abnormal olanzapine toxicokinetic profiles - population pharmacokinetic analysis"	"TOXICOLOGY MECHANISMS AND METHODS"	"English"	"Article"	"Enterohepatic circulation; Monolix; resorption"	"ENTEROHEPATIC CIRCULATION; GALLBLADDER CONTRACTION; CHOLECYSTOKININ; IDENTIFIABILITY; SCHIZOPHRENIA; TOXICITY; OVERDOSE; SUICIDE; SYSTEM; RISK"	"Context: Olanzapine is widely used in the treatment of schizophrenia and it is becoming more frequently responsible for overdoses. Standard pharmacokinetic models do not fit to the toxic concentration data. Objective: The aim of present study is to investigate the reasons for an abnormal olanzapine plasma concentration time curve in the range of toxic concentrations. Two hypotheses were verified: entering the enterohepatic cycle, and drug deposition and its desorption from activated charcoal used for gastrointestinal decontamination. Materials and methods: One-hundred thirty-five plasma concentration data from 21 patients hospitalized for acute olanzapine poisoning were analyzed with the use of the population pharmacokinetic approach. A non-linear mixed-effects modeling approach with Monolix 4.3.1 was employed. Results: A model assuming gallbladder emptying at irregular intervals was developed. Also, a model that describes desorption of olanzapine from the charcoal surface, in which the dose is divided into two absorbed fractions, was constructed. The analysis has found gastrointestinal decontamination and previous olanzapine treatment, as the significant covariates for toxicokinetic parameters of olanzapine. Conclusion: Our study provides interesting models for investigation of toxic concentration of olanzapine, which may also be used as the basis for further model development for other drugs as well. The investigated population was not large enough to reliably confirm any of the proposed models. It would be well worth continuing this study with more substantial data. Also, any additional information about olanzapine metabolite concentration could be vital."	"[Tylutki, Zofia; Jawien, Wojciech] Jagiellonian Univ, Fac Pharm, Dept Pharmacokinet & Phys Pharm, PL-30688 Krakow, Poland; [Ciszowski, Krzysztof] Jagiellonian Univ, Coll Med, Fac Med, Chair Toxicol & Environm Dis, PL-30688 Krakow, Poland; [Wilimowska, Jolanta] Krakow Univ Hosp, Lab Diagnost Unit, Krakow, Poland; [Anand, Jacek Sein] Med Univ Gdansk, Dept Clin Toxicol, Gdansk, Poland; [Anand, Jacek Sein] Pomerania Ctr Toxicol, Gdansk, Poland"	"Jawien, W (corresponding author), Jagiellonian Univ, Fac Pharm, Ul Medyczna 9, PL-30688 Krakow, Poland."	"wojciech.jawien@uj.edu.pl"	"Jawien, Wojciech/AAR-9855-2020"	"Jawien, Wojciech/0000-0002-1741-490X; Tylutki, Zofia/0000-0003-4541-0815"	"NA"	"NA"	26	3	3	1	11	"TAYLOR & FRANCIS LTD"	"ABINGDON"	"2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND"	"1537-6516"	"1537-6524"	"NA"	"TOXICOL MECH METHOD"	"Toxicol. Mech. Methods"	"JAN"	2015	25	1	1	12	"NA"	"10.3109/15376516.2014.971137"	12	"Toxicology"	"Toxicology"	"AW9TO"	"WOS:000346600500001"	25264211	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Areberg, J; Petersen, KB; Chen, G; Naik, H"	"Areberg, Johan; Petersen, Kamilla B.; Chen, Grace; Naik, Himanshu"	"NA"	"A"	"Population Pharmacokinetic Meta-Analysis of Vortioxetine in Healthy Individuals"	"BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY"	"English"	"Article"	"NA"	"LU AA21004; KIDNEY-DISEASE; ANTIDEPRESSANT; METABOLISM; DISCOVERY; IMPACT"	"The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75mg (single dose) and 2.5-60mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two-compartment model with first-order absorption, lag-time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7L/hr for oral clearance and 1.97.10(3)L for the central volume of distribution. The average elimination half-life was 65.8hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate-parameter relationships. For CYP2D6 poor metabolisers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolisers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterise pharmacokinetics of vortioxetine in the healthy population."	"[Areberg, Johan; Petersen, Kamilla B.] H Lundbeck & Co AS, Div Clin & Quantitat Pharmacol, DK-2500 Valby, Denmark; [Chen, Grace; Naik, Himanshu] Takeda Pharmaceut Ltd, Deerfield, IL USA"	"Areberg, J (corresponding author), H Lundbeck & Co AS, Dept Quantitat Pharmacol, Ottiliavej 9, DK-2500 Valby, Denmark."	"joar@lundbeck.com"	"NA"	"NA"	"H. Lundbeck A/S or Takeda Pharmaceuticals Ltd"	"All authors are employed by H. Lundbeck A/S or Takeda Pharmaceuticals Ltd, the sponsors of the original studies."	17	22	22	2	10	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1742-7835"	"1742-7843"	"NA"	"BASIC CLIN PHARMACOL"	"Basic Clin. Pharmacol. Toxicol."	"DEC"	2014	115	6	552	559	"NA"	"10.1111/bcpt.12256"	8	"Pharmacology & Pharmacy; Toxicology"	"Pharmacology & Pharmacy; Toxicology"	"AU0WC"	"WOS:000345341900011"	24766668	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Brill, MJE; van Rongen, A; Houwink, API; Burggraaf, J; van Ramshorst, B; Wiezer, RJ; van Dongen, EPA; Knibbe, CAJ"	"Brill, Margreke J. E.; van Rongen, Anne; Houwink, Aletta P. I.; Burggraaf, Jacobus; van Ramshorst, Bert; Wiezer, Rene J.; van Dongen, Eric P. A.; Knibbe, Catherijne A. J."	"NA"	"A"	"Midazolam Pharmacokinetics in Morbidly Obese Patients Following Semi-Simultaneous Oral and Intravenous Administration: A Comparison with Healthy Volunteers"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"DRUG-METABOLIZING-ENZYMES; BIOAVAILABILITY ESTIMATION; HEPATIC STEATOSIS; EXPRESSION; INFLAMMATION; LIVER; MODEL; PREDICTION; IMPACT; ADULTS"	"Background While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bio-availability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers. Methods Twenty morbidly obese patients [mean body weight 144 kg (range 112-186 kg) and mean body mass index 47 kg/m(2) (range 40-68 kg/m(2))] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 � 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM (R). Results In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min(-1), P < 0.001]. Conclusions In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings."	"[Brill, Margreke J. E.; van Rongen, Anne; Burggraaf, Jacobus; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Brill, Margreke J. E.; van Rongen, Anne; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3435 CM Nieuwegein, Netherlands; [Houwink, Aletta P. I.; van Dongen, Eric P. A.] St Antonius Hosp, Dept Anaesthesiol Intens Care & Pain Management, NL-3435 CM Nieuwegein, Netherlands; [Burggraaf, Jacobus] Ctr Human Drug Res, Leiden, Netherlands; [van Ramshorst, Bert; Wiezer, Rene J.] St Antonius Hosp, Dept Surg, NL-3435 CM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"NA"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"ZonMW (The Netherlands Organisation for Health Research and Development)Netherlands Organization for Health Research and Development [836011008]"	"This study was sponsored by ZonMW (The Netherlands Organisation for Health Research and Development), project number 836011008. In addition, we thank bariatric nurses Brigitte Bliemer and Silvia Samsom for their help in recruiting patients. Margreke J. E. Brill, Anne van Rongen, Aletta P. I. Houwink, Jacobus Burggraaf, Bert van Ramshorst, Rene J. Wiezer, Eric P. A. van Dongen and Catherijne A. J. Knibbe have no potential conflicts of interest to declare."	49	48	48	0	8	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"OCT"	2014	53	10	931	941	"NA"	"10.1007/s40262-014-0166-x"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AU1NZ"	"WOS:000345388700007"	25141974	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, CG; Allegaert, K; Tibboel, D; Danhof, M; van der Marel, CD; Mathot, RAA; Knibbe, CAJ"	"Wang, Chenguang; Allegaert, Karel; Tibboel, Dick; Danhof, Meindert; van der Marel, Caroline D.; Mathot, Ron A. A.; Knibbe, Catherijne A. J."	"NA"	"A"	"Population Pharmacokinetics of Paracetamol Across the Human Age-Range From (Pre) term Neonates, Infants, Children to Adults"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"allometry; paracetamol; pharmacokinetics; clearance; pediatric"	"MAJOR CRANIOFACIAL SURGERY; INTRAVENOUS PARACETAMOL; PROPACETAMOL PHARMACOKINETICS; ACETAMINOPHEN; MODEL; CLEARANCE; CLOSURE"	"In order to characterize the variation in pharmacokinetics of paracetamol across the human age span, we performed a population pharmacokinetic analysis from preterm neonates to adults with specific focus on clearance. Concentration-time data obtained in 220 neonates (post-natal age 1-76 days, gestational age 27-42 weeks), infants (0.11-1.33 yrs), children (2-7 yrs) and adults (19-34 yrs) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight-dependent exponent were tested. Between preterm neonates and adults, linear bodyweight functions were identified for Q2, Q3, V1, V2, and V3, while for CL a power function with a bodyweight-dependent exponent k was identified (CLi=CL(p)x(BW/70)(k)). The exponent k was found to decrease in a sigmoidal manner with bodyweight from 1.2 to 0.75, with half the decrease in exponent reached at 12.2kg. No other covariates such as age were identified. A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the pediatric age-range was developed. Clearance was found to change in a nonlinear manner with bodyweight. Based on the final model, dosing guidelines are proposed from preterm neonates to adolescents resulting in similar exposure across all age ranges."	"[Wang, Chenguang; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Wang, Chenguang; Tibboel, Dick] Erasmus MC Sophia Childrens Hosp, Rotterdam, Netherlands; [Wang, Chenguang; Tibboel, Dick] Erasmus MC Sophia Childrens Hosp, Dept Paediat Intens Care, Rotterdam, Netherlands; [Allegaert, Karel] Katholieke Univ Leuven, Dept Dev & Regenerat, Louvain, Belgium; [Allegaert, Karel] Katholieke Univ Leuven Hosp, Neonatal Intens Care Unit, Louvain, Belgium; [van der Marel, Caroline D.] Erasmus MC, Dept Anesthesiol, Rotterdam, Netherlands; [Mathot, Ron A. A.] Univ Amsterdam, Acad Med Ctr, Dept Hosp Pharm, NL-1105 AZ Amsterdam, Netherlands; [Mathot, Ron A. A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Pharmacol, NL-1105 AZ Amsterdam, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"allegaert, karel/C-3611-2016"	"allegaert, karel/0000-0001-9921-5105"	"Top Institute Pharma [D2-104]; Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship) [1800209N]"	"This study was performed within the framework of Top Institute Pharma project number D2-104. The clinical research of Karel Allegaert is supported by the Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800209N). The authors would like to thank Bristol-Myers Squibb for sharing adult data of paracetamol (Gregoire et al)."	36	27	28	0	7	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JUN"	2014	54	6	619	629	"NA"	"10.1002/jcph.259"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AH0PL"	"WOS:000335822500003"	24375166	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Jullien, V; Valecha, N; Srivastava, B; Sharma, B; Kiechel, JR"	"Jullien, Vincent; Valecha, Neena; Srivastava, Bina; Sharma, Bhawna; Kiechel, Jean-Rene"	"NA"	"A"	"Population pharmacokinetics of mefloquine, administered as a fixed-dose combination of artesunate-mefloquine in Indian patients for the treatment of acute uncomplicated Plasmodium falciparum malaria"	"MALARIA JOURNAL"	"English"	"Article"	"Mefloquine; Population pharmacokinetics; Adults; Malaria"	"FORMULATION; RESISTANCE; EFFICACY; THERAPY; AMAZON; SAFETY; TRIAL"	"Background: Fixed-dose combinations of artemisinin combination therapy are strongly recommended to facilitate drug administration and compliance. New fixed-dose combinations must nevertheless be evaluated in relevant populations in terms of efficacy and pharmacokinetics. Methods: A single-arm, open-label, clinical trial was performed in Indian patients with acute uncomplicated Plasmodium falciparum malaria to investigate the efficacy and the pharmacokinetics of mefloquine when combined with artesunate in a fixed-dose combination (400/200 mg of mefloquine base/artesunate). The pharmacokinetic analysis was performed using a population approach. Results: Seventy-seven patients were included in the study. Mefloquine pharmacokinetics obeys a two-compartment model with first-order absorption and elimination. Mean parameter estimates (% inter-individual variability) were as follows: 0.16 h(-1) (75%) for the absorption rate constant, 1.13 L/h (30%) for the apparent plasma clearance, 271 L (21%) for the apparent central distribution volume, 344 L (54%) for the apparent peripheral distribution volume, and 1.43 L/h for the apparent distribution clearance. These values were consistent with the pharmacokinetic results described in Thai patients. No significant covariate was found for clearance. Body weight explained the inter-individual variability of the apparent central and peripheral distribution volumes. The PCR-adjusted efficacy of the treatment was 100%. Conclusions: The lack of significant covariate explaining the inter-individual variability of mefloquine clearance, combined with the excellent efficacy, supports the use of the standard 200/400 mg of artesunate-mefloquine fixed-dose combination in Indian patients with uncomplicated P. falciparum malaria."	"[Jullien, Vincent] Univ Paris 05, INSERM, U1129, Paris, France; [Jullien, Vincent] Hop Europeen Georges Pompidou, Serv Pharmacol, Paris, France; [Jullien, Vincent] AP HP, Paris, France; [Valecha, Neena; Srivastava, Bina] Natl Inst Malaria Res, New Delhi, India; [Sharma, Bhawna] Drugs Neglected Dis Initiat, New Delhi 110016, India; [Kiechel, Jean-Rene] Drugs Neglected Dis Initiat, CH-1202 Geneva, Switzerland"	"Kiechel, JR (corresponding author), Drugs Neglected Dis Initiat, 15 Chemin Louis Dunant, CH-1202 Geneva, Switzerland."	"jean-rene.kiechel@wanadoo.fr"	"NA"	"NA"	"Department for International Development, UK; Dutch Ministry of Foreign Affairs; French Development Agency, France; NetherlandsNetherlands Government"	"Clinical trials were monitored by GVK (India), and the bio-analytical determinations were performed by Sitec Labs, Mumbai (India). We thank the following for their contribution in conducting the clinical study: N G Dubhashi (Goa Medical College and Hospital, Bambolim), B H Krishnamoorthy Rao (Wenlock District Government Hospital, Mangalore), Ashwani Kumar (National Institute of Malaria Research - Field Unit, Panjim), S K Ghosh (National Institute of Malaria Research, Bengaluru), Jai Prakash Narayan Singh and A P Dash (both of National Institute of Malaria Research, New Delhi). We thank patients for participating in the study and the local health personnel who contributed to the study execution, and acknowledge the assistance of Susan Wells (DNDi) in editing the manuscript. This manuscript bears the NIMR publication screening committee approval no. 01/2014. This work was supported by the Department for International Development, UK, the Dutch Ministry of Foreign Affairs, the Netherlands, and the French Development Agency, France."	24	6	6	0	2	"BIOMED CENTRAL LTD"	"LONDON"	"236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND"	"1475-2875"	"NA"	"NA"	"MALARIA J"	"Malar. J."	"MAY 23"	2014	13	"NA"	"NA"	"NA"	187	"10.1186/1475-2875-13-187"	7	"Infectious Diseases; Parasitology; Tropical Medicine"	"Infectious Diseases; Parasitology; Tropical Medicine"	"AL2IP"	"WOS:000338949500002"	24886117	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Perez-Ruixo, C; Peris, JE; Escudero-Ortiz, V; Bretcha-Boix, P; Farre-Alegre, J; Perez-Ruixo, JJ; Valenzuela, B"	"Perez-Ruixo, Carlos; Peris, Jose E.; Escudero-Ortiz, Vanesa; Bretcha-Boix, Pedro; Farre-Alegre, Jose; Jose Perez-Ruixo, Juan; Valenzuela, Belen"	"NA"	"A"	"Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Oxaliplatin bioavailability; Peritoneal carcinomatosis; Pharmacokinetics; NONMEM (R); Hyperthermic intraperitoneal chemotherapy; Cytoreductive surgery"	"IMPAIRED RENAL-FUNCTION; CYTOREDUCTIVE SURGERY; COLORECTAL-CANCER; POPULATION PHARMACOKINETICS; CHEMOTHERAPY HIPEC; CLINICAL-EFFICACY; RANDOMIZED-TRIAL; OVARIAN-CANCER; PHASE-I; SURVIVAL"	"To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters. Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model (NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap. An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (V (a)) exponentially decreased due to the carrier solute absorption. The reduction in V (a) was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h(-1) for icodextrin 4 % and from 0.86 to 1.09 h(-1) for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution. Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min."	"[Perez-Ruixo, Carlos; Peris, Jose E.] Univ Valencia, Pharm & Pharmaceut Technol Dept, Valencia, Spain; [Perez-Ruixo, Carlos] Consulting Projects Res, Valencia, Spain; [Escudero-Ortiz, Vanesa; Bretcha-Boix, Pedro; Farre-Alegre, Jose; Valenzuela, Belen] Hosp Quiron Torrevieja, Alicante 03180, Spain; [Escudero-Ortiz, Vanesa; Bretcha-Boix, Pedro; Farre-Alegre, Jose] UCAM Catholic Univ San Antonio, Murcia, Spain; [Jose Perez-Ruixo, Juan] Amgen Inc, Pharmacokinet & Drug Metab, Valencia, Spain"	"Valenzuela, B (corresponding author), Hosp Quiron Torrevieja, Personalized Pharmacotherapy Unit, Partida Loma S-N, Alicante 03180, Spain."	"belen.valenzuela@quiron.es"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"Conselleria de Sanidad of Comunidad Valenciana [GE-079/11]"	"The authors would like to thank the patients and their families, as well as the medical, nursing, and laboratory staff of the Hospital Quiron Torrevieja who participated in the present study. This work was supported by Conselleria de Sanidad of Comunidad Valenciana. Grant GE-079/11."	52	6	6	0	10	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"MAY"	2014	73	5	1009	1020	"NA"	"10.1007/s00280-014-2436-6"	12	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"AG4LO"	"WOS:000335391500016"	24663502	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Piana, C; Zhao, W; Adkison, K; Burger, D; Jacqz-Aigrain, E; Danhof, M; Della Pasqua, O"	"Piana, Chiara; Zhao, Wei; Adkison, Kimberly; Burger, David; Jacqz-Aigrain, Evelyne; Danhof, Meindert; Della Pasqua, Oscar"	"NA"	"A"	"Covariate effects and population pharmacokinetics of lamivudine in HIVinfected children"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"dose rationale; drug development; lamivudine; paediatrics; population pharmacokinetics"	"TWICE-DAILY LAMIVUDINE; CLINICAL-PHARMACOLOGY; ZIDOVUDINE; ABACAVIR; MODEL; PERFORMANCE; SELECTION; PLASMA; NONMEM"	"AimLamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and C-max). MethodsData from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building. ResultsA one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6kg), CL and V were 16.5 (95% CI 15.2, 17.7) lh(-1) and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12h) after twice daily doses of 4mgkg(-1) ranged from 4.44mgl(-1)h for children <14kg to 7.25mgl(-1)h for children >30kg. ConclusionsThe use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered."	"[Piana, Chiara; Danhof, Meindert; Della Pasqua, Oscar] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Zhao, Wei; Jacqz-Aigrain, Evelyne] Univ Paris 07, Hop Robert Debre, AP HP, Dept Paediat Pharmacol & Pharmacogenet, Paris, France; [Zhao, Wei; Jacqz-Aigrain, Evelyne] INSERM, Clin Invest Ctr CIC9202, Paris, France; [Adkison, Kimberly] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Res Triangle Pk, NC USA; [Burger, David] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, NL-6525 ED Nijmegen, Netherlands; [Burger, David] Radboud Univ Nijmegen, Med Ctr, N4i, NL-6525 ED Nijmegen, Netherlands; [Della Pasqua, Oscar] GlaxoSmithKline, Clin Pharmacol Modelling & Simulat, Stockley Pk, England"	"Della Pasqua, O (corresponding author), Leiden Acad Ctr Drug Res, Div Pharmacol, POB 9502, NL-2300 RA Leiden, Netherlands."	"odp72514@gsk.com"	"Zhao, Wei/D-3322-2011; Burger, David/C-9929-2013"	"Zhao, Wei/0000-0002-1830-338X; Jacqz-Aigrain, Evelyne/0000-0002-4285-7067"	"European Commission (EC)European Commission Joint Research CentreEuropean Community (EC) [LSHP-CT-2006-018865, QLK2-2000-00150]; PENTA Foundation; PENTA LABNET (EC)European Commission Joint Research Centre [201057]; GlaxoSmithKline, UKGlaxoSmithKline"	"PENTA is a Co-ordinated Action of the European Commission (EC), supported by the Sixth Framework contract LSHP-CT-2006-018865 and Fifth Framework Program contract QLK2-2000-00150. PENTA activities are also supported by the PENTA Foundation and PENTA LABNET (EC Seventh Framework contract 201057). Financial support for PENTA 13 and 15 was also received from GlaxoSmithKline, UK."	36	13	13	1	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"MAY"	2014	77	5	861	872	"NA"	"10.1111/bcp.12247"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"AF5VY"	"WOS:000334782800014"	24118070	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Boak, LM; Rayner, CR; Grayson, ML; Paterson, DL; Spelman, D; Khumra, S; Capitano, B; Forrest, A; Li, J; Nation, RL; Bulitta, JB"	"Boak, Lauren M.; Rayner, Craig R.; Grayson, M. Lindsay; Paterson, David L.; Spelman, Denis; Khumra, Sharmila; Capitano, Blair; Forrest, Alan; Li, Jian; Nation, Roger L.; Bulitta, Jurgen B."	"NA"	"A"	"Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"COMPASSIONATE-USE PROGRAM; GRAM-POSITIVE INFECTIONS; CYSTIC-FIBROSIS PATIENTS; HEALTHY-VOLUNTEERS; ORAL BIOAVAILABILITY; LIFE-SPAN; THROMBOCYTOPENIA; PHARMACODYNAMICS; MODELS; THERAPY"	"Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 x 10(9)/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h."	"[Boak, Lauren M.; Rayner, Craig R.; Li, Jian; Nation, Roger L.; Bulitta, Jurgen B.] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic, Australia; [Rayner, Craig R.] D3 Med LLC, Parsippany, NJ USA; [Grayson, M. Lindsay; Khumra, Sharmila] Austin Hosp, Dept Med, Melbourne, Vic 3084, Australia; [Grayson, M. Lindsay] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia; [Paterson, David L.; Capitano, Blair] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA; [Spelman, Denis] Alfred Hosp, Dept Infect Dis, Melbourne, Vic, Australia; [Spelman, Denis] Monash Univ, Melbourne, Vic 3004, Australia; [Forrest, Alan; Bulitta, Jurgen B.] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Buffalo, NY 14260 USA; [Khumra, Sharmila; Bulitta, Jurgen B.] Monash Univ, Ctr Med Use & Safety, Parkville, Vic, Australia"	"Nation, RL (corresponding author), Monash Univ, Monash Inst Pharmaceut Sci, Parkville Campus, Parkville, Vic, Australia."	"roger.nation@monash.edu; jurgen.bulitta@monash.edu"	"Bulitta, Jurgen B/P-3355-2018; Li, Jian/I-5538-2016"	"Bulitta, Jurgen B/0000-0001-7352-3097; Li, Jian/0000-0001-7953-8230; Paterson, David/0000-0003-2079-4437"	"Australian National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [284347]; PfizerPfizer"	"This work was supported by Australian National Health and Medical Research Council (NHMRC) grant number 284347. J.B.B. is an Australian Research Council DECRA Fellow (DE120103084). J.L. is an Australian NHMRC Senior Research Fellow. A.F. and J.B.B. received collaborative research grants from Pfizer; these collaborative Pfizer grants were not related to the work presented in the manuscript."	44	48	52	0	6	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2014	58	4	2334	2343	"NA"	"10.1128/AAC.01885-13"	10	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"AD9SU"	"WOS:000333605600062"	24514086	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Wilbaux, M; Henin, E; Oza, A; Colomban, O; Pujade-Lauraine, E; Freyer, G; Tod, M; You, B"	"Wilbaux, M.; Henin, E.; Oza, A.; Colomban, O.; Pujade-Lauraine, E.; Freyer, G.; Tod, M.; You, B."	"NA"	"A"	"Prediction of tumour response induced by chemotherapy using modelling of CA-125 kinetics in recurrent ovarian cancer patients"	"BRITISH JOURNAL OF CANCER"	"English"	"Article"	"CA-125 kinetics; ovarian epithelial cancer; mathematical modelling; K-PD modelling; tumour size prediction"	"NA"	"Background: The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment. Methods: The data from the CALYPSO-randomised phase III trial, comparing two platinum-based regimens in recurrent ovarian cancer (ROC) patients, was randomly split into a `learning data set' to estimate model parameters and a ` validation data set' to validate model performances. A kinetic-pharmacodynamic semi-mechanistic model was built to describe tumour size and CA-125 kinetics during chemotherapy. The ability of the model to predict tumour response induced by chemotherapy, based on CA-125 values, was assessed. Results: Data from 535 ROC patients were used to model CA-125 kinetics and tumour size changes during the first 513 days after treatment initiation. Using the validated model, we could predict with accuracy the tumour size changes induced by chemotherapy based on the baseline imaging assessment and longitudinal CA-125 values (mean prediction error: 0.3%, mean absolute prediction error: 10.6%). Conclusions: Using a semi-mechanistic model, the dynamic relationships between tumour size changes and CA-125 kinetics induced by chemotherapy were established in ROC patients. A modelling approach allowed CA-125 to be assessed as a biomarker for tumour size dynamics, to predict treatment efficacy for research and clinical purposes."	"[Wilbaux, M.; Henin, E.; Colomban, O.; Freyer, G.; Tod, M.; You, B.] Univ Lyon 1, EMR 3738, Fac Med & Maieut Lyon Sud Charles Merieux, F-69600 Oullins, France; [Oza, A.] Univ Hlth Network, Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M5T 2M9, Canada; [Pujade-Lauraine, E.] Hop Hotel Dieu, F-75004 Paris, France; [Freyer, G.; You, B.] Hosp Civils Lyon, Ctr Hosp Lyon Sud, Invest Ctr Treatments Oncol & Hematol Lyon, Med Oncol Serv, F-69310 Pierre Benite, France"	"Wilbaux, M (corresponding author), Univ Lyon 1, EMR 3738, Fac Med & Maieut Lyon Sud Charles Merieux, F-69600 Oullins, France."	"melanie.wilbaux@gmail.com"	"You, Benoit/M-4558-2014"	"COLOMBAN, OLIVIER/0000-0003-1671-3470; Oza, Amit/0000-0002-9510-8641; HENIN, Emilie/0000-0001-7478-2154"	"Fondation Synergie Lyon Cancer; La Ligue Nationale contre le CancerLigue nationale contre le cancer"	"EH was funded by Fondation Synergie Lyon Cancer and La Ligue Nationale contre le Cancer."	23	16	16	0	3	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"0007-0920"	"1532-1827"	"NA"	"BRIT J CANCER"	"Br. J. Cancer"	"MAR 18"	2014	110	6	1517	1524	"NA"	"10.1038/bjc.2014.75"	8	"Oncology"	"Oncology"	"AD4DB"	"WOS:000333195800015"	24556626	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Brill, MJE; Houwink, API; Schmidt, S; Van Dongen, EPA; Hazebroek, EJ; van Ramshorst, B; Deneer, VH; Mouton, JW; Knibbe, CAJ"	"Brill, Margreke J. E.; Houwink, Aletta P. I.; Schmidt, Stephan; Van Dongen, Eric P. A.; Hazebroek, Eric J.; van Ramshorst, Bert; Deneer, Vera H.; Mouton, Johan W.; Knibbe, Catherijne A. J."	"NA"	"A"	"Reduced subcutaneous tissue distribution of cefazolin in morbidly obese versus non-obese patients determined using clinical microdialysis"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"subcutaneous ISF; population pharmacokinetics; Monte Carlo simulations; surgical prophylaxis"	"ADIPOSE-TISSUE; PROTEIN-BINDING; BLOOD-FLOW; ANTIBIOTIC-PROPHYLAXIS; IN-VIVO; PHARMACOKINETICS; PENETRATION; CIPROFLOXACIN"	"Objectives: As morbidly obese patients are prone to surgical site infections, adequate blood and subcutaneous tissue concentrations of prophylactic antibiotic agents during surgery are imperative. In this study we evaluated cefazolin subcutaneous adipose tissue distribution in morbidly obese and non-obese patients, thereby quantifying the influence of morbid obesity on cefazolin pharmacokinetics and enabling Monte Carlo simulations for subsequent dose adjustments. Methods: Nine morbidly obese patients [body mass index (BMI) 47 � 6 kg/m(2)], of whom eight were evaluable, and seven non-obese patients (BMI 28 � 3 kg/m(2)) received cefazolin 2 g intravenously before surgery (NCT01309152). Using microdialysis, interstitial space fluid (ISF) samples of subcutaneous adipose tissue were collected together with total and unbound plasma cefazolin samples until 240 min after dosing. Using NONMEM, population pharmacokinetic modelling, covariate analysis and Monte Carlo simulations were performed. Results: The unbound (free) cefazolin ISF penetration ratio (fAUC(tissue)/fAUC(plasma)) was 0.70 (range 0.68-0.83) in morbidly obese patients versus 1.02 (range 0.85-1.41) in non-obese patients (P<0.05). A two-compartment model with saturable protein binding was identified in which the central volume of distribution and cefazolin distribution from the central compartment to the ISF compartment proved dependent on body weight (P<0.001 and P<0.01, respectively). Monte Carlo simulations showed reduced probability of target attainment for morbidly obese versus non-obese patients for MIC values of 2 and 4 mg/L. Conclusions: This study shows that cefazolin tissue distribution is lower in morbidly obese patients and reduces with increasing body weight, and that dose adjustments are required in this patient group."	"[Brill, Margreke J. E.; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Brill, Margreke J. E.; Deneer, Vera H.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3435 CM Nieuwegein, Netherlands; [Houwink, Aletta P. I.; Van Dongen, Eric P. A.] St Antonius Hosp, Dept Anaesthesiol & Intens Care, NL-3435 CM Nieuwegein, Netherlands; [Schmidt, Stephan] Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Coll Pharm, Orlando, FL USA; [Hazebroek, Eric J.; van Ramshorst, Bert] St Antonius Hosp, Dept Surg, NL-3435 CM Nieuwegein, Netherlands; [Mouton, Johan W.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6525 ED Nijmegen, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, Koekoekslaan 1, NL-3435 CM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"NA"	"Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Fonds Nuts OHRA [1002-026]"	"This work was supported by a research grant from Fonds Nuts OHRA (1002-026)."	29	56	57	1	12	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"MAR"	2014	69	3	715	723	"NA"	"10.1093/jac/dkt444"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"AB5KL"	"WOS:000331827200020"	24214905	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Dahlberg, AM; Kaminskas, LM; Smith, A; Nicolazzo, JA; Porter, CJH; Bulitta, JB; McIntosh, MP"	"Dahlberg, Annette M.; Kaminskas, Lisa M.; Smith, Alanna; Nicolazzo, Joseph A.; Porter, Christopher J. H.; Bulitta, Juergen B.; McIntosh, Michelle P."	"NA"	"A"	"The Lymphatic System Plays a Major Role in the Intravenous and Subcutaneous Pharmacokinetics of Trastuzumab in Rats"	"MOLECULAR PHARMACEUTICS"	"English"	"Article"	"trastuzumab; lymphatic; pharmacokinetics; monoclonal antibody; subcutaneous"	"BREAST-CANCER; POPULATION PHARMACOKINETICS; MONOCLONAL-ANTIBODIES; HEALTHY-VOLUNTEERS; ABSORPTION; INJECTION; MODEL; SHEEP; FORMULATION; RITUXIMAB"	"Therapeutic monoclonal antibodies are currently delivered mainly via the intravenous route, since large volumes are often required to deliver a therapeutic dose. Administration via the subcutaneous route would have several therapeutic advantages; the absorption mechanisms for antibodies dosed subcutaneously are poorly understood. This study was conducted to develop a better understanding of the mechanisms governing the subcutaneous absorption and trafficking of monoclonal antibodies. Specifically, the role of the lymphatic system in the absorption and prolonged plasma exposure of trastuzumab was explored in thoracic lymph duct-cannulated rats after SC and IV dosing. A population pharmacokinetic model was developed in S-ADAPT to simultaneously fit all plasma and lymph concentrations and to predict the pharmacokinetics in nonlymph duct-cannulated animals. The estimated absolute bioavailability of trastuzumab after SC administration in rats was 85.5%. Following SC administration, 53.1% of the trastuzumab dose was absorbed via a first-order process (mean absorption time: 99.6 h) into the peripheral lymph compartment and 32.4% of the dose was absorbed by a Michaelis Menten process into the central compartment. Recovery in thoracic lymph over 30 h was 26.7% after SC and 44.1% after IV administration. This study highlights for the first time the significant role of the lymphatic system in maintaining the long plasma exposure of trastuzumab, with the model predicting an extensive distribution of this monoclonal antibody into the lymph following SC and IV administration. This extensive direct absorption from the SC injection site into lymph may enable novel therapeutic strategies for the treatment of lymph resident metastatic cancer."	"[Dahlberg, Annette M.; Kaminskas, Lisa M.; Smith, Alanna; Nicolazzo, Joseph A.; Porter, Christopher J. H.; McIntosh, Michelle P.] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia; [Bulitta, Juergen B.] Monash Univ, Ctr Med Use & Safety, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia"	"McIntosh, MP (corresponding author), Monash Univ, Monash Inst Pharmaceut Sci, 381 Royal Pde, Parkville, Vic 3052, Australia."	"michelle.mcintosh@monash.edu"	"Bulitta, Jurgen B/P-3355-2018; Porter, Christopher JH/C-6333-2011"	"Bulitta, Jurgen B/0000-0001-7352-3097; Porter, Christopher JH/0000-0003-3474-7551; Kaminskas, Lisa/0000-0003-4821-4262; McIntosh, Michelle Paula/0000-0002-1605-7226"	"Faculty of Pharmacy Postgraduate Research Scholarship; Australian National Health and Medical Research Council (NHMRC) Career Development fellowshipNational Health and Medical Research Council of Australia [APP1022732]; NHMRCNational Health and Medical Research Council of Australia [APP1044802]; Australian Research Council Discovery Early Career Research AwardAustralian Research Council [DE120103084]"	"A.M.D. was supported by a Faculty of Pharmacy Postgraduate Research Scholarship. L.M.K. was supported by an Australian National Health and Medical Research Council (NHMRC) Career Development fellowship (APP1022732) and by NHMRC project funding (APP1044802). J.B.B. is the recipient of an Australian Research Council Discovery Early Career Research Award (DE120103084)."	37	24	24	1	24	"AMER CHEMICAL SOC"	"WASHINGTON"	"1155 16TH ST, NW, WASHINGTON, DC 20036 USA"	"1543-8384"	"NA"	"NA"	"MOL PHARMACEUT"	"Mol. Pharm."	"FEB"	2014	11	2	496	504	"NA"	"10.1021/mp400464s"	9	"Medicine, Research & Experimental; Pharmacology & Pharmacy"	"Research & Experimental Medicine; Pharmacology & Pharmacy"	"AA0UI"	"WOS:000330812500013"	24350780	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Kim, TH; Park, GY; Shin, S; Kwon, DR; Seo, WS; Shin, JC; Choi, JH; Joo, SH; Weon, KY; Min, BS; Baek, KM; Upadhyay, M; Zhao, BT; HeeWoo, M; Kwon, SH; Shin, BS"	"Kim, Tae Hwan; Park, Gi-Young; Shin, Soyoung; Kwon, Dong Rak; Seo, Won Sik; Shin, Jeong Cheol; Choi, Jin Ho; Joo, Sang Hoon; Weon, Kwon-Yeon; Min, Byung Sun; Baek, Kyung Min; Upadhyay, Mahesh; Zhao, Bing Tian; HeeWoo, Mi; Kwon, So Hee; Shin, Beom Soo"	"NA"	"A"	"Pharmacokinetic Alteration of Baclofen by Multiple Oral Administration of Herbal Medicines in Rats"	"EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE"	"English"	"Article"	"NA"	"CONTINUOUS INTRATHECAL BACLOFEN; POPULATION PHARMACOKINETICS; DRUG"	"The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42-4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C-max) and longer time to reach C-max (T-max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F-urine). The absorption rate (K-a) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance."	"[Kim, Tae Hwan] Sungkyunkwan Univ, Sch Pharm, Suwon 440746, Gyeonggi Do, South Korea; [Park, Gi-Young; Kwon, Dong Rak] Catholic Univ Daegu, Sch Med, Dept Rehabil Med, Taegu 705718, South Korea; [Shin, Soyoung; Upadhyay, Mahesh] Wonkwang Univ, Coll Pharm, Dept Pharm, Iksan 570749, Jeonbuk, South Korea; [Seo, Won Sik; Shin, Jeong Cheol; Choi, Jin Ho; Joo, Sang Hoon; Weon, Kwon-Yeon; Min, Byung Sun; Zhao, Bing Tian; HeeWoo, Mi; Shin, Beom Soo] Catholic Univ Daegu, Coll Pharm, Gyongsan 712702, Gyeongbuk, South Korea; [Baek, Kyung Min] Daegu Haany Univ, Dept Cardiovasc & Neurol Dis, Coll Oriental Med, Taegu 706060, South Korea; [Kwon, So Hee] Yonsei Univ, Yonsei Inst Pharmaceut Sci, Coll Pharm, Inchon 406840, South Korea"	"Shin, BS (corresponding author), Catholic Univ Daegu, Coll Pharm, 13-13 Hayang Ro, Gyongsan 712702, Gyeongbuk, South Korea."	"bsshin@cu.ac.kr"	"Kwon, So/AAG-8971-2020"	"NA"	"Comprehensive and Interactive Medicine Institute (CIMI); National Research Foundation of Korea (NRF)National Research Foundation of Korea [2012R1A1A2008588, 22A2013000073]"	"This work was supported by the Comprehensive and Interactive Medicine Institute (CIMI) and the National Research Foundation of Korea (NRF) Grant nos. 2012R1A1A2008588 and 22A2013000073 (BK21 Plus)."	32	4	4	0	2	"HINDAWI LTD"	"LONDON"	"ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND"	"1741-427X"	"1741-4288"	"NA"	"EVID-BASED COMPL ALT"	"Evid.-based Complement Altern. Med."	"NA"	2014	"NA"	"NA"	"NA"	"NA"	402126	"10.1155/2014/402126"	9	"Integrative & Complementary Medicine"	"Integrative & Complementary Medicine"	"AT1AB"	"WOS:000344664400001"	25530781	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Perez-Ruixo, C; Valenzuela, B; Peris, JE; Bretcha-Boix, P; Escudero-Ortiz, V; Farre-Alegre, J; Perez-Ruixo, JJ"	"Perez-Ruixo, Carlos; Valenzuela, Belen; Esteban Peris, Jose; Bretcha-Boix, Pedro; Escudero-Ortiz, Vanesa; Farre-Alegre, Jose; Jose Perez-Ruixo, Juan"	"NA"	"A"	"Neutrophil Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"COLONY-STIMULATING FACTOR; BREAST-CANCER PATIENTS; POPULATION PHARMACOKINETICS; MODEL; CHEMOTHERAPY; KINETICS; GRANULOPOIESIS; LEUKOCYTOSIS; TOXICITY; THERAPY"	"Peritoneal carcinomatosis is an abdominal metastatic manifestation of a life-threatening tumour progression requiring standard palliative surgery and/or chemotherapy treatment. The aim of this study was to characterize the immediate neutrophilia response induced by cytoreductive surgery (CRS) and the myelosuppression effect of hyperthermic intraperitoneal oxaliplatin (HIO) in peritoneal carcinomatosis patients. Absolute neutrophil counts (ANCs) from 45 patients treated with CRS and HIO diluted in isotonic 4 % icodextrin (cohort A), 21 patients undergoing CRS followed by HIO diluted in isotonic 5 % dextrose (cohort B) and 18 patients treated with CRS without HIO (cohort C) were used to estimate the system-related parameters [baseline ANC (Circ(0)), mean transit time (MTT) and feedback on proliferation (gamma)] and drug-specific (alpha) parameters of a modified Friberg's model that accounts for the surgical stress-induced neutrophilia. The plasma oxaliplatin concentrations, C (p), were assumed to reduce the proliferation rate of the progenitor cells according to the function alpha x C (p). Model evaluation and simulations were undertaken to evaluate the effect of the dose, treatment duration and carrier solution on the incidence of severe neutropenia. The typical values [between-subject variability, expressed in coefficient of variation values (%)] of the Circ(0), MTT, gamma and alpha were estimated to be 3.58 x 10(9) cells/L (41.2 %), 144 h (70.9 %), 0.155 and 0.066 L/mg (134.9 %), respectively. Surgical stress induced a maximal 3.37-fold increase in the proliferation rate that was attenuated with a half-life of 10 days, and a maximal 68 % reduction in the MTT that was attenuated with a half-life of 28 days. Age, body surface area, sex, total proteins and carrier solution did not impact the model parameters. The model evaluation evidenced an accurate prediction of the incidence of neutropenia grade a parts per thousand yen2 and/or a parts per thousand yen3. Simulations indicated that (i) the neutropenia was reversible and short-lasting; and (ii) the HIO dose and treatment duration were the main determinants of the severity and duration of neutropenia. The time course of neutropenia was well characterized by the model that was developed, which simultaneously accounts for the acute-immediate neutrophilia response induced by CRS and the HIO myelosuppressive effect produced in the bone marrow. This model suggests that higher doses than those evaluated to date could be used in peritoneal carcinomatosis patients without substantially increasing the risk of severe neutropenia."	"[Perez-Ruixo, Carlos; Esteban Peris, Jose] Univ Valencia, Pharm & Pharmaceut Technol Dept, Valencia, Spain; [Valenzuela, Belen; Bretcha-Boix, Pedro; Escudero-Ortiz, Vanesa; Farre-Alegre, Jose] Hosp Quiron Torrevieja, Alicante 03184, Spain; [Jose Perez-Ruixo, Juan] Amgen Inc, Pharmacokinet & Drug Metab, Valencia, Spain"	"Valenzuela, B (corresponding author), Hosp Quiron Torrevieja, Partida Loma S-N, Alicante 03184, Spain."	"belen.valenzuela@quiron.es"	"Ruixo, Juan Jose Perez/AAL-2987-2020; Ruixo, Juan Jose Perez/AAF-3160-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"Conselleria de Sanidad of Comunidad Valenciana [GE-079/11]"	"The authors would like to thank the patients and the medical, nursing and laboratory staff of the Hospital Quiron Torrevieja who participated in the present study. The authors would like to thank Dr. Ricardo Nalda for his valuable help during the simulation exercise. This work was supported by Conselleria de Sanidad of Comunidad Valenciana (grant GE-079/11). The authors also like to thank the peer reviewers of this manuscript for their valuable comments, which helped to improve the quality of the work and Dr. Ricardo Nalda-Molina for his comments and support at the beginning of this project."	59	10	10	0	4	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"DEC"	2013	52	12	1111	1125	"NA"	"10.1007/s40262-013-0092-3"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"257RK"	"WOS:000327403400006"	23828617	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Pastor, ML; Laffont, CM; Gladieff, L; Schmitt, A; Chatelut, E; Concordet, D"	"Pastor, Melanie L.; Laffont, Celine M.; Gladieff, Laurence; Schmitt, Antonin; Chatelut, Etienne; Concordet, Didier"	"NA"	"A"	"Model-Based Approach to Describe G-CSF Effects in Carboplatin-Treated Cancer Patients"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"chemotherapy; G-CSF; myelotoxicity; neutropenia; pharmacokinetic/pharmacodynamic (PK/PD) modeling"	"COLONY-STIMULATING FACTOR; INDUCED FEBRILE NEUTROPENIA; HUMAN GRANULOPOIESIS; PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS; HEMATOLOGICAL TOXICITY; EORTC GUIDELINES; ADULT PATIENTS; SOLID TUMORS; RHG-CSF; CHEMOTHERAPY"	"Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects. The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation. Our model well described the data in all patients. Model simulations showed that G-CSF was not as beneficial as expected in some patients. Furthermore, a longer and stronger effect was observed for the pegylated formulation in comparison with the daily standard formulation even if the latter was given for 11 consecutive days. The proposed model allows a mechanistic interpretation of G-CSF effects on ANC and raises the question of a systematic beneficial effect of G-CSF treatment. Other studies are needed to confirm these findings and help identifying patients for whom G-CSF is beneficial."	"[Pastor, Melanie L.] Univ Toulouse, Ecole Natl Vet Toulouse, Unite Med, INP, F-31076 Toulouse, France; [Pastor, Melanie L.; Laffont, Celine M.; Concordet, Didier] Toxalim, INRA ENVT, UMR1331, F-31027 Toulouse, France; [Gladieff, Laurence; Chatelut, Etienne] Univ Toulouse, Inst Claudius Regaud, EA4553, F-31052 Toulouse, France; [Schmitt, Antonin] Univ Bourgogne, UFR Sci Pharmaceut & Biol, F-21079 Dijon, France"	"Pastor, ML (corresponding author), Univ Toulouse, Ecole Natl Vet Toulouse, Unite Med, INP, F-31076 Toulouse, France."	"m.pastor@envt.fr"	"GLADIEFF, Laurence/O-5129-2014; , Chatelut/I-7916-2014; Concordet, Didier/AAT-1120-2020; Schmitt, Antonin/AAG-9397-2020"	"GLADIEFF, Laurence/0000-0002-6980-9719; , Chatelut/0000-0002-7740-9096; Concordet, Didier/0000-0003-3916-577X; Schmitt, Antonin/0000-0002-3132-7730"	"NA"	"NA"	46	11	11	0	5	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"NOV"	2013	30	11	2795	2807	"NA"	"10.1007/s11095-013-1099-z"	13	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"236EH"	"WOS:000325776700007"	23801085	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Fouliard, S; Robert, R; Jacquet-Bescond, A; du Rieu, QC; Balasubramanian, S; Loury, D; Loriot, Y; Hollebecque, A; Kloos, I; Soria, JC; Chenel, M; Depil, S"	"Fouliard, Sylvain; Robert, Renata; Jacquet-Bescond, Anne; du Rieu, Quentin Chalret; Balasubramanian, Sriram; Loury, David; Loriot, Yohann; Hollebecque, Antoine; Kloos, Ioana; Soria, Jean-Charles; Chenel, Marylore; Depil, Stephane"	"NA"	"A"	"Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I"	"EUROPEAN JOURNAL OF CANCER"	"English"	"Article"	"Decision support techniques; Drug administration schedule Drug toxicity; Pharmacokinetics; Pharmacodynamics; Mechanism of action"	"TIME-COURSE; CANCER-CELLS; MECHANISMS; AGENTS; DRUGS"	"Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC-402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m(2) BID (twice daily) and the recommended dose at 60 mg/m(2) BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia. The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m(2) BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m(2) BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m(2) BID and the recommended dose 90 mg/m(2) BID. In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat. (C) 2013 Elsevier Ltd. All rights reserved."	"[Fouliard, Sylvain; du Rieu, Quentin Chalret; Chenel, Marylore] Inst Rech Int Servier, F-92284 Suresnes, France; [Robert, Renata; Jacquet-Bescond, Anne; Kloos, Ioana; Depil, Stephane] Inst Rech Int Servier, Oncol R&D Unit, F-92284 Suresnes, France; [Balasubramanian, Sriram; Loury, David] Pharmacyclics, Sunnyvale, CA USA; [Loriot, Yohann; Hollebecque, Antoine; Soria, Jean-Charles] Inst Gustave Roussy, Villejuif, France"	"Chenel, M (corresponding author), Inst Rech Int Servier, 50 Rue Carnot, F-92284 Suresnes, France."	"marylore.chenel@fr.netgrs.com; stephane.depil@fr.netgrs.com"	"Hollebecque, Antoine/M-2695-2013; Loriot, Yohann/W-5572-2019"	"Hollebecque, Antoine/0000-0003-2869-7551;"	"Institut de Recherches International Servier"	"Quentin Chalret du Rieu is a doctoral fellow whose researches are financed by Institut de Recherches International Servier."	22	24	24	0	7	"ELSEVIER SCI LTD"	"OXFORD"	"THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND"	"0959-8049"	"NA"	"NA"	"EUR J CANCER"	"Eur. J. Cancer"	"SEP"	2013	49	13	2791	2797	"NA"	"10.1016/j.ejca.2013.05.009"	7	"Oncology"	"Oncology"	"194JD"	"WOS:000322627300003"	23790467	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"You, B; Colomban, O; Heywood, M; Lee, C; Davy, M; Reed, N; Pignata, S; Varsellona, N; Emons, G; Rehman, K; Steffensen, KD; Reinthaller, A; Pujade-Lauraine, E; Oza, A"	"You, Benoit; Colomban, Olivier; Heywood, Mark; Lee, Chee; Davy, Margaret; Reed, Nicholas; Pignata, Sandro; Varsellona, Nenzi; Emons, Guenter; Rehman, Khalid; Steffensen, Karina Dahl; Reinthaller, Alexander; Pujade-Lauraine, Eric; Oza, Amit"	"NA"	"A"	"The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: Data from CALYPSO trial (a GINECO-GCIG study)"	"GYNECOLOGIC ONCOLOGY"	"English"	"Article"	"CA-125 antigen; Kinetics; Ovarian epithelial cancer; Survival analysis; Computer simulation"	"CA-125 HALF-LIFE; INDUCTION CHEMOTHERAPY; PSA CLEARANCE; FREE SURVIVAL; CA125; DEFINITION; CARCINOMA; DECREASE; DECLINE; NADIR"	"Background. Unexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters. Methods. Data from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum [CA-125] concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: d[CA-125] / dt = (KPROD * exp (BETA * t)) * Effect - KELIM * [CA-125] with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors. Results. Individual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P < 0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR = 0.53; 95% CI 0.45-0.61; P < 0.001). Conclusions. Mathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted. (c) 2013 Elsevier Inc. All rights reserved."	"[You, Benoit; Colomban, Olivier] Univ Lyon, Univ Lyon 1, Fac Med Lyon Sud, EMR UCBL HCL 3738, Lyon, France; [You, Benoit; Colomban, Olivier] Hosp Civils Lyon, Ctr Hosp Lyon Sud, Lyon, France; [Lee, Chee] Univ Sydney, NHMRC Clin Trials Ctr, Camperdown, NSW, Australia; [Davy, Margaret] Royal Adelaide Hosp, Surg & Specialties Serv, Adelaide, SA 5000, Australia; [Reed, Nicholas] Gartnavel Royal Hosp, Beatson Oncol Ctr, Glasgow, Lanark, Scotland; [Pignata, Sandro] Natl Canc Inst, Div Med Oncol B, Naples, Italy; [Varsellona, Nenzi] AOR Villa Sofia Cervello, Dept Gynecol & Obstet, Palermo, Italy; [Emons, Guenter] Univ Gottingen, Univ Frauenklin, Dept Obstet & Gynecol, D-37073 Gottingen, Germany; [Rehman, Khalid; Pujade-Lauraine, Eric] Univ Paris 05, Hop Univ Paris Ctr, AP HP, Dept Oncol, Paris, France; [Steffensen, Karina Dahl] Vejle Hosp, Dept Clin Oncol, Vejle, Denmark; [Reinthaller, Alexander] Gen Hosp Vienna, Med Univ Vienna, Dept Gynecol & Gynecol Oncol, Vienna, Austria; [Oza, Amit] Princess Margaret Hosp, Dept Med Oncol, Toronto, ON M4X 1K9, Canada"	"You, B (corresponding author), Ctr Hosp Lyon Sud, EMR UCBL HCL 3738, Med Oncol Serv, Chemin Grand Revoyet, F-69495 Pierre Benite, France."	"benoit.you@chu-lyon.fr"	"You, Benoit/M-4558-2014"	"Oza, Amit/0000-0002-9510-8641; Dahl Steffensen, Karina/0000-0002-9217-3907; pignata, sandro/0000-0002-8836-2633; Lee, Chee Khoon/0000-0003-2955-9820; COLOMBAN, OLIVIER/0000-0003-1671-3470"	"NA"	"NA"	40	6	6	0	4	"ACADEMIC PRESS INC ELSEVIER SCIENCE"	"SAN DIEGO"	"525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA"	"0090-8258"	"1095-6859"	"NA"	"GYNECOL ONCOL"	"Gynecol. Oncol."	"AUG"	2013	130	2	289	294	"NA"	"10.1016/j.ygyno.2013.05.013"	6	"Oncology; Obstetrics & Gynecology"	"Oncology; Obstetrics & Gynecology"	"191KD"	"WOS:000322410900008"	23694718	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"You, B; Harvey, R; Henin, E; Mitchell, H; Golfier, F; Savage, PM; Tod, M; Wilbaux, M; Freyer, G; Seckl, MJ"	"You, B.; Harvey, R.; Henin, E.; Mitchell, H.; Golfier, F.; Savage, P. M.; Tod, M.; Wilbaux, M.; Freyer, G.; Seckl, M. J."	"NA"	"A"	"Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements"	"BRITISH JOURNAL OF CANCER"	"English"	"Article"	"gestational trophoblastic neoplasia; methotrexate; drug resistance; neoplasm; prognosis; decision support techniques; chorionic gonadotropin"	"SINGLE-AGENT METHOTREXATE; HANDLING DATA; QUANTIFICATION; TUMORS; CHEMOTHERAPY; MANAGEMENT; OUTCOMES; DISEASE; LIMIT"	"Background: In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort. Methods: Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: '(hCG(time)) = hCG0*exp(-k*time)  hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance. Results: Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l(-1): receiver-operating characteristic (ROC) area under the curve (AUC) = 0.87; Se = 0.91; Sp = 0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC = 0.87; Se = 0.88; Sp = 0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR = 1.01, P < 0.0001) and MTX failure-free survival (HR = 13.25, P < 0.0001) than other reported predictive factors. Conclusion: hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance."	"[You, B.; Henin, E.; Tod, M.; Wilbaux, M.; Freyer, G.] Univ Claude Bernard Lyon 1, Hosp Civils Lyon, EMR UBCL HCL 3738, Lyon, France; [You, B.; Golfier, F.] Hosp Civils Lyon, Ctr Reference Malad Trophoblast, Lyon, France; [Harvey, R.; Mitchell, H.; Savage, P. M.; Seckl, M. J.] Charing Cross Hosp Trophoblast Dis Ctr, London, England"	"You, B (corresponding author), Univ Claude Bernard Lyon 1, Hosp Civils Lyon, EMR UBCL HCL 3738, Lyon, France."	"benoit.you@chu-lyon.fr"	"You, Benoit/M-4558-2014; HENIN, Emilie/B-7576-2014; Gilly, Francois Noel FN/C-9450-2014"	"Gilly, Francois Noel FN/0000-0003-3808-6244; Savage, Philip/0000-0002-4792-6869; HENIN, Emilie/0000-0001-7478-2154"	"Imperial Experimental Cancer Medicine Centre; Biomedical Research Centre; Cancer Research UKCancer Research UK; UK Department of Health and National Institute for Health Research"	"MJS and RH are supported by the Imperial Experimental Cancer Medicine Centre and by the Biomedical Research Centre grants from Cancer Research UK, the UK Department of Health and National Institute for Health Research."	29	23	26	0	7	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"0007-0920"	"1532-1827"	"NA"	"BRIT J CANCER"	"Br. J. Cancer"	"MAY 14"	2013	108	9	1810	1816	"NA"	"10.1038/bjc.2013.123"	7	"Oncology"	"Oncology"	"146WI"	"WOS:000319125300008"	23591194	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Duong, JK; Kumar, SS; Kirkpatrick, CM; Greenup, LC; Arora, M; Lee, TC; Timmins, P; Graham, GG; Furlong, TJ; Greenfield, JR; Williams, KM; Day, RO"	"Duong, Janna K.; Kumar, Shaun S.; Kirkpatrick, Carl M.; Greenup, Louise C.; Arora, Manit; Lee, Toong C.; Timmins, Peter; Graham, Garry G.; Furlong, Timothy J.; Greenfield, Jerry R.; Williams, Kenneth M.; Day, Richard O."	"NA"	"A"	"Population Pharmacokinetics of Metformin in Healthy Subjects and Patients with Type 2 Diabetes Mellitus: Simulation of Doses According to Renal Function"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"CATION TRANSPORTERS OCT1; LACTIC-ACIDOSIS; EXPRESSION; CLEARANCE"	"Background and Objective Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. Methods Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM (R) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. Results Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. Conclusion The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment."	"[Duong, Janna K.; Kumar, Shaun S.; Arora, Manit; Graham, Garry G.; Williams, Kenneth M.; Day, Richard O.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia; [Duong, Janna K.; Kumar, Shaun S.; Greenup, Louise C.; Graham, Garry G.; Williams, Kenneth M.; Day, Richard O.] St Vincents Hosp, Dept Clin Pharmacol & Toxicol, Sydney, NSW 2010, Australia; [Kirkpatrick, Carl M.] Monash Univ, Ctr Med Use & Safety, Melbourne, Vic 3004, Australia; [Lee, Toong C.] Univ Sains Malaysia, George Town, Malaysia; [Timmins, Peter] Bristol Myers Squibb, Drug Product Sciefnce & Technol, Moreton, Merseyside, England; [Furlong, Timothy J.] St Vincents Hosp, Dept Nephrol, Sydney, NSW 2010, Australia; [Greenfield, Jerry R.] St Vincents Hosp, Dept Endocrinol, Sydney, NSW 2010, Australia; [Greenfield, Jerry R.] Garvan Inst Med Res, Diabet & Obes Res Program, Sydney, NSW, Australia"	"Day, RO (corresponding author), St Vincents Hosp, Dept Clin Pharmacol & Toxicol, Level 2 Xavier Bldg,390 Victoria St, Sydney, NSW 2010, Australia."	"r.day@unsw.edu.au"	"Kirkpatrick, Carl MJ/F-1222-2010; Day, Richard/D-8699-2011; Kumar, Shaun/P-4680-2017; Duong, Janna K/H-9795-2019; Arora, Manit/I-2235-2016"	"Day, Richard/0000-0002-6045-6937; Kumar, Shaun/0000-0001-8514-1707; Duong, Janna K/0000-0003-2347-7277; Kirkpatrick, Carl/0000-0002-5715-1534; Arora, Manit/0000-0001-9939-3198"	"NH&MRC Programme GrantNational Health and Medical Research Council of Australia [568612]; Australian Research Council GrantAustralian Research Council [LP 0990670]; St Vincent's Clinic Foundation Sister Mary Bernice Research Grant"	"The authors would like to thank Prof. Kathleen Giacomini for advice on the selection of SNPs in metformin transporters and Dr. Pavel Bitter for the analyses of SNPs. Funding for this study was provided by the NH&MRC Programme Grant 568612, Australian Research Council Grant LP 0990670, and St Vincent's Clinic Foundation Sister Mary Bernice Research Grant."	40	68	70	2	17	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAY"	2013	52	5	373	384	"NA"	"10.1007/s40262-013-0046-9"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"138RI"	"WOS:000318525700005"	23475568	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Perez-Ruixo, C; Valenzuela, B; Peris, JE; Bretcha-Boix, P; Escudero-Ortiz, V; Farre-Alegre, J; Perez-Ruixo, JJ"	"Perez-Ruixo, Carlos; Valenzuela, Belen; Esteban Peris, Jose; Bretcha-Boix, Pedro; Escudero-Ortiz, Vanesa; Farre-Alegre, Jose; Jose Perez-Ruixo, Juan"	"NA"	"A"	"Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery"	"CANCER CHEMOTHERAPY AND PHARMACOLOGY"	"English"	"Article"	"Hyperthermic intraperitoneal chemotherapy (HIPEC); Oxaliplatin; Peritoneal carcinomatosis; Population pharmacokinetics"	"METASTATIC COLORECTAL-CANCER; COMPLETE RESECTION; CARRIER SOLUTIONS; RANDOMIZED-TRIAL; CHEMOTHERAPY; MALIGNANCIES; DRUGS; HIPEC"	"To characterize the hyperthermic intraperitoneal oxaliplatin (HIO) pharmacokinetics in peritoneum and plasma in patients with peritoneal carcinomatosis (PC) after cytoreductive surgery (CRS). Data from 36 patients receiving HIO diluted in isotonic 4 % icodextrin were combined with data from 13 patients receiving HIO diluted in isotonic 5 % dextrose. Total oxaliplatin in peritoneal and plasma fluids were used to characterize an open two-compartment disposition model with linear distribution and elimination and first-order absorption from peritoneum to plasma using NONMEM software. The effect of patient- and treatment-related covariates on oxaliplatin pharmacokinetic parameters was explored. The typical value (interindividual variability, %) in k (a) , CL, and V (ss) were 0.57 h(-1) (43 %), 1.71 L h(-1) (39 %), and 77 L (65 %), respectively. No significant effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic parameters was found. A 12-15 % reduction in peritoneal volume of distribution was observed in patients receiving HIO diluted in 5 % dextrose relative to those patients receiving HIO diluted in 4 % icodextrin. The integration of peritoneal and plasma data demonstrated oxaliplatin linear absorption from peritoneum to plasma, non-specific distribution to a peripheral compartment, and linear elimination from the central compartment when HIO was administered with isotonic carrier solutions to PC patients who underwent CRS. Only the effect of the carrier solution had an impact in the peritoneal volume of distribution, but its clinical relevance seems to be limited, especially for short HIO infusions (< 60 min)."	"[Perez-Ruixo, Carlos; Esteban Peris, Jose] Univ Valencia, Pharm & Pharmaceut Technol Dept, Valencia, Spain; [Valenzuela, Belen; Bretcha-Boix, Pedro; Escudero-Ortiz, Vanesa; Farre-Alegre, Jose] Hosp San Jaime, Alicante 03184, Spain; [Jose Perez-Ruixo, Juan] Amgen Inc, Valencia, Spain"	"Valenzuela, B (corresponding author), Hosp San Jaime, Partida Loma S-N, Alicante 03184, Spain."	"belen.valenzuela@quiron.es"	"Ruixo, Juan Jose Perez/AAL-2987-2020; Ruixo, Juan Jose Perez/AAF-3160-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"Conselleria de Sanidad of Comunidad Valenciana, Spain [GE-079/11]"	"The authors would like to thank the patients, medical, nursing, and laboratory staff of the Hospital San Jaime who participated in the present study. This work was supported by Conselleria de Sanidad of Comunidad Valenciana, Spain. Grant GE-079/11."	39	11	12	0	13	"SPRINGER"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0344-5704"	"1432-0843"	"NA"	"CANCER CHEMOTH PHARM"	"Cancer Chemother. Pharmacol."	"MAR"	2013	71	3	693	704	"NA"	"10.1007/s00280-012-2060-2"	12	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"096OH"	"WOS:000315413500016"	23274396	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, CG; Sadhavisvam, S; Krekels, EHJ; Dahan, A; Tibboel, D; Danhof, M; Vinks, AA; Knibbe, CAJ"	"Wang, Chenguang; Sadhavisvam, Senthilkumar; Krekels, Elke H. J.; Dahan, Albert; Tibboel, Dick; Danhof, Meindert; Vinks, Alexander A.; Knibbe, Catherijne A. J."	"NA"	"A"	"Developmental Changes in Morphine Clearance Across the Entire Paediatric Age Range are Best Described by a Bodyweight-Dependent Exponent Model"	"CLINICAL DRUG INVESTIGATION"	"English"	"Article"	"NA"	"DRUG CLEARANCE; MAJOR SURGERY; BODY-WEIGHT; INFANTS; PHARMACOKINETICS; CHILDREN; PRETERM; GLUCURONIDATION; POPULATION; PREDICTION"	"Background and Objective Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential (BDE) function and age younger or older than 10 days. The aim of the current study was to characterize the developmental changes in morphine clearance across the entire paediatric age range. Methods Morphine and morphine-3-glucuronide (M3G) concentration data from 358 (pre)term neonates, infants, children and adults, and morphine concentration data from 117 adolescents were analysed using NONMEM 7.2. Based on available data, two models were developed: I. using morphine data; II. using morphine and M3G data. Results In model I, morphine clearance across the paediatric age range was very well described by a BDE function in which the allometric exponent decreased in a sigmoidal manner with bodyweight (BDE model) from 1.47 to 0.88, with half the decrease in exponent reached at 4.01 kg. In model II, the exponent for the formation and elimination clearance of M3G was found to decrease from 1.56 to 0.89 and from 1.06 to 0.61, with half the decrease reached at 3.89 and 4.87 kg, respectively. Using the BDE model, there was no need to use additional measures for size or age. Conclusion The BDE model was able to scale both total morphine clearance and glucuronidation clearance through the M3G pathway across all age ranges between (pre)term neonates and adults by allowing the allometric exponent to decrease across the paediatric age range from values higher than 1 for neonates to values lower than 1 for infants and children."	"[Wang, Chenguang; Krekels, Elke H. J.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, Div Pharmacol, LACDR, Leiden, Netherlands; [Wang, Chenguang; Krekels, Elke H. J.; Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Hosp, Dept Intens Care & Paediat Surg, Rotterdam, Netherlands; [Sadhavisvam, Senthilkumar] Cincinnati Childrens Hosp Med Ctr, Dept Anesthesia, Cincinnati, OH USA; [Sadhavisvam, Senthilkumar; Vinks, Alexander A.] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA; [Dahan, Albert] Leiden Univ, Med Ctr, Dept Anesthesiol, NL-2300 RC Leiden, Netherlands; [Vinks, Alexander A.] Cincinnati Childrens Hosp Med Ctr, Dept Clin Pharmacol, Cincinnati, OH 45229 USA; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"NA"	"Vinks, Alexander/0000-0003-4224-2967; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Top Institute Pharma project [D2-104]; Innovational Research Incentives Scheme (Veni grant) of the Dutch Organization for Scientific Research (NWO); USPHS from the National Center for Research Resources, NIH [UL1 RR026314]; Place Outcomes Research Award; Translational Research Award; Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA"	"This study was performed within the framework of Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organization for Scientific Research (NWO). The clinical study on morphine pharmacokinetics in older children and adolescents was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources, NIH and with the Place Outcomes Research Award and Translational Research Award (PI: Sadhasivam) and was supported by the Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. The authors would like to thank Dr Richard van Lingen, Dr Caroline van der Marel, Professor Imti Choonara and Professor Anne Lynn for their willingness to share their morphine and morphine-3-glucuronide data in children in this project."	30	37	38	0	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"1173-2563"	"1179-1918"	"NA"	"CLIN DRUG INVEST"	"Clin. Drug Invest."	"NA"	2013	33	7	523	534	"NA"	"10.1007/s40261-013-0097-6"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"170VO"	"WOS:000320882900008"	23754691	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Dumont, C; Mentre, F; Gaynor, C; Brendel, K; Gesson, C; Chenel, M"	"Dumont, Cyrielle; Mentre, France; Gaynor, Clare; Brendel, Karl; Gesson, Charlotte; Chenel, Marylore"	"NA"	"M"	"Optimal Sampling Times for a Drug and its Metabolite using SIMCYP (R) Simulations as Prior Information"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"MIXED-EFFECTS MODELS; OPTIMAL-DESIGN; POPULATION PHARMACOKINETICS; SIZE CALCULATIONS; CHILDREN; OPTIMIZATION; PREDICTION; MATRIX; ALGORITHM; INFANTS"	"Background Since 2007, it is mandatory for the pharmaceutical companies to submit a Paediatric Investigation Plan to the Paediatric Committee at the European Medicines Agency for any drug in development in adults, and it often leads to the need to conduct a pharmacokinetic study in children. Pharmacokinetic studies in children raise ethical and methodological issues. Because of limitation of sampling times, appropriate methods, such as the population approach, are necessary for analysis of the pharmacokinetic data. The choice of the pharmacokinetic sampling design has an important impact on the precision of population parameter estimates. Approaches for design evaluation and optimization based on the evaluation of the Fisher information matrix (MF) have been proposed and are now implemented in several software packages, such as PFIM in R. Objectives The objectives of this work were to (1) develop a joint population pharmacokinetic model to describe the pharmacokinetic characteristics of a drug S and its active metabolite in children after intravenous drug administration from simulated plasma concentration-time data produced using physiologically based pharmacokinetic (PBPK) predictions; (2) optimize the pharmacokinetic sampling times for an upcoming clinical study using a multi-response design approach, considering clinical constraints; and (3) evaluate the resulting design taking data below the lower limit of quantification (BLQ) into account. Methods Plasma concentration-time profiles were simulated in children using a PBPK model previously developed with the software SIMCYP (R) for the parent drug and its active metabolite. Data were analysed using non-linear mixed-effect models with the software NONMEM (R), using a joint model for the parent drug and its metabolite. The population pharmacokinetic design, for the future study in 82 children from 2 to 18 years old, each receiving a single dose of the drug, was then optimized using PFIM, assuming identical times for parent and metabolite concentration measurements and considering clinical constraints. Design evaluation was based on the relative standard errors (RSEs) of the parameters of interest. In the final evaluation of the proposed design, an approach was used to assess the possible effect of BLQ concentrations on the design efficiency. This approach consists of rescaling the MF, using, at each sampling time, the probability of observing a concentration BLQ computed from Monte-Carlo simulations. Results A joint pharmacokinetic model with three compartments for the parent drug and one for its active metabolite, with random effects on four parameters, was used to fit the simulated PBPK concentration-time data. A combined error model best described the residual variability. Parameters and dose were expressed per kilogram of bodyweight. Reaching a compromise between PFIM results and clinical constraints, the optimal design was composed of four samples at 0.1, 1.8, 5 and 10 h after drug injection. This design predicted RSE lower than 30 % for the four parameters of interest. For this design, rescaling MF for BLQ data had very little influence on predicted RSE. Conclusion PFIM was a useful tool to find an optimal sampling design in children, considering clinical constraints. Even if it was not forecasted initially by the investigators, this approach showed that it was really necessary to include a late sampling time for all children. Moreover, we described an approach to evaluate designs assuming expected proportions of BLQ data are omitted."	"[Dumont, Cyrielle; Gaynor, Clare; Brendel, Karl; Gesson, Charlotte; Chenel, Marylore] Inst Rech Int Servier, Div Clin Pharmacokinet, Suresnes, France; [Dumont, Cyrielle; Mentre, France] Univ Paris Diderot, UMR 738, Sorbonne Paris Cite, F-75018 Paris, France; [Dumont, Cyrielle; Mentre, France] INSERM, UMR 738, F-75018 Paris, France"	"Dumont, C (corresponding author), Univ Paris Diderot, UMR 738, Sorbonne Paris Cite, 16 Rue Henri Huchard, F-75018 Paris, France."	"cyrielle.dumont@inserm.fr"	"NA"	"NA"	"NA"	"NA"	46	18	18	0	9	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JAN"	2013	52	1	43	57	"NA"	"10.1007/s40262-012-0022-9"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"138QA"	"WOS:000318522200005"	23212609	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Sostelly, A; Henin, E; Chauvenet, L; Hardy-Bessard, AC; Jestin-Le Tallec, V; Kirsher, S; Leyronnas, C; Ligeza-Poisson, C; Ramdane, S; Salavt, J; Van-Hult, S; Vannetzel, JM; Freyer, G; Tod, M; Falandry, C"	"Sostelly, Alexandre; Henin, Emilie; Chauvenet, Laure; Hardy-Bessard, Anne-Claire; Jestin-Le Tallec, Veronique; Kirsher, Sylvie; Leyronnas, Cecile; Ligeza-Poisson, Catherine; Ramdane, Soraya; Salavt, Jacques; Van-Hult, Sylvie; Vannetzel, Jean-Michel; Freyer, Gilles; Tod, Michel; Falandry, Claire"	"NA"	"A"	"Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO"	"JOURNAL OF GERIATRIC ONCOLOGY"	"English"	"Article"	"Modeling; Pharmacodynamics; Age-related toxicity"	"METASTATIC BREAST-CANCER; COMPREHENSIVE GERIATRIC ASSESSMENT; ANTICANCER DRUGS; ADJUVANT CHEMOTHERAPY; INTERNATIONAL-SOCIETY; OLDER PATIENTS; GROWTH-FACTORS; RECOMMENDATIONS; TOXICITY; CYCLOPHOSPHAMIDE"	"Introduction: Use of anthracyclines is often limited in older patients due to cardiac and hematologic toxicities. Thanks to its reduced toxicity profile, Pegylated Liposomal Doxorubicin (PLD) allows an extended use of doxorubicin to this population. We aimed at modeling PLD-induced hematotoxicity in patients with metastatic breast cancer >= 70 years old and at finding predictive factors of neutrophil nadir value. Methods: Sixty patients, enrolled in the DOGMES prospective multicentric phase II trial, were treated with PLD at 40 mg/m(2) every 28 days during six cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of cells count every week for three cycles. A population model was developed to describe hematopoiesis and hematopoietic reserve in these patients. The effect of co-administered G-CSF (granulocyte colony-stimulating factor) was also examined. Results: A pharmacodynamic model was built using data from 53 patients not receiving G-CSF. This model assumed an instantaneous effect of PLD on the system. Based on this model, exact neutrophil nadir value was computed and ranged between 0.069 K/mm(3) and 2.63 K/mm(3) confirming the weak hematotoxicity of PLD. The same model was then applied to the 7 patients receiving G-CSF and showed that basal neutrophil count was higher for these patients. No other difference was found between both cohorts. Among the covaiiates collected, three were predictive of neutrophil nadir value: diabetes, frailty syndrome and assistance at home. Conclusion: This developed model allowed the identification of predictive factors of nadir ANC and the identification of patients that are more likely to develop hematotoxicity that should be monitored with attention. (C) 2012 Elsevier Ltd. All rights reserved."	"[Sostelly, Alexandre; Henin, Emilie; Freyer, Gilles; Tod, Michel] Univ Lyon 1, Fac Med & Maieut Lyon Sud, EMR3738, F-69921 Oullins, France; [Chauvenet, Laure] Hop Hotel Dieu, F-75004 Paris, France; [Hardy-Bessard, Anne-Claire] Clin Armoricaine Radiol, F-22015 St Brieuc, France; [Jestin-Le Tallec, Veronique] Hop Morvan CHU, F-29200 Brest, France; [Kirsher, Sylvie] Inst St Catherine, F-84082 Avignon, France; [Leyronnas, Cecile] Grp Hosp Mutualiste Grenoble, F-38028 Grenoble, France; [Ligeza-Poisson, Catherine] Ctr Etienne DOLET, F-44600 St Nazaire, France; [Ramdane, Soraya] Hop Beauvais, F-60000 Beauvais, France; [Salavt, Jacques] Ctr Hosp THONON LES BAINS, F-74203 Thonon Les Bains, France; [Van-Hult, Sylvie] CHU CAREMEAU, F-30029 Nimes, France; [Vannetzel, Jean-Michel] Inst Oncol HARTMANN, F-92300 Levallois Perret, France; [Falandry, Claire] Ctr Hosp Lyon Sud, Dept Med Oncol, F-69495 Pierre Benite, France; [Tod, Michel] Hop Croix Rousse, F-69004 Lyon, France"	"Sostelly, A (corresponding author), Fac Med Lyon Sud, EMR 3738, BP12, F-69921 Oullins, France."	"alexandre.sostelly@gmail.com"	"HENIN, Emilie/B-7576-2014; FALANDRY, Claire/H-6055-2012"	"FALANDRY, Claire/0000-0001-7267-4723; HENIN, Emilie/0000-0001-7478-2154"	"NA"	"NA"	41	8	8	0	8	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"1879-4068"	"1879-4076"	"NA"	"J GERIATR ONCOL"	"J. Geriatr. Oncol."	"JAN"	2013	4	1	48	57	"NA"	"10.1016/j.jgo.2012.06.004"	10	"Oncology; Geriatrics & Gerontology"	"Oncology; Geriatrics & Gerontology"	"082FB"	"WOS:000314376600007"	24071492	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Bulitta, JB; Okusanya, OO; Forrest, A; Bhavnani, SM; Clark, K; Still, JG; Fernandes, P; Ambrose, PG"	"Bulitta, Juergen B.; Okusanya, Olanrewaju O.; Forrest, Alan; Bhavnani, Sujata M.; Clark, Kay; Still, J. Gordon; Fernandes, Prabhavathi; Ambrose, Paul G."	"NA"	"A"	"Population Pharmacokinetics of Fusidic Acid: Rationale for Front-Loaded Dosing Regimens Due to Autoinhibition of Clearance"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"HEALTHY-SUBJECTS; SODIUM FUSIDATE; METABOLISM; MODEL; SINGLE; PHARMACODYNAMICS; ARTEMISININ; VOLUNTEERS; SAFETY"	"The objectives of this analysis were to develop a population pharmacokinetic (PK) model to describe the absorption and disposition of fusidic acid after single and multiple doses and to determine the effect of food on the rate and extent of bioavailability. Plasma PK data from three phase 1 studies (n = 75; n = 14 with and without food) in which healthy subjects received sodium fusidate (500 to 2,200 mg) as single or multiple oral doses every 8 h (q8h) or q12h for up to 7 days were modeled using S-ADAPT (MCPEM algorithm). Accumulation of fusidic acid after multiple doses was more than that predicted based on single-dose data. The PK of fusidic acid was best described using a time-dependent mixed-order absorption process, two disposition compartments, and a turnover process to describe the autoinhibition of clearance. The mean total clearance (% coefficient of variation) was 1.28 liters/h (33%) and the maximum extent of autoinhibition was 71.0%, with a 50% inhibitory concentration (IC50) of 46.3 mg/liter (36%). Food decreased the extent of bioavailability by 18%. As a result of the autoinhibition of clearance, steady state can be achieved earlier with dosing regimens that contain higher doses (after 8 days for 750 mg q12h and 1 day for 1,500 mg q12h on day 1 followed by 600 mg q12h versus 3 weeks for 500 mg q12h). Given that large initial doses autoinhibit the clearance of fusidic acid, this characteristic provides a basis for the administration of front-loaded dosing regimens of sodium fusidate which would allow for effective concentrations to be achieved early in therapy."	"[Bulitta, Juergen B.] Monash Univ, Ctr Med Use & Safety, Parkville, Vic, Australia; [Okusanya, Olanrewaju O.; Forrest, Alan; Bhavnani, Sujata M.; Ambrose, Paul G.] Inst Clin Pharmacodynam, Latham, NY USA; [Bulitta, Juergen B.; Okusanya, Olanrewaju O.; Forrest, Alan; Bhavnani, Sujata M.; Ambrose, Paul G.] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Buffalo, NY 14260 USA; [Clark, Kay; Still, J. Gordon; Fernandes, Prabhavathi] Cempra Inc, Chapel Hill, NC USA; [Ambrose, Paul G.] Univ Oxford, Oxford, England"	"Bulitta, JB (corresponding author), Monash Univ, Ctr Med Use & Safety, Parkville Campus, Parkville, Vic, Australia."	"Jurgen.Bulitta@monash.edu"	"Bulitta, Jurgen B/P-3355-2018"	"Bulitta, Jurgen B/0000-0001-7352-3097"	"Cempra, Inc."	"This analysis was supported by Cempra, Inc. J.B.B. is an Australian Research Council DECRA fellow (DE120103084)."	32	28	28	0	7	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"NA"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JAN"	2013	57	1	498	507	"NA"	"10.1128/AAC.01354-12"	10	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"062XS"	"WOS:000312958400064"	23147726	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Perez-Ruixo, JJ; Green, B; Doshi, S; Wang, YM; Mould, DR"	"Perez-Ruixo, J. J.; Green, B.; Doshi, S.; Wang, Y. -M.; Mould, D. R."	"NA"	"A"	"Romiplostim Dose Response in Patients With Immune Thrombocytopenia"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Immune thrombocytopenia; platelets; population pharmacodynamics; romiplostim"	"MEGAKARYOCYTE GROWTH; HUMAN THROMBOPOIETIN; MPL LIGAND; IN-VITRO; MODEL; PHARMACOKINETICS; PHARMACODYNAMICS; CHEMOTHERAPY; ANTIBODIES; RECEPTOR"	"A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2-10 mu g/kg). The model consisted of a drug-sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 x 10(9)/L, 170 hours, and 0.6 day(-1), respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351%/100 mu g/wk and 12%/100 mu g/wk in 68% and 32% of patients, respectively. Visual and numerical predictive checks suggested accurate prediction of platelet time course and durable response rate in ITP patients. Model-based simulations confirmed the effectiveness of dose reduction to prevent platelet counts >400 x 10(9)/L."	"[Perez-Ruixo, J. J.] Amgen SA, Barcelona, Spain; [Green, B.; Mould, D. R.] Project Res Inc, Phoenixville, PA USA; [Doshi, S.; Wang, Y. -M.] Amgen Inc, Thousand Oaks, CA 91320 USA"	"Perez-Ruixo, JJ (corresponding author), Dept Pharmacokinet & Drug Metab, 3 Puzol, Valencia 46530, Spain."	"juanjose@amgen.com"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"Amgen Inc.Amgen"	"This study was funded by Amgen Inc. J. J. Perez-Ruixo, S. Doshi, and Y.-M. Wang are employees at Amgen Inc, who supported this study. B. Green and D. Mould were consultants for Amgen Inc and received consultation fees for this project."	36	5	5	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"OCT"	2012	52	10	1540	1551	"NA"	"10.1177/0091270011420843"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"005PV"	"WOS:000308763200009"	22167563	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Ribba, B; Kaloshi, G; Peyre, M; Ricard, D; Calvez, V; Tod, M; Cajavec-Bernard, B; Idbaih, A; Psimaras, D; Dainese, L; Pallud, J; Cartalat-Carel, S; Delattre, JY; Honnorat, J; Grenier, E; Ducray, F"	"Ribba, Benjamin; Kaloshi, Gentian; Peyre, Mathieu; Ricard, Damien; Calvez, Vincent; Tod, Michel; Cajavec-Bernard, Branka; Idbaih, Ahmed; Psimaras, Dimitri; Dainese, Linda; Pallud, Johan; Cartalat-Carel, Stephanie; Delattre, Jean-Yves; Honnorat, Jerome; Grenier, Emmanuel; Ducray, Francois"	"NA"	"A"	"A Tumor Growth Inhibition Model for Low-Grade Glioma Treated with Chemotherapy or Radiotherapy"	"CLINICAL CANCER RESEARCH"	"English"	"Article"	"NA"	"LUNG-CANCER PATIENTS; BRAIN-TUMORS; PROLIFERATION; OLIGODENDROGLIOMAS; MANAGEMENT; INVASION"	"Purpose: To develop a tumor growth inhibition model for adult diffuse low-grade gliomas (LGG) able to describe tumor size evolution in patients treated with chemotherapy or radiotherapy. Experimental Design: Using longitudinal mean tumor diameter (MTD) data from 21 patients treated with first-line procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) chemotherapy, we formulated a model consisting of a system of differential equations, incorporating tumor-specific and treatment-related parameters that reflect the response of proliferative and quiescent tumor tissue to treatment. The model was then applied to the analysis of longitudinal tumor size data in 24 patients treated with first-line temozolomide (TMZ) chemotherapy and in 25 patients treated with first-line radiotherapy. Results: The model successfully described the MTD dynamics of LGG before, during, and after PCV chemotherapy. Using the same model structure, we were also able to successfully describe the MTD dynamics in LGG patients treated with TMZ chemotherapy or radiotherapy. Tumor-specific parameters were found to be consistent across the three treatment modalities. The model is robust to sensitivity analysis, and preliminary results suggest that it can predict treatment response on the basis of pretreatment tumor size data. Conclusions: Using MTD data, we propose a tumor growth inhibition model able to describe LGG tumor size evolution in patients treated with chemotherapy or radiotherapy. In the future, this model might be used to predict treatment efficacy in LGG patients and could constitute a rational tool to conceive more effective chemotherapy schedules. Clin Cancer Res; 18(18); 5071-80. (c) 2012 AACR."	"[Ribba, Benjamin; Calvez, Vincent; Cajavec-Bernard, Branka; Grenier, Emmanuel] Ecole Normale Super Lyon, INRIA, Project Team NUMED, F-69007 Lyon 07, France; [Peyre, Mathieu; Cartalat-Carel, Stephanie; Honnorat, Jerome; Ducray, Francois] Hop Neurol, Hosp Civils Lyon, Oullins, France; [Tod, Michel] Fac Med Lyon Sud, CTO EA3738, Oullins, France; [Tod, Michel] Hosp Civils Lyon, Hop Croix Rousse, Lyon, France; [Tod, Michel; Honnorat, Jerome; Ducray, Francois] Univ Lyon 1, F-69365 Lyon, France; [Honnorat, Jerome; Ducray, Francois] CNRS UMR 5292, INSERM U1028, Lyon Neurosci Res Ctr, Lyon, France; [Kaloshi, Gentian; Idbaih, Ahmed; Psimaras, Dimitri; Delattre, Jean-Yves] Grp Hosp Pitie Salpetriere, AP HP, Serv Neurol Mazarin, F-75634 Paris, France; [Kaloshi, Gentian; Idbaih, Ahmed; Psimaras, Dimitri; Delattre, Jean-Yves] Inst Cerveau & Moelle, Ctr Rech, INSERM, U975, Paris, France; [Kaloshi, Gentian; Idbaih, Ahmed; Psimaras, Dimitri; Delattre, Jean-Yves] Univ Paris 06, Fac Med Pitie Salpetriere, CNRS UMR 7225, Paris, France; [Kaloshi, Gentian; Idbaih, Ahmed; Psimaras, Dimitri; Delattre, Jean-Yves] UMR S975, Paris, France; [Ricard, Damien] Hop Instruct Armees Val de Grace, Paris, France; [Dainese, Linda] Hop La Pitie Salpetriere, Serv Neuropathol, Paris, France; [Pallud, Johan] Univ Paris 05, Serv Neurochirurg, Ctr Hosp St Anne, Paris, France"	"Ribba, B (corresponding author), Ecole Normale Super Lyon, INRIA, Project Team NUMED, 46 Allee Italie, F-69007 Lyon 07, France."	"benjamin.ribba@inria.fr"	"Honnorat, jerome/G-6394-2017; Calvez, Vincent/D-1119-2014; Idbaih, Ahmed/N-8746-2017"	"Honnorat, jerome/0000-0002-4721-5952; Calvez, Vincent/0000-0002-3674-1965; Pallud, Johan/0000-0002-1652-9844; Ducray, Francois/0000-0002-8150-5785; Idbaih, Ahmed/0000-0001-5290-1204"	"RocheRoche Holding; ETOILE project consortium: Espace de Traitement Oncologique par Ions Legers dans le cadre Europeen"	"F. Ducray had travel grants to attend ASCO by Roche. No potential conflicts of interest were disclosed by other authors.; B. Cajavec-Bernard was funded by the ETOILE project consortium: Espace de Traitement Oncologique par Ions Legers dans le cadre Europeen."	30	63	63	0	12	"AMER ASSOC CANCER RESEARCH"	"PHILADELPHIA"	"615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA"	"1078-0432"	"NA"	"NA"	"CLIN CANCER RES"	"Clin. Cancer Res."	"SEP 15"	2012	18	18	5071	5080	"NA"	"10.1158/1078-0432.CCR-12-0084"	10	"Oncology"	"Oncology"	"022NI"	"WOS:000309965700024"	22761472	"Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Stirnemann, JJ; Samson, A; Thalabard, JC"	"Stirnemann, J. J.; Samson, A.; Thalabard, J. C."	"NA"	"M"	"Individual predictions based on nonlinear mixed modeling: application to prenatal twin growth"	"STATISTICS IN MEDICINE"	"English"	"Article"	"prediction; nonlinear mixed model; growth; fetus; twin pregnancy"	"WORLD-HEALTH-ORGANIZATION; LAPLACES APPROXIMATION; CONSTRUCTION; STANDARDS; ALGORITHM; CURVES"	"The assessment of growth during fetal life and childhood commonly relies upon cross'sectional reference ranges or centiles. However, individual sequential predictions may help the timewise assessment of a growth process. In twin pregnancies for example, which are at risk of growth restriction, such predictions may improve the detection of abnormal trajectories. In this article, we present a simple forecasting method, assuming that a given normal individual behaves in the same way as a reference population. We consider, as a prediction in a given individual, the forecast of a future observation conditional to any previous observation and a set of population parameters obtained by nonlinear mixed modeling in a reference population. We suggest an estimator for this prediction without resorting to linear approximation and show that it enjoys interesting asymptotics when the amount of observations increases over time. We use two independent real datasets of twin pregnancies with normal growth and outcome to illustrate the application of such predictions in prenatal growth. We consider the first dataset as a reference dataset and model it using a two'level nonlinear model. We perform illustration and validation of predictions on the second dataset. Copyright (c) 2012 John Wiley & Sons, Ltd."	"[Stirnemann, J. J.] Univ Paris 05, Ctr Univ St Peres, MAP5, UMR CNRS 8145, F-75006 Paris, France; [Stirnemann, J. J.] Univ Paris 05, GHU Necker Enfants Malades, Dept Obstet & Maternal Fetal Med, F-75006 Paris, France"	"Stirnemann, JJ (corresponding author), Univ Paris 05, Ctr Univ St Peres, MAP5, UMR CNRS 8145, 45 Rue St Peres, F-75006 Paris, France."	"j.stirnemann@gmail.com"	"NA"	"NA"	"NA"	"NA"	29	1	1	0	6	"WILEY-BLACKWELL"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0277-6715"	"NA"	"NA"	"STAT MED"	"Stat. Med."	"AUG 15"	2012	31	18	1986	1999	"NA"	"10.1002/sim.5319"	14	"Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability"	"Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics"	"974XO"	"WOS:000306471100007"	22388672	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Ince, I; de Wildt, SN; Peeters, MYM; Murry, DJ; Tibboel, D; Danhof, M; Knibbe, CAJ"	"Ince, Ibrahim; de Wildt, Saskia N.; Peeters, Mariska Y. M.; Murry, Daryl J.; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"A"	"Critical Illness Is a Major Determinant of Midazolam Clearance in Children Aged 1 Month to 17 Years"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"critical illness; CYP3A4; midazolam; population pharmacokinetics; pediatrics; therapeutic drug monitoring"	"DRUG-METABOLISM; POPULATION PHARMACOKINETICS; ILL PATIENTS; INFANTS; MODEL; PREDICTION; INFLAMMATION"	"Background: In children, a large variability in pharmacokinetics of midazolam, a cytochrome P450 3A4/5 (CYP3A4/5) enzyme substrate, has been described, which cannot be explained by age-related changes alone. In this study, these age-related changes are studied in relation to other covariates to explain the variability in the pharmacokinetics of midazolam in children. Methods: Population pharmacokinetic modeling was performed using a joint dataset of 3 studies conducted previously: study 1: pediatric intensive care patients requiring sedation in the intensive care unit; study 2: pediatric oncology patients undergoing an invasive procedure; study 3: otherwise healthy infants admitted for postoperative monitoring after elective major craniofacial surgery. Midazolam, 1-hydroxymidazolam, and 1-hydroxymidazolam glucuronide concentrations were considered to determine the pharmacokinetics of midazolam and metabolites using NONMEM 6.2. SimCYP pediatric simulator was used for simulation. Results: Fifty-four children aged between 1 month and 17 years who received intravenous midazolam (bolus and/or continuous infusion) for sedation were included in this study. A reduction of 93% for CYP3A4/5 (midazolam to 1-hydroxymidazolam) and 86% for uridine diphosphate glucuronosyltransferase (1-hydroxymidazolam to 1-hydroxymidazolam glucuronide) mediated clearance was found in pediatric intensive care patients compared with the other 2 patient groups. We did not find a significant influence of age or bodyweight on CYP3A4/5-mediated total clearance. For uridine diphosphate glucuronosyltransferase-mediated clearance, bodyweight explained 41.5% of the variability. Conclusions: From infancy to adolescence, critical illness seems to be a major determinant of midazolam clearance, which may result from reduced CYP3A4/5 activity due to inflammation. This may have important implications for dosing of midazolam and other CYP3A drug substrates in critically ill children."	"[Peeters, Mariska Y. M.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands; [Ince, Ibrahim; de Wildt, Saskia N.; Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg & Intens Care, Rotterdam, Netherlands; [Ince, Ibrahim; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Amsterdam Ctr Drug Res, Dept Pharmacol, Leiden, Netherlands; [Murry, Daryl J.] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"de Wildt, Saskia/A-9589-2008"	"de Wildt, Saskia/0000-0002-0502-0647"	"Innovational Research Incentives Scheme of the Dutch Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); Erasmus MC; ZonMW clinical fellowships; Dutch Top Institute Pharma [D2-104]"	"This work was performed within the framework of Dutch Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organization for Scientific Research (NWO). Dr. de Wildt's research is supported by Erasmus MC and ZonMW clinical fellowships."	39	27	28	0	9	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"AUG"	2012	34	4	381	389	"NA"	"10.1097/FTD.0b013e31825a4c3a"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"972PW"	"WOS:000306290500005"	22660604	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Freise, KJ; Linton, DD; Newbound, GC; Tudan, C; Clark, TP"	"Freise, K. J.; Linton, D. D.; Newbound, G. C.; Tudan, C.; Clark, T. P."	"NA"	"A"	"Population pharmacokinetics of transdermal fentanyl solution following a single dose administered prior to soft tissue and orthopedic surgery in dogs"	"JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS"	"English"	"Article"	"NA"	"POSTOPERATIVE PAIN; PATCHES; BEHAVIOR"	"Freise, K. J., Linton, D. D., Newbound, G. C., Tudan, C., Clark, T. P. Population pharmacokinetics of transdermal fentanyl solution following a single dose administered prior to soft tissue and orthopedic surgery in dogs. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 6572. A novel, long-acting transdermal fentanyl solution (TFS) that delivers sustained plasma fentanyl concentrations following a single application for the control of postoperative pain has recently been approved for use in dogs. The pharmacokinetics (PKs) of this formulation have been evaluated in healthy laboratory dogs, but they have not been reported in a clinical population of dogs for which it is indicated. Plasma fentanyl concentrations were determined from 215 dogs following a single, small-volume (similar to 50 mu L/kg) dose of TFS administered 24 h prior to orthopedic or soft tissue surgery. A population PK model was fit, and a 1-compartment open PK model with first-order absorption and an absorption lag-time best described the data. No tested clinical covariates had a significant effect on the PKs. The final model adequately described the population PKs and gave results consistent with laboratory PK studies in healthy dogs. The PKs were primarily characterized by a rapid initial increase in plasma fentanyl concentrations and a long terminal half-life of 74.0 (95% C.I. [54.7113]) h governed by flip-flop kinetics for the typical subject. The plasma fentanyl concentrations were sustained over days in the range considered to be analgesic for postoperative pain in dogs."	"[Freise, K. J.; Linton, D. D.; Newbound, G. C.; Clark, T. P.] Nexcyon Pharmaceut Inc, Madison, WI 53703 USA; [Tudan, C.] BioAccurate Enterprises Inc, Vancouver, BC, Canada"	"Clark, TP (corresponding author), Nexcyon Pharmaceut Inc, 644 W Washington Ave, Madison, WI 53703 USA."	"clarktp@nexcyon.com"	"NA"	"NA"	"Nexcyon Pharmaceuticals, Inc."	"The study was funded by Nexcyon Pharmaceuticals, Inc."	22	14	14	0	12	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0140-7783"	"1365-2885"	"NA"	"J VET PHARMACOL THER"	"J. Vet. Pharmacol. Ther."	"AUG"	2012	35	"NA"	65	72	"NA"	"10.1111/j.1365-2885.2012.01407.x"	8	"Pharmacology & Pharmacy; Veterinary Sciences"	"Pharmacology & Pharmacy; Veterinary Sciences"	"963IO"	"WOS:000305614000008"	22731777	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Janoly-Dumenil, A; Rouvet, I; Bleyzac, N; Morfin, F; Zabot, MT; Tod, M"	"Janoly-Dumenil, Audrey; Rouvet, Isabelle; Bleyzac, Nathalie; Morfin, Florence; Zabot, Marie-Therese; Tod, Michel"	"NA"	"A"	"A Pharmacodynamic Model of Ganciclovir Antiviral Effect and Toxicity for Lymphoblastoid Cells Suggests a New Dosing Regimen To Treat Cytomegalovirus Infection"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"BONE-MARROW-TRANSPLANTATION; PREEMPTIVE THERAPY; IN-VIVO; INTRAVENOUS GANCICLOVIR; PROGENITOR CELLS; RISK-FACTORS; CORD BLOOD; VIRAL LOAD; RECIPIENTS; DYNAMICS"	"In bone marrow transplantation, the efficacy of ganciclovir in cytomegalovirus (CMV) disease treatment or prophylaxis remains partial. Because its hematological toxicity is dose limiting, optimization of the dosing schedule is required to increase its therapeutic index. The goal of our study was to describe the influence of the ganciclovir concentration and duration of exposure on cell survival and antiviral efficacy. The study was carried out in vitro on cultures of lymphoblastoid cells infected or not with the CMV AD169 reference strain and exposed to ganciclovir at different concentrations for 1, 2, 7, or 14 days. The data were analyzed by a mathematical model that allowed a quantitative characterization of ganciclovir pharmacodynamics and its variability. Simulations of the model were undertaken to determine the optimal concentration profile for maximizing the ganciclovir therapeutic index. Ganciclovir had very little toxic and antiviral effect, even at 20 mg liter(-1), when the duration of exposure was <= 7 days. A biologically significant effect was observed only with a 14-day exposure. Complete inhibition of viral replication was obtained at 20 mg liter(-1). The utility function, assuming equal weights for antiviral effect and toxicity, showed that maximal utility was reached around 10 mg liter(-1). The optimal ganciclovir concentration profile consisted of maintaining the concentration at 20 mg liter(-1) at the intervals 0 to 2 days and 7.58 to 9.58 days and a null concentration at other times. This optimal profile could be obtained by intravenous (i.v.) ganciclovir at 10 mg/kg of body weight twice daily (b.i.d.) at days 1, 2, 8.5, and 9.5 in stem cell transplant patients with normal renal function."	"[Tod, Michel] Hosp Civils Lyon, Hop Croix Rousse, Lyon, France; [Rouvet, Isabelle; Zabot, Marie-Therese] Hosp Civils Lyon, Ctr Biol Est, Dept Biotechnol Cellulaire, Lyon, France; [Janoly-Dumenil, Audrey] Hosp Civils Lyon, Hop Lyon Sud, Lyon, France; [Bleyzac, Nathalie] Ctr Leon Berard, Inst Oncohematol Pediat, F-69373 Lyon, France; [Morfin, Florence] Hosp Civils Lyon, EMR, Ctr Biol Est, Virol Lab, Lyon, France; [Tod, Michel] Univ Lyon, ISPB, Lyon, France"	"Tod, M (corresponding author), Hosp Civils Lyon, Hop Croix Rousse, Lyon, France."	"michel.tod@chu-lyon.fr"	"MORFIN, Florence/M-7176-2014"	"NA"	"NA"	"NA"	30	11	11	1	4	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"NA"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"JUL"	2012	56	7	3732	3738	"NA"	"10.1128/AAC.06423-11"	7	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"964DD"	"WOS:000305673000036"	22526305	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Wang, CG; Peeters, MYM; Allegaert, K; van Oud-Alblas, HJB; Krekels, EHJ; Tibboel, D; Danhof, M; Knibbe, CAJ"	"Wang, Chenguang; Peeters, Mariska Y. M.; Allegaert, Karel; van Oud-Alblas, Heleen J. Blusse; Krekels, Elke H. J.; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J."	"NA"	"M"	"A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"allometric; clearance; life-span; pharmacokinetics; propofol"	"UNIVERSAL METABOLIC ALLOMETRY; DRUG CLEARANCE; POPULATION PHARMACOKINETICS; PROPOFOL PHARMACOKINETICS; CHILDREN; PREDICTION; PRETERM; INFANTS; MODEL; GLUCURONIDATION"	"To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best. A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight."	"[Wang, Chenguang; Krekels, Elke H. J.; Danhof, Meindert; Knibbe, Catherijne A. J.] Leiden Univ, LACDR, Div Pharmacol, Leiden, Netherlands; [Wang, Chenguang; Krekels, Elke H. J.; Tibboel, Dick; Knibbe, Catherijne A. J.] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Rotterdam, Netherlands; [Peeters, Mariska Y. M.; Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, NL-3430 EM Nieuwegein, Netherlands; [Allegaert, Karel] Univ Hosp Leuven, Neonatal Intens Care Unit, Louvain, Belgium; [van Oud-Alblas, Heleen J. Blusse] Erasmus MC, Dept Anesthesiol, Rotterdam, Netherlands"	"Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, POB 2500, NL-3430 EM Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"allegaert, karel/C-3611-2016"	"allegaert, karel/0000-0001-9921-5105; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415"	"Dutch Top Institute Pharma [D2-104]"	"We would like to thank Dr. Murat, and Dr. Kataria and Dr. Schnider (www.opentci.org) for kindly sharing their clinical data. We would also like to thank for Dr. Tamara van Steeg, Dr. Joost DeJongh, and Dr. Lia Liefaard for their technical support. This study was performed within the framework of Dutch Top Institute Pharma project number D2-104. All authors declare no conflict of interest."	42	52	54	0	5	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"NA"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"JUN"	2012	29	6	1570	1581	"NA"	"10.1007/s11095-012-0668-x"	12	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"943JQ"	"WOS:000304117700013"	22287046	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Cella, M; Danhof, M; Della Pasqua, O"	"Cella, M.; Danhof, M.; Della Pasqua, O."	"NA"	"M"	"Bridging Strategies for Drug Combinations in Pediatric Indications"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"THERAPY; ATOVAQUONE; PROGUANIL; PHARMACOKINETICS; POPULATION; TRIAL; MANAGEMENT; MALARIA"	"Concurrent prescription of different drugs is common and is often necessary in many pediatric indications. A randomized concentration-controlled trial (RCCT) is proposed for pediatric studies in which drug combinations are used. The aim of our investigation was to show the relevance of flexible designs for accurate dose selection in such cases. We used the combination of atovaquone (ATV) and proguanil (PGN) as a paradigm to illustrate our approach. Pharmacokinetic models were developed for ATV and PGN using data pertaining to adults, The median area under the curve (AUC) in adults was considered the target exposure for bridging purposes. A pediatric population was simulated according to scenarios in which clearance varied from 20 to 100% of the reference adult values or allometrically correlated with body weight (BW). Doses were subsequently adapted according to the individual AUC estimates. Our results show that adaptive protocols are critical for accurate dose selection when evaluating drug combinations in children, ensuring that target exposure is achieved with respect to both active moieties in each individual patient."	"[Cella, M.; Danhof, M.; Della Pasqua, O.] Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands; [Della Pasqua, O.] GlaxoSmithKline Inc, Clin Pharmacol & Discovery Med, Stockley Pk, England"	"Della Pasqua, O (corresponding author), Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands."	"odp72514@gsk.com"	"Cella, Massimo/K-8375-2019"	"NA"	"GlaxoSmithKline (UK)GlaxoSmithKline"	"GlaxoSmithKline (UK) has provided financial support in the form of a fellowship to M.C. for work on model-based strategies for pediatric dose recommendation. The other authors declared no conflict of interest."	33	2	2	0	0	"NATURE PUBLISHING GROUP"	"NEW YORK"	"75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA"	"0009-9236"	"NA"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"APR"	2012	91	4	726	733	"NA"	"10.1038/clpt.2011.298"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"913QF"	"WOS:000301891800025"	22398968	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Cella, M; Kloprogge, F; Danhof, M; Della Pasqua, O"	"Cella, M.; Kloprogge, F.; Danhof, M.; Della Pasqua, O."	"NA"	"M"	"Dosing Rationale for Fixed-Dose Combinations in Children: Shooting From the Hip?"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; ATOVAQUONE-PROGUANIL; MALARIA; DISPOSITION"	"In this investigation we evaluate the relevance of a model-based approach for pharmacokinetic (PK) bridging and dose selection of drug combinations in children. The fixed-dose combination of atovaquone (ATV) and proguanil (PGN) was used for illustration purposes. A population PK model was developed for each compound using plasma concentration data from adult and pediatric patients. PK parameter estimates were subsequently used to simulate drug exposure in children treated with different dose levels of these drugs. We show that, contrary to common practice, different dose ratios may be required across age groups in order to achieve target exposure levels comparable to adults. This example illustrates the effects of covariate interactions, specifically the ones involving body weight (BW) and ethnicity, on the PK of drugs. A model-based approach is critical for dose selection and the rational use of drug combinations in children. Flexible rather than fixed-dose ratios may be needed to ensure comparable target exposure in bridging studies."	"[Cella, M.; Kloprogge, F.; Danhof, M.; Della Pasqua, O.] Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands; [Della Pasqua, O.] GlaxoSmithKline, Clin Pharmacol & Discovery Med, Stockley Pk, England"	"Della Pasqua, O (corresponding author), Leiden Univ, Div Pharmacol, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands."	"odp72514@gsk.com"	"Cella, Massimo/K-8375-2019"	"Kloprogge, Frank/0000-0001-7213-4559"	"GlaxoSmithKline (UK)GlaxoSmithKline"	"GlaxoSmithKline (UK) has provided financial support in the form of a fellowship to M.C. for work on model-based strategies for pediatric dose recommendation. The other authors declared no conflict of interest."	30	4	4	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"APR"	2012	91	4	718	725	"NA"	"10.1038/clpt.2011.297"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"913QF"	"WOS:000301891800024"	22398964	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Gonzalez-Sales, M; Valenzuela, B; Perez-Ruixo, C; Teruel, CF; Miguel-Lillo, B; Soto-Matos, A; Perez-Ruixo, JJ"	"Gonzalez-Sales, Mario; Valenzuela, Belen; Perez-Ruixo, Carlos; Fernandez Teruel, Carlos; Miguel-Lillo, Bernardo; Soto-Matos, Arturo; Jose Perez-Ruixo, Juan"	"NA"	"A"	"Population Pharmacokinetic-Pharmacodynamic Analysis of Neutropenia in Cancer Patients Receiving PM00104 (Zalypsis (R))"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"COLONY-STIMULATING FACTOR; HEMATOLOGICAL TOXICITY; MODEL; KINETICS; CHEMOTHERAPY; PHARMACOLOGY; TRABECTEDIN; REVEALS; REGIMEN; CSF"	"Background and Objective PM00104 (Zalypsis (R)) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients. Methods Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving PM00104 doses ranging from 0.053 to 5 mg/m(2) were used to estimate the system-related (baseline ANC [Circ(0)], mean transit time [MTT], feedback on proliferation [gamma] and maturation [delta]) and drug-specific (first-order elimination rate constant from effect compartment [k(e0)] [alpha and beta]) parameters of a modified Friberg's model. The concentrations in the effect compartment (C-c) were assumed to reduce the proliferation rate of the progenitor cells according to the function alpha x C-e(beta). Model evaluation and simulations were undertaken to evaluate the effect of dose intensity, dose density and the intravenous infusion duration on severe neutropenia incidence. Results The typical values (between-subject variability [%]) of the Circ(0), MTT, gamma, delta k(c0), alpha and beta were estimated to be 5.66 x 10(9) cells/L (13 %), 149 h (29 %), 0.136, 0.191, 0.00639 h(-1) (32 %), 0.332 L/mu g (24 %) and 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, number of previous chemotherapy lines and performance status were not associated with model parameters. The model evaluation evidenced an accurate prediction of the neutropenia grade 3 and/or 4 incidence. Simulations indicated that PM00104 dose and dosing interval, but not infusion duration, were the main determinants of the neutropenia severity and duration. Conclusions The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative."	"[Gonzalez-Sales, Mario; Perez-Ruixo, Carlos] Consulting Projects Res, Valencia 46530, Spain; [Valenzuela, Belen] USP Hosp San Jaime, Alicante, Spain; [Fernandez Teruel, Carlos; Miguel-Lillo, Bernardo; Soto-Matos, Arturo] Pharma Mar SA, Dept Clin Pharmacol, Madrid, Spain; [Jose Perez-Ruixo, Juan] Pharmacokinet & Drug Metab, Amgen, Spain"	"Perez-Ruixo, C (corresponding author), Consulting Projects Res, 3 Puzol, Valencia 46530, Spain."	"carlos@cpr-projects.com"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"NA"	"NA"	35	9	11	0	6	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2012	51	11	751	764	"NA"	"10.1007/s40262-012-0011-z"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"037AO"	"WOS:000311073600004"	23055348	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Sanchez, A; Cabrera, S; Santos, D; Valverde, MP; Fuertes, A; Dominguez-Gil, A; Garcia, MJ"	"Sanchez, Almudena; Cabrera, Salvador; Santos, Dolores; Paz Valverde, M.; Fuertes, Aurelio; Dominguez-Gil, Alfonso; Garcia, Maria J."	"Tormes Grp"	"A"	"Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"IMMUNODEFICIENCY-VIRUS-INFECTION; PLASMA-CONCENTRATIONS; HIV-1-INFECTED INDIVIDUALS; ANTIRETROVIRAL THERAPY; VIROLOGICAL RESPONSE; CYP2B6 POLYMORPHISM; CONTAINING REGIMENS; PHARMACOKINETICS; PHARMACOGENETICS; METABOLISM"	"Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C -> T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 - 0.00279 . GGT) . 0.602(CYP2B6*6) ([G/T]) . 0.354(CYP2B6*6 [T/T]) . 0.793(MRP4 1497C -> T), where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C -> T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population."	"[Sanchez, Almudena; Cabrera, Salvador; Paz Valverde, M.; Dominguez-Gil, Alfonso] Hosp Univ Salamanca, Serv Farm, Salamanca 37007, Spain; [Cabrera, Salvador] Univ Austral Chile, Inst Pharm, Valdivia, Chile; [Santos, Dolores; Dominguez-Gil, Alfonso; Garcia, Maria J.] Univ Salamanca, Dept Pharm & Pharmaceut Technol, E-37008 Salamanca, Spain; [Fuertes, Aurelio] Hosp Univ Salamanca, Infect Dis Serv, Salamanca 37007, Spain"	"Cabrera, S (corresponding author), Hosp Univ Salamanca, Serv Farm, Paseo San Vicente 58, Salamanca 37007, Spain."	"scabrera@uach.cl"	"Garcia, Maria Jose/P-8475-2019"	"Garcia, Maria Jose/0000-0003-2760-7083"	"Europharma Foundation; University of Salamanca; University Austral of Chile"	"This research was supported by funding granted by the Europharma Foundation under an agreement of collaboration between the University of Salamanca and the University Austral of Chile."	58	37	40	0	3	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"NOV"	2011	55	11	5314	5324	"NA"	"10.1128/AAC.00194-11"	11	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"839NX"	"WOS:000296375600051"	21896912	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Thuo, N; Ungphakorn, W; Karisa, J; Muchohi, S; Muturi, A; Kokwaro, G; Thomson, AH; Maitland, K"	"Thuo, Nahashon; Ungphakorn, Wanchana; Karisa, Japhet; Muchohi, Simon; Muturi, Alex; Kokwaro, Gilbert; Thomson, Alison H.; Maitland, Kathryn"	"NA"	"A"	"Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"quinolone; drug absorption; marasmus; kwashiorkor; Gram-negative"	"CYSTIC-FIBROSIS PATIENTS; PROTEIN-CALORIE MALNUTRITION; GLOMERULAR-FILTRATION-RATE; RENAL-FUNCTION; INTRAVENOUS CIPROFLOXACIN; MALNOURISHED CHILDREN; ILL-PATIENTS; BIOAVAILABILITY; ABSORPTION; MODEL"	"Background: Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown. Methods: Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC(0-24)/MIC ratio of >= 125. Results: Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8-102 months. Absorption as generally rapid but variable; C(max) ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h)=42.7 (L/h/70 kg)x[weight (kg)/70](0.75)x[1�.0368 (Na() - 136)]x[1 - 0.283 (high risk)] and V (L)=372x(L/70 kg)x[1�.0291 (Na() - 136)]. Estimates of AUC(0-24) ranged from 8 to 61 mg.h/L. The breakpoint for Gram-negative organisms was <0.06 mg/L with doses of 20 mg/kg/day and <0.125 mg/L with doses of 30 or 45 mg/kg/day. The cumulative fraction of response with 30 mg/kg/day was >= 80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa. Conclusions: An oral ciprofloxacin dose of 10 mg/kg three times daily (30 mg/kg/day) may be a suitable alternative antibiotic for the management of sepsis in severely malnourished children. Absorption was unaffected by the simultaneous administration of feeds."	"[Thuo, Nahashon; Karisa, Japhet; Muchohi, Simon; Muturi, Alex; Maitland, Kathryn] Ctr Geog Med Res Coast, KEMRI Wellcome Trust Res Programme, Kilifi 80108, Kenya; [Ungphakorn, Wanchana; Thomson, Alison H.] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow G4 0RE, Lanark, Scotland; [Kokwaro, Gilbert] Univ Nairobi, Dept Pharmaceut & Pharm Practice, Sch Pharm, Nairobi, Kenya; [Kokwaro, Gilbert] CNHR, Nairobi 00202, Kenya; [Thomson, Alison H.] Western Infirm & Associated Hosp, Dept Pharm, Pharm & Prescribing Support Unit, NHS Greater Glasgow & Clyde, Glasgow G11 6NT, Lanark, Scotland; [Maitland, Kathryn] Univ London Imperial Coll Sci Technol & Med, Wellcome Trust Ctr Clin Trop Med, Fac Med, London W2 1PG, England"	"Maitland, K (corresponding author), Ctr Geog Med Res Coast, KEMRI Wellcome Trust Res Programme, POB 230, Kilifi 80108, Kenya."	"kathryn.maitland@gmail.com"	"Thomson, Alison H H/H-9743-2016"	"Thomson, Alison H H/0000-0002-2354-6116; Maitland, Kathryn/0000-0002-0007-0645; Thuo, Nahashon/0000-0003-3719-6695; Ungphakorn, Wanchana/0000-0002-4170-7008"	"Wellcome TrustWellcome Trust [077092, 089353/Z/09/Z]"	"This study was supported by Wellcome Trust core funding to KEMRI-Wellcome Trust Research Programme (grant Reference No. 077092). Nahashon Thuo is supported by a Wellcome Trust Masters Training Fellowship (grant reference No. 089353/Z/09/Z). The funding sources had no role in study design, analysis or in the writing of the report."	49	9	10	0	2	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"NA"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"OCT"	2011	66	10	2336	2345	"NA"	"10.1093/jac/dkr314"	10	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"821IY"	"WOS:000294969700024"	21831986	"Bronze, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Aspiroz, EL; Buelga, DS; Figueroa, SC; Galera, RML; Pascuet, ER; Hurle, ADG; Sanchez, MJG"	"Lopez Aspiroz, Elena; Santos Buelga, Dolores; Cabrera Figueroa, Salvador; Lopez Galera, Rosa Maria; Ribera Pascuet, Esteban; Dominguez-Gil Hurle, Alfonso; Garcia Sanchez, Maria Jose"	"NA"	"A"	"Population Pharmacokinetics of Lopinavir/Ritonavir (Kaletra) in HIV-Infected Patients"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"therapeutic drug monitoring; lopinavir; ritonavir; NONMEM; HIV; patients"	"IMMUNODEFICIENCY-VIRUS PROTEASE; REVERSE-TRANSCRIPTASE INHIBITORS; LOPINAVIR PLASMA-CONCENTRATIONS; STEADY-STATE PHARMACOKINETICS; RANDOMIZED CONTROLLED-TRIAL; HIV-1-INFECTED PATIENTS; EXPERIENCED PATIENTS; ANTIRETROVIRAL THERAPY; VIROLOGICAL RESPONSE; COMBINATION THERAPY"	"Background: A relationship between plasma concentrations and viral suppression in patients receiving lopinavir (LPV)/ritonavir (RTV) has been observed. Therefore, it is important to increase our knowledge about factors that determine interpatient variability in LPV pharmacokinetics (PK). Methods: The study, designed to develop and validate population PK models for LPV and RTV, involved 263 ambulatory patients treated with 400/100 mg of LPV/RTV twice daily. A database of 1110 concentrations of LPV and RTV (647 from a single time-point and 463 from 73 full PK profiles) was available. Concentrations were determined at steady state using high-performance liquid chromatography with ultraviolet detection. PK analysis was performed with NONMEM software. Age, gender, height, total body weight, body mass index, RTV trough concentration (RTC), hepatitis C virus coinfection, total bilirubin, hospital of origin, formulation and concomitant administration of efavirenz (EFV), saquinavir (SQV), atazanavir (ATV), and tenofovir were analyzed as possible covariates influencing LPV/RTV kinetic behavior. Results: Population models were developed with 954 drug plasma concentrations from 201 patients, and the validation was conducted in the remaining 62 patients (156 concentrations). A 1-compartment model with first-order absorption (including lag-time) and elimination best described the PK. Proportional error models for interindividual and residual variability were used. The final models for the drugs oral clearance (CL/F) were as follows: CL/F-LPV(L/h) = 0.216 . BMI . 0.81(RTC) . 1.25(EFV) . 0.84(ATV) CL/F-RTV(L/h) = 8.00 . 1.34(SQV) . 1.77(EFV) . 1.35(ATV). The predictive performance of the final population PK models was tested using standardized mean prediction errors, showing values of 0.03 � 0.74 and 0.05 � 0.91 for LPV and RTV, and normalized prediction distribution error, confirming the suitability of both models. Conclusions: These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs."	"[Lopez Aspiroz, Elena; Cabrera Figueroa, Salvador; Dominguez-Gil Hurle, Alfonso] Hosp Univ Salamanca, Serv Farm, Salamanca 37007, Spain; [Santos Buelga, Dolores; Dominguez-Gil Hurle, Alfonso; Garcia Sanchez, Maria Jose] Univ Salamanca, Fac Pharm, Dept Pharm & Pharmaceut Technol, E-37008 Salamanca, Spain; [Cabrera Figueroa, Salvador] Univ Austral Chile, Inst Pharm, Valdivia, Chile; [Lopez Galera, Rosa Maria] Hosp Clin Barcelona, Serv Biochem & Mol Genet, Barcelona, Spain; [Ribera Pascuet, Esteban] Vall dHebron Hosp Barcelona, Infect Dis Serv, Barcelona, Spain"	"Figueroa, SC (corresponding author), Hosp Univ Salamanca, Serv Farm, Paseo San Vicente 58, Salamanca 37007, Spain."	"scabrera@uach.cl"	"NA"	"NA"	"Europharma Foundation under University of Salamanca; Europharma Foundation under University Austral of Chile"	"Supported by the Europharma Foundation under an agreement of collaboration between the University of Salamanca and the University Austral of Chile."	76	17	17	1	11	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"OCT"	2011	33	5	573	582	"NA"	"10.1097/FTD.0b013e31822d578b"	10	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"822XE"	"WOS:000295083000002"	21912331	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Oudin, C; Vialet, R; Boulamery, A; Martin, C; Simon, N"	"Oudin, C.; Vialet, R.; Boulamery, A.; Martin, C.; Simon, N."	"NA"	"A"	"Vancomycin prescription in neonates and young infants: toward a simplified dosage"	"ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; PEDIATRIC INPATIENTS; REFERENCE RANGES; CHILDREN; CREATININE; ERRORS; MODEL"	"Background There is no consensus on vancomycin dosing in newborns and young infants. Objective The first objective was to assess the efficiency of a simplified dosing regimen with a cohort study. The secondary objective was to examine pharmacokinetic data to determine how this simplified dosing could be improved. Methods All neonates admitted to our intensive care unit and treated with vancomycin were included in the pharmacokinetic study (PK group, 83 treatments, 156 measurements). The vancomycin dosing regimen consisted of a loading dose of 7 mg/kg, followed by a constant continuous dose of 30 mg/kg/day. The target serum vancomycin concentration ranged from 10 mg/l to 30 mg/l. Data from patients whose medications followed the scheduled dosing without modifications or prescription errors (actual dosing group: 62 treatments, 108 measurements) were analysed separately. A population pharmacokinetic analysis was performed (PK group) to simulate several vancomycin dosings. Results Prescription errors were found in 10 of 83 treatments (12%). In the actual dosing group, 89.2% of vancomycin measurements were within the target range. Serum creatinine remained stable throughout treatment. Vancomycin concentrations varied widely. The modified regimen for a target vancomycin concentration of 25 mg/l consisted of a bolus of 20 mg/kg followed by continuous infusion of 30 mg/kg. Conclusion Our pharmacokinetic data and bedside results suggest that a simplified schedule of vancomycin can achieve the targeted drug concentrations in most patients while avoiding secondary renal toxicity. The proposed new dosing scheme should be validated in a drug survey, but due to pharmacokinetic variability, still requires therapeutic drug monitoring."	"[Oudin, C.; Vialet, R.; Martin, C.] Hop Nord Marseille, Assistance Publ Hop Marseille, Dept Anesthesie Reanimat, F-13915 Marseille, France; [Boulamery, A.; Simon, N.] Univ Aix Marseille 2, Hop Timone, Assistance Publ Hop Marseille, Dept Pharmacol, Marseille, France"	"Vialet, R (corresponding author), Hop Nord Marseille, Assistance Publ Hop Marseille, Dept Anesthesie Reanimat, Chemin Bourely, F-13915 Marseille, France."	"renaud.vialet@ap-hm.fr"	"Simon, Nicolas/B-1235-2016"	"Simon, Nicolas/0000-0003-4393-2257"	"NA"	"NA"	25	36	36	0	3	"B M J PUBLISHING GROUP"	"LONDON"	"BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND"	"1359-2998"	"NA"	"NA"	"ARCH DIS CHILD-FETAL"	"Arch. Dis. Child.-Fetal Neonatal Ed."	"SEP"	2011	96	5	"F365"	"F370"	"NA"	"10.1136/adc.2010.196402"	6	"Pediatrics"	"Pediatrics"	"817GP"	"WOS:000294659600014"	21378399	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Thai, HT; Veyrat-Follet, C; Vivier, N; Dubruc, C; Sanderink, G; Mentre, F; Comets, E"	"Thai, Hoai-Thu; Veyrat-Follet, Christine; Vivier, Nicole; Dubruc, Catherine; Sanderink, Gerard; Mentre, France; Comets, Emmanuelle"	"NA"	"A"	"A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"aflibercept; MONOLIX; population pharmacokinetics; target-mediated drug disposition; VEGF"	"ENDOTHELIAL GROWTH-FACTOR; MEDIATED DRUG DISPOSITION; VEGF"	"AIM Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects. METHODS Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration-time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1. RESULTS The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis-Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day(-1) and 0.14 l day(-1), respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day(-1) and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 mu g ml(-1). Interindividual variability of model parameters was moderate, ranging from 13.6% (V-max) to 49.8% (Q). CONCLUSION The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF."	"[Thai, Hoai-Thu; Mentre, France; Comets, Emmanuelle] Univ Paris Diderot, INSERM, UMR738, F-75018 Paris, France; [Thai, Hoai-Thu; Veyrat-Follet, Christine; Vivier, Nicole; Dubruc, Catherine; Sanderink, Gerard] Sanofi Aventis, Global Metab & Pharmacokinet Dept, Paris, France"	"Thai, HT (corresponding author), Univ Paris Diderot, INSERM, UMR738, 16 Rue Henri Huchard, F-75018 Paris, France."	"hoai-thu.thai@inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"Sanofi-aventisSanofi-Aventis; Global Metabolism; Pharmacokinetics Department, Sanofi-aventis, ParisSanofi-Aventis"	"Hoai-Thu Thai received a research grant from Sanofi-aventis to perform this research and is now doing a PhD funded by a research grant from Sanofi-aventis. Emmanuelle Comets acted as a consultant for Sanofi-aventis in 2009-10. France Mentre is the director of Inserm UMR 738 which receives a research grant from Sanofi-aventis and has been paid for running an education program at Sanofi-Aventis. Christine Veyrat-Follet and Gerard Sanderink are employees of Sanofi-aventis. Nicole Vivier and Catherine Dubruc are former employees of Sanofi-aventis.; The authors thank Global Metabolism and the Pharmacokinetics Department, Sanofi-aventis, Paris which supported Hoai-Thu Thai by a research grant during this work."	23	13	13	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2011	72	3	402	414	"NA"	"10.1111/j.1365-2125.2011.04015.x"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"804LD"	"WOS:000293654400005"	21575034	"Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"van Hasselt, JGC; Boekhout, AH; Beijnen, JH; Schellens, JHM; Huitema, ADR"	"van Hasselt, J. G. C.; Boekhout, A. H.; Beijnen, J. H.; Schellens, J. H. M.; Huitema, A. D. R."	"NA"	"A"	"Population Pharmacokinetic-Pharmacodynamic Analysis of Trastuzumab-Associated Cardiotoxicity"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"HER2-POSITIVE BREAST-CANCER; CONGESTIVE-HEART-FAILURE; ADJUVANT CHEMOTHERAPY; CARDIAC DYSFUNCTION; CLINICAL-TRIALS; DOXORUBICIN; PACLITAXEL; THERAPY; PLUS; B-31"	"Trastuzumab treatment is associated with cardiac dysfunction. The aim of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for the relationship between left ventricular ejection fraction (LVEF) and trastuzumab exposure and to identify associated clinically relevant covariates. Data from an unselected cohort of patients with early and advanced HER2-positive breast cancer receiving treatment with trastuzumab were analyzed using a nonlinear mixed-effects modeling approach. LVEF values from 240 patients were available. The data were best described by an effect-compartment model. The population LVEF recovery half-life after trastuzumab treatment (T-1/2rec) was estimated at 49.7 days. The cumulative anthracycline dose was a significant determinant of the half maximal effect concentration (EC50), causing a 45.9% increase in sensitivity (decrease in EC50) at the maximum cumulative anthracycline dose. The developed population PK-PD model may be used to establish optimal treatment and cardiac monitoring strategies for trastuzumab."	"[van Hasselt, J. G. C.; Boekhout, A. H.] Netherlands Canc Inst, Dept Clin Pharmacol, Amsterdam, Netherlands; [van Hasselt, J. G. C.; Boekhout, A. H.; Beijnen, J. H.; Schellens, J. H. M.; Huitema, A. D. R.] Netherlands Canc Inst, Slotervaart Hosp, Dept Pharm & Pharmacol, Amsterdam, Netherlands; [Beijnen, J. H.; Schellens, J. H. M.] Univ Utrecht, Dept Pharmaceut Sci, Utrecht, Netherlands"	"van Hasselt, JGC (corresponding author), Netherlands Canc Inst, Dept Clin Pharmacol, Amsterdam, Netherlands."	"coenvanhasselt@gmail.com"	"van Hasselt, Coen/H-5593-2019"	"NA"	"NA"	"NA"	22	17	17	1	9	"NATURE PUBLISHING GROUP"	"NEW YORK"	"75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA"	"0009-9236"	"NA"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"JUL"	2011	90	1	126	132	"NA"	"10.1038/clpt.2011.74"	7	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"780KD"	"WOS:000291853800022"	21633346	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Paule, I; Sassi, H; Habibi, A; Pham, KPD; Bachir, D; Galacteros, F; Girard, P; Hulin, A; Tod, M"	"Paule, Ines; Sassi, Hind; Habibi, Anoosha; Pham, Kim P. D.; Bachir, Dora; Galacteros, Frederic; Girard, Pascal; Hulin, Anne; Tod, Michel"	"NA"	"A"	"Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen"	"ORPHANET JOURNAL OF RARE DISEASES"	"English"	"Article"	"NA"	"FETAL-HEMOGLOBIN; MODEL; RESPONSES"	"Background: Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods: The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF %) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results: The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median I-max was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions: The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU."	"[Paule, Ines; Girard, Pascal; Tod, Michel] Univ Lyon, Lyon, France; [Paule, Ines; Girard, Pascal; Tod, Michel] Univ Lyon 1, Fac Med Lyon Sud, CTO EMR3738, Oullins, France; [Sassi, Hind; Pham, Kim P. D.; Hulin, Anne] Univ Paris Est Creteil, AP HP, GH H Mondor, Pharmacol Lab, Creteil, France; [Habibi, Anoosha; Bachir, Dora; Galacteros, Frederic] Univ Paris Est Creteil, AP HP, GH H Mondor, Ctr Reference Syndromes Drepanocytaires Majeu, Creteil, France; [Tod, Michel] Hosp Civils Lyon, Hop Croix Rousse, Lyon, France"	"Tod, M (corresponding author), Univ Lyon, Lyon, France."	"michel.tod@chu-lyon.fr"	"NA"	"NA"	"OTL-Pharma Laboratories; Centre de reference pour les syndromes drepanocytaires majeurs; Laboratoire de Pharmacologie, AP-HP, GH H"	"We thank Emilie Henin for advice concerning VPC plots and Christine Fauroux for collecting the data. The PK study was funded by OTL-Pharma Laboratories which participated solely to the study design. The PKPD study was funded by the Centre de reference pour les syndromes drepanocytaires majeurs and the Laboratoire de Pharmacologie, AP-HP, GH H. Mondor to which belong most authors."	26	19	19	0	3	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"NA"	"1750-1172"	"NA"	"ORPHANET J RARE DIS"	"Orphanet J. Rare Dis."	"MAY 28"	2011	6	"NA"	"NA"	"NA"	30	"10.1186/1750-1172-6-30"	12	"Genetics & Heredity; Medicine, Research & Experimental"	"Genetics & Heredity; Research & Experimental Medicine"	"780OK"	"WOS:000291867400001"	21619673	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Sun, XY; Li, J"	"Sun, Xiaoyong; Li, Jun"	"NA"	"M"	"PKreport: report generation for checking population pharmacokinetic model assumptions"	"BMC MEDICAL INFORMATICS AND DECISION MAKING"	"English"	"Article"	"NA"	"PERSPECTIVE; GRAPHICS"	"Background: Graphics play an important and unique role in population pharmacokinetic (PopPK) model building by exploring hidden structure among data before modeling, evaluating model fit, and validating results after modeling. Results: The work described in this paper is about a new R package called PKreport, which is able to generate a collection of plots and statistics for testing model assumptions, visualizing data and diagnosing models. The metric system is utilized as the currency for communicating between data sets and the package to generate special-purpose plots. It provides ways to match output from diverse software such as NONMEM, Monolix, R nlme package, etc. The package is implemented with S4 class hierarchy, and offers an efficient way to access the output from NONMEM 7. The final reports take advantage of the web browser as user interface to manage and visualize plots. Conclusions: PKreport provides 1) a flexible and efficient R class to store and retrieve NONMEM 7 output, 2) automate plots for users to visualize data and models, 3) automatically generated R scripts that are used to create the plots; 4) an archive-oriented management tool for users to store, retrieve and modify figures, 5) high-quality graphs based on the R packages, lattice and ggplot2. The general architecture, running environment and statistical methods can be readily extended with R class hierarchy. PKreport is free to download at http://cran.r-project.org/web/packages/PKreport/index.html."	"[Sun, Xiaoyong] Iowa State Univ, Dept Stat, Bioinformat & Computat Biol Program, Ames, IA 50011 USA; [Li, Jun] Univ Montreal, Fac Pharm, Succ Ctr Ville, Montreal, PQ H3C 3J7, Canada; [Li, Jun] Univ Montreal, Ctr Rech Math, Succ Ctr Ville, Montreal, PQ H3C 3J7, Canada"	"Sun, XY (corresponding author), Iowa State Univ, Dept Stat, Bioinformat & Computat Biol Program, Ames, IA 50011 USA."	"johnsunx1@gmail.com"	"NA"	"NA"	"NovartisNovartis"	"This work was fully funded by an unrestricted fellowship from Novartis. We thank Dr. Di Cook for helpful discussions and advices on this work."	21	5	5	0	6	"BMC"	"LONDON"	"CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"1472-6947"	"NA"	"NA"	"BMC MED INFORM DECIS"	"BMC Med. Inform. Decis. Mak."	"MAY 16"	2011	11	"NA"	"NA"	"NA"	31	"10.1186/1472-6947-11-31"	10	"Medical Informatics"	"Medical Informatics"	"783LY"	"WOS:000292085700001"	21575245	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-01"
"J"	"Brown, AN; Bulitta, JB; McSharry, JJ; Weng, QM; Adams, JR; Kulawy, R; Drusano, GL"	"Brown, Ashley N.; Bulitta, Juergen B.; McSharry, James J.; Weng, Qingmei; Adams, Jonathan R.; Kulawy, Robert; Drusano, George L."	"NA"	"A"	"Effect of Half-Life on the Pharmacodynamic Index of Zanamivir against Influenza Virus Delineated by a Mathematical Model"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"NA"	"A H1N1 VIRUS; IN-VITRO; OSELTAMIVIR-RESISTANT; DRUG SUSCEPTIBILITY; INHIBITION ASSAY; INFECTION; PHARMACOKINETICS; HUMANS; AMANTADINE; RWJ-270201"	"Intravenous zanamivir is recommended for the treatment of hospitalized patients with complicated oseltamivir-resistant influenza virus infections. In a companion paper, we show that the time above the 50% effective concentration (time > EC50) is the pharmacodynamic (PD) index predicting the inhibition of viral replication by intravenous zanamivir. However, for other neuraminidase inhibitors, the ratio of the area under the concentration-time curve to the EC50 (AUC/EC50) is the most predictive index. Our objectives are (i) to explain the dynamically linked variable of intravenous zanamivir by using different half-lives and (ii) to develop a new, mechanism-based population pharmacokinetic (PK)/PD model for the time course of viral load. We conducted dose fractionation studies in the hollow-fiber infection model (HFIM) system with zanamivir against an oseltamivir-resistant influenza virus. A clinical 2.5-h half-life and an artificially prolonged 8-h half-life were simulated for zanamivir. The values for the AUC from 0 to 24 h (AUC(0-24)) of zanamivir were equivalent for the two half-lives. Viral loads and zanamivir pharmacokinetics were comodeled using data from the present study and a previous dose range experiment via population PK/PD modeling in S-ADAPT. Dosing every 8 h (Q8h) suppressed the viral load better than dosing Q12h or Q24h at the 2.5-h half-life, whereas all regimens suppressed viral growth similarly at the 8-h half-life. The model provided unbiased and precise individual (Bayesian) (r(2), > 0.96) and population (pre-Bayesian) (r(2), > 0.87) fits for log(10) viral load. Zanamivir inhibited viral release (50% inhibitory concentration [IC50], 0.0168 mg/liter; maximum extent of inhibition, 0.990). We identified AUC/EC50 as the pharmacodynamic index for zanamivir at the 8-h half-life, whereas time > EC50 best predicted viral suppression at the 2.5-h half-life, since the trough concentrations approached the IC50 for the 2.5-h but not for the 8-h half-life. The model explained data at both half-lives and holds promise for optimizing clinical zanamivir dosage regimens."	"[Brown, Ashley N.; Bulitta, Juergen B.; McSharry, James J.; Weng, Qingmei; Adams, Jonathan R.; Kulawy, Robert; Drusano, George L.] Ordway Res Inst, Ctr Med Sci, Ctr Biodef & Emerging Infect, Virol Therapeut & Pharmacodynam Lab, Albany, NY 12208 USA"	"Drusano, GL (corresponding author), Ordway Res Inst, Ctr Med Sci, Ctr Biodef & Emerging Infect, Virol Therapeut & Pharmacodynam Lab, 150 New Scotland Ave, Albany, NY 12208 USA."	"gdrusano@ordwayresearch.org"	"Bulitta, Jurgen B/P-3355-2018"	"Bulitta, Jurgen B/0000-0001-7352-3097"	"NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [RO1-AI079729-02]"	"This work was supported by grant RO1-AI079729-02 from NIAID to the Virology Therapeutics and Pharmacodynamics laboratory. We thank Diane Singer for providing tissue culture cells for these experiments."	28	18	18	0	3	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"APR"	2011	55	4	1747	1753	"NA"	"10.1128/AAC.01629-10"	7	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"737US"	"WOS:000288594600053"	21263045	"Green Published, Bronze"	"NA"	"NA"	"2020-10-01"
"J"	"Launay, O; Tod, M; Tschope, I; Si-Mohamed, A; Belarbi, L; Charpentier, C; Goujard, C; Taburet, AM; Lortholary, O; Leroy, V; Belec, L"	"Launay, Odile; Tod, Michel; Tschoepe, Inga; Si-Mohamed, Ali; Belarbi, Linda; Charpentier, Charlotte; Goujard, Cecile; Taburet, Anne-Marie; Lortholary, Olivier; Leroy, Valeriane; Belec, Laurent"	"ANRS EP24 GYNODYN Study Grp"	"A"	"Residual HIV-1 RNA and HIV-1 DNA production in the genital tract reservoir of women treated with HAART: the prospective ANRS EP24 GYNODYN study"	"ANTIVIRAL THERAPY"	"English"	"Article"	"NA"	"IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; CERVICOVAGINAL SECRETIONS; INFECTED WOMEN; HETEROSEXUAL TRANSMISSION; PLASMA; MODEL; LOAD; COMPARTMENTALIZATION; QUANTIFICATION"	"Background: The female genital tract constitutes a reservoir for HIV providing active production of both cell-free HIV RNA and cell-associated DNA within the cervicovaginal secretions. The objective of this study was to prospectively assess residual HIV-1 RNA and HIV-1 DNA production in the genital tract reservoir of women initiating HAART over an 18-month period. Methods: Paired blood and cervicovaginal lavage samples were collected at inclusion and 1, 6, 12 and 18 months after HAART initiation, in 23 women in first-line HAART and six women in virological failure, for measurement of HIV-1 RNA and HIV-1 DNA shedding and/or drug concentrations. Results: A dramatic decrease of HIV-1 RNA and HIV-1 DNA occurred in both blood and cervicovaginal samples over the first 6 months on HAART, followed by a shelf up to 18 months, independently of the drugs' genital pharmacokinetics. While cervicovaginal HIV-1 RNA became undetectable in >90% of women from 6 months on HAART, genital HIV-1 DNA remained frequently detectable (27-50%). Nearly 40% of women with sustained undetectable plasma HIV-1 RNA after 6-18 months on HAART harboured transient HIV-1 RNA (15% of women) or HIV-1 DNA (31% of women) in their genital secretions. Conclusions: Low-level cervicovaginal HIV-1 shedding is frequently evidenced in HAART-treated women with transient HIV-1 RNA and persistent HIV-1 DNA despite a systemic control of viral replication, resulting in possible residual genital infectivity."	"[Launay, Odile; Lortholary, Olivier; Belec, Laurent] Univ Paris 05, Fac Med Paris Descartes, Paris, France; [Launay, Odile; Belarbi, Linda] Grp Hosp Cochin St Vincent de Paul, AP HP, Ctr Invest Clin Vaccinol Cochin Pasteur, Paris, France; [Tschoepe, Inga; Leroy, Valeriane] Univ Bordeaux 2, INSERM U897, F-33076 Bordeaux, France; [Si-Mohamed, Ali; Charpentier, Charlotte; Belec, Laurent] Hop Europeen Georges Pompidou, AP HP, Paris, France; [Goujard, Cecile; Taburet, Anne-Marie] Hop Bicetre, AP HP, Le Kremlin Bicetre, France; [Lortholary, Olivier] Grp Hosp Necker Enfants Malad, AP HP, Ctr Infectiol Necker Pasteur, Paris, France"	"Launay, O (corresponding author), Univ Paris 05, Fac Med Paris Descartes, Paris, France."	"odile.launay@cch.aphp.fr"	"lacarelle, bruno/C-5585-2015; Leroy, Valeriane/AAO-5175-2020; Charpentier, Charlotte/C-3579-2019; , Leroy/F-8129-2013"	"lacarelle, bruno/0000-0002-7122-5851; Leroy, Valeriane/0000-0003-3542-8616; , Leroy/0000-0003-3542-8616"	"French National Agency for Research on AIDS and Viral Hepatitis (ANRS)ANRSFrench National Research Agency (ANR)"	"The authors thank the study women and all participating clinicians at each site. The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) sponsored the research. After approval of the protocol, the sponsor was not involved in the collection, analysis or interpretation of the data, the writing of the report or the decision to submit the paper for publication. The authors would like to thank Genevieve Chene, Carine Grondin and Valerie Journot for their valuable comments on methods used. The work was presented in part at the 14th Conference on Retroviruses and Opportunistic Infections, 25-28 February 2007, Los Angeles, CA, USA (Abstract 782)."	51	22	22	0	4	"INT MEDICAL PRESS LTD"	"LONDON"	"2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND"	"1359-6535"	"NA"	"NA"	"ANTIVIR THER"	"Antivir. Ther."	"NA"	2011	16	6	843	852	"NA"	"10.3851/IMP1856"	10	"Infectious Diseases; Pharmacology & Pharmacy; Virology"	"Infectious Diseases; Pharmacology & Pharmacy; Virology"	"830LC"	"WOS:000295657500007"	21900716	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Wittau, M; Scheele, J; Bulitta, JB; Mayer, B; Kaever, V; Burhenne, H; Henne-Bruns, D; Isenmann, R; Brockschmidt, C"	"Wittau, M.; Scheele, J.; Bulitta, J. B.; Mayer, B.; Kaever, V.; Burhenne, H.; Henne-Bruns, D.; Isenmann, R.; Brockschmidt, C."	"NA"	"A"	"Pharmacokinetics of Ertapenem in Colorectal Tissue"	"CHEMOTHERAPY"	"English"	"Article"	"Pharmacokinetics; Carbapenem; Tissue penetration; Ertapenem"	"CRITICALLY-ILL PATIENTS; COMPLICATED INTRAABDOMINAL INFECTIONS; POPULATION PHARMACOKINETICS; PHARMACODYNAMICS; PENETRATION; PLASMA; CEFTRIAXONE; RESISTANCE; THERAPY; MICE"	"Background: There are only limited data on tissue kinetics of ertapenem in colorectal tissue more than 3 h after administration of the drug. The purpose of this study was to assess the pharmacokinetics (PK) of ertapenem in colorectal tissue via population PK modeling. Patients and Methods: Patients >= 18 years requiring surgical intervention at the colon and/or rectum were eligible (ClinicalTrials.gov identifier: NCT 00535652). Tissue and blood samples were taken during surgery after a single dose of 1 g ertapenem. Ertapenem concentration was determined by high-performance liquid chromatography/mass spectrometry. Population PK modeling was performed in S-ADAPT. Results: Twenty-three patients were enrolled. The highest tissue concentration was 6.4 � 2.3 mg/kg, the highest total plasma concentration 51.34 � 9.4 mg/l, the highest unbound plasma concentration 7.05 � 1.1 mg/l, and the unbound fraction in plasma was 14-15% for total ertapenem concentrations below approximately 22 mg/l, 19% at 100 mg/l, and 25% at 250 mg/l. The estimated geometric mean terminal half-life was 2.5 h for plasma and tissue. In the Monte Carlo simulation, a single dose of 1,000 mg ertapenem achieved robust (>= 90%) probabilities of target attainment up to a minimum inhibitory concentration (MIC) of approximately 2 mg/l for the bacteriostasis target (free time above MIC, fT(> MIC) = 20%) and up to 0.25-0.5 mg/l for the near-maximal killing target (40% fT(> MIC)). Conclusion: Our data indicate an adequate penetration of ertapenem into uninfected colorectal tissue up to 8.5 h (35% of the dosing interval) after administration of 1 g intravenously. Copyright (C) 2011 S. Karger AG, Basel"	"[Wittau, M.; Scheele, J.; Henne-Bruns, D.; Brockschmidt, C.] Univ Ulm, Dept Visceral Surg, DE-89075 Ulm, Germany; [Mayer, B.] Univ Ulm, Dept Biometry, DE-89075 Ulm, Germany; [Kaever, V.; Burhenne, H.] Hannover Med Sch, Inst Pharmacol, D-3000 Hannover, Germany; [Isenmann, R.] St Anna Virngrundklin, Dept Visceral Surg, Ellwangen, Germany; [Bulitta, J. B.] Monash Univ, Ctr Med Use & Safety, Fac Pharm & Pharmaceut Sci, Melbourne, Vic 3004, Australia"	"Wittau, M (corresponding author), Univ Ulm, Dept Visceral Surg, Steinhovelstr 9, DE-89075 Ulm, Germany."	"mathias.wittau@uniklinik-ulm.de"	"Kaever, Volkhard/G-3280-2013; Burhenne, Heike/G-4835-2013; Bulitta, Jurgen B/P-3355-2018"	"Bulitta, Jurgen B/0000-0001-7352-3097"	"University of Ulm, Department of Visceral Surgery; MSD Sharp & Dohme, Haar, Germany"	"This study was supported by the University of Ulm, Department of Visceral Surgery, and in parts by a grant from MSD Sharp & Dohme, Haar, Germany."	40	6	6	0	3	"KARGER"	"BASEL"	"ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND"	"0009-3157"	"1421-9794"	"NA"	"CHEMOTHERAPY"	"Chemotherapy"	"NA"	2011	57	5	437	448	"NA"	"10.1159/000333377"	12	"Oncology; Pharmacology & Pharmacy"	"Oncology; Pharmacology & Pharmacy"	"870HT"	"WOS:000298660700010"	22189340	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Cotte, E; Colomban, O; Guitton, J; Tranchand, B; Bakrin, N; Gilly, FN; Glehen, O; Tod, M"	"Cotte, Eddy; Colomban, Olivier; Guitton, Jerome; Tranchand, Brigitte; Bakrin, Nawel; Gilly, Francois-Noel; Glehen, Olivier; Tod, Michel"	"NA"	"A"	"Population Pharmacokinetics and Pharmacodynamics of Cisplatinum During Hyperthermic Intraperitoneal Chemotherapy Using a Closed Abdominal Procedure"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Cisplatinum; hyperthermic intraperitoneal chemotherapy; population pharmacokinetics; pharmacodynamics; toxicity"	"CYTOREDUCTIVE SURGERY; PERITONEAL CARCINOMATOSIS; MITOMYCIN-C; CYTOTOXICITY; CHEMOHYPERTHERMIA; ENHANCEMENT"	"The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software. Different covariables were analyzed to identify those that explain part of the interindividual variability of the pharmacokinetic parameters. Relationships between the area under the concentration-time curve (AUC) and hematological and renal toxicity and efficiency were explored. The pharmacokinetics of cisplatinum were modeled with a 3-compartment model. Estimations of the plasma and peritoneal pharmacokinetic parameters were obtained. No clinical or biological covariates correlated with these parameters. No direct relationship between the AUC of the peritoneal or plasma and toxicity or efficiency was demonstrated. The pharmacokinetics during HIPEC could be modeled with a 3-compartment model using a population pharmacokinetics approach. This work is the basis of further studies. Notably, studies including new patients will analyze the impact of abdominal cavity volume and the variation of the abdominal pressure during HIPEC on the pharmacokinetics of cisplatinum."	"[Cotte, Eddy] Ctr Hosp Lyon Sud, Serv Chirug Digest Thorac & Endocrinienne, Dept Digest Surg, F-69495 Pierre Benite, France; [Cotte, Eddy; Colomban, Olivier; Guitton, Jerome; Tranchand, Brigitte; Bakrin, Nawel; Gilly, Francois-Noel; Glehen, Olivier; Tod, Michel] Univ Lyon 1, Fac Med Lyon Sud, Oullins, France; [Guitton, Jerome] Ctr Hosp Lyon Sud, Dept Pharmacol, F-69495 Pierre Benite, France; [Tod, Michel] Hop Croix Rousse, F-69317 Lyon, France"	"Cotte, E (corresponding author), Ctr Hosp Lyon Sud, Serv Chirug Digest Thorac & Endocrinienne, Dept Digest Surg, F-69495 Pierre Benite, France."	"eddy.cotte@chu-lyon.fr"	"bakrin, naoual/B-6765-2014; Gilly, Francois Noel FN/C-9450-2014"	"Gilly, Francois Noel FN/0000-0003-3808-6244; Guitton, Jerome/0000-0001-6180-5708; COLOMBAN, OLIVIER/0000-0003-1671-3470; Glehen, Olivier/0000-0002-2802-4974"	"NA"	"NA"	22	24	25	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JAN"	2011	51	1	9	18	"NA"	"10.1177/0091270009360980"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"694ZS"	"WOS:000285341000002"	20173087	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"de Winter, BCM; Mathot, RAA; Sombogaard, F; Neumann, I; van Hest, RM; Doorduijn, JK; van Gelder, T"	"de Winter, Brenda C. M.; Mathot, Ron A. A.; Sombogaard, Ferdi; Neumann, Irmgard; van Hest, Reinier M.; Doorduijn, Jeanette K.; van Gelder, Teun"	"NA"	"A"	"Differences in Clearance of Mycophenolic Acid Among Renal Transplant Recipients, Hematopoietic Stem Cell Transplant Recipients, and Patients With Autoimmune Disease"	"THERAPEUTIC DRUG MONITORING"	"English"	"Article"	"mycophenolic acid; mycophenolate mofetil; pharmacokinetics; clearance; renal transplantation; hematopoietic stem cell transplantation; autoimmune disease; therapeutic drug monitoring"	"POPULATION PHARMACOKINETICS; ACUTE REJECTION; KIDNEY-TRANSPLANTATION; MOFETIL; CYCLOSPORINE; PREVENTION; IMMUNOSUPPRESSION; CYCLOPHOSPHAMIDE; VARIABILITY; STRATEGIES"	"For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients."	"[de Winter, Brenda C. M.; Mathot, Ron A. A.; Sombogaard, Ferdi; van Hest, Reinier M.; van Gelder, Teun] Erasmus Univ, Dept Hosp Pharm, Med Ctr, Clin Pharmacol Unit, NL-3000 CA Rotterdam, Netherlands; [van Gelder, Teun] Erasmus Univ, Dept Internal Med, Med Ctr, Renal Transplant Unit, NL-3000 CA Rotterdam, Netherlands; [Doorduijn, Jeanette K.] Erasmus Univ, Dept Hematol, Med Ctr, NL-3000 CA Rotterdam, Netherlands; [Neumann, Irmgard] Wilhelminenspital Stadt Wien, Dept Nephrol, Vienna, Austria"	"van Gelder, T (corresponding author), Erasmus Univ, Dept Hosp Pharm, Med Ctr, Clin Pharmacol Unit, POB 2040, NL-3000 CA Rotterdam, Netherlands."	"t.vangelder@erasmusmc.nl"	"Sombogaard, Ferdi/AAJ-4225-2020"	"van Hest, Reinier/0000-0002-2506-8795"	"NA"	"NA"	37	19	19	0	2	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0163-4356"	"1536-3694"	"NA"	"THER DRUG MONIT"	"Ther. Drug Monit."	"OCT"	2010	32	5	606	614	"NA"	"10.1097/FTD.0b013e3181efd715"	9	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology"	"653NY"	"WOS:000282099700011"	20720518	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Simon, N; Castinetti, F; Ouliac, F; Lesavre, N; Brue, T; Oliver, C"	"Simon, Nicolas; Castinetti, Frederic; Ouliac, Floriane; Lesavre, Nathalie; Brue, Thierry; Oliver, Charles"	"NA"	"A"	"Pharmacokinetic Evidence for Suboptimal Treatment of Adrenal Insufficiency with Currently Available Hydrocortisone Tablets"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"GLUCOCORTICOID REPLACEMENT THERAPY; MODIFIED-RELEASE HYDROCORTISONE; QUALITY-OF-LIFE; ADDISONS-DISEASE; CORTISOL; DEFICIENCY; AXIS; HYPOPITUITARISM; DEXAMETHASONE; HYPERPLASIA"	"Background and Objective: Adrenal insufficiency is caused by primary adrenal failure or by impairment of the corticotropic axis. In both situations, cortisol secretion is deficient, and hydrocortisone is a logical replacement therapy. However, no consensus guideline for dosing has been published, and clinicians adapt the dose empirically after only a clinical evaluation. Under this regimen, some patients receiving an inappropriately high dose of cortisol feel comfortable and also have an increased risk of adverse effects. We performed a pharmacokinetic study of cortisol in patients with adrenal insufficiency to evaluate plasma concentrations when the dosing was based on clinical examination and to develop a model allowing optimization of drug dosing. Study Design: This was a prospective, open-label study in two endocrinology departments and a clinical investigation centre (Assistance Publique Hopitaux de Marseille, Marseille, France). Methods: Fifty patients with primary (n = 20) or secondary (n = 30) adrenal insufficiency were recruited. All patients were given their usual hydrocortisone replacement regimen. Blood samples for cortisol measurements were drawn at 0600, 0800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 and 0000 h. The observed values were compared with the known physiological range throughout the day (0800, 1600 and 0000 h). A population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling software (NONMEM (R)). The final pharmacokinetic model was then used to simulate several hydrocortisone dosing scenarios. Results: Thirteen different treatment regimens for 50 patients were observed. The cortisol plasma concentrations were compared with the physiological range and showed that 79%, 55% and 45% of patients were over- or under-treated at 0800, 1600 and 2400 h, respectively. The cortisol concentrations showed wide variability and were best described using a one-compartment model with zero-order input and first-order elimination. The pharmacokinetic parameters (intersubject variability) were the following: duration of absorption 0.54 hour, volume of distribution 38.7 L (39.7%) and clearance 12.1 L/h (23.2%). The proportional residual error was 32.3%. This final model was then used to simulate 18 different dosing regimens. The regimen with the highest proportion of simulated patients within the physiological targets was 10  5  5 mg at 0730, 1200 and 1630 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over- or under-treated at 0800, 1600 and 2400 h, respectively. Conclusions: Most patients with adrenal insufficiency are imperfectly treated with hydrocortisone relative to their plasma cortisol concentrations. Using simulation, a standard dosing regimen is suggested, which increases the proportion of patients within the physiological target concentrations. However, an individualized dose adjustment would be more accurate."	"[Simon, Nicolas] Univ Aix Marseille 2, Sch Med, Dept Clin Pharmacol, Marseille, France; [Simon, Nicolas; Castinetti, Frederic; Ouliac, Floriane; Lesavre, Nathalie; Brue, Thierry; Oliver, Charles] Assistance Publ Hop Marseille, Marseille, France; [Castinetti, Frederic; Brue, Thierry; Oliver, Charles] Univ Aix Marseille 2, Timone Hosp, Dept Endocrinol, Marseille, France; [Ouliac, Floriane] Univ Aix Marseille 2, North Hosp, Dept Endocrinol, Marseille, France; [Lesavre, Nathalie] Univ Aix Marseille 2, INSERM 13385, Clin Invest Ctr, Marseille, France"	"Simon, N (corresponding author), Med Sch Marseille, Dept Clin Pharmacol, 27 Bd Jean Moulin, F-13385 Marseille 05, France."	"nicolas.simon@univmed.fr"	"Castinetti, Frederic/AAG-3695-2020; Brue, Thierry/AAI-2328-2019; Brue, Thierry/P-6571-2019; Simon, Nicolas/B-1235-2016"	"Castinetti, Frederic/0000-0002-1808-8800; Brue, Thierry/0000-0001-8482-6691; Brue, Thierry/0000-0001-8482-6691; Simon, Nicolas/0000-0003-4393-2257"	"Assistance Publique Hospitaux de Marseille"	"This work was supported by a grant from Assistance Publique Hospitaux de Marseille. The authors have no conflicts of interest that are directly relevant to the content of this study."	24	48	48	0	8	"ADIS INT LTD"	"AUCKLAND"	"41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND"	"0312-5963"	"NA"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	2010	49	7	455	463	"NA"	"10.2165/11531290-000000000-00000"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"620CY"	"WOS:000279477800004"	20528006	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Fasanmade, AA; Adedokun, OJ; Ford, J; Hernandez, D; Johanns, J; Hu, CP; Davis, HM; Zhou, HH"	"Fasanmade, Adedigbo A.; Adedokun, Omoniyi J.; Ford, Joyce; Hernandez, Danika; Johanns, Jewel; Hu, Chuanpu; Davis, Hugh M.; Zhou, Honghui"	"NA"	"A"	"Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Infliximab; Population pharmacokinetics; Ulcerative colitis; Immunomodulators Albumin"	"RHEUMATOID-ARTHRITIS PATIENTS; INFLAMMATORY-BOWEL-DISEASE; ALPHA MONOCLONAL-ANTIBODY; PLACEBO-CONTROLLED TRIAL; CROHNS-DISEASE; DOUBLE-BLIND; MODEL; IMPROVEMENT; ETANERCEPT; PSORIASIS"	"Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population. Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM. A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value � standard error), based on the final covariate model, were clearance (CL: 0.407 � 0.0103 L/day), apparent volumes of distribution in the central (V-1: 3.29 � 0.0679 L) and peripheral (V-2: 4.13 � 0.16 L) compartments, and intercompartment clearance (Q: 7.14 � 0.489 L/day). Infliximab exhibited interindividual variability for CL and V-1 of 37.7% and 22.1%, respectively. Infliximab t(1/2) is approximately 14 days. Covariate analysis showed that V-1 increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population. The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels."	"[Fasanmade, Adedigbo A.] Centocor Res & Dev Inc, Pharmacokinet Modeling & Simulat, Clin Pharmacol Sci, Malvern, PA 19355 USA"	"Fasanmade, AA (corresponding author), Centocor Res & Dev Inc, Pharmacokinet Modeling & Simulat, Clin Pharmacol Sci, 200 Great Valley Pkwy, Malvern, PA 19355 USA."	"afasanma@its.jnj.com"	"NA"	"NA"	"Centocor R & D Inc., Malvern, PA, USA; Schering Plough Corp., Keniworth, NJ, USA"	"The authors thank the patients, investigators and study personnel who made the ACT studies possible. They also thank Ms. Hong Yan, of Centocor R&D Inc. for assistance in data collation and Mr. James P. Barrett of the Medical Affairs Publication Group, Medical Affairs, Centocor Ortho Biotech, Inc. for writing and editorial support. This study was funded by Centocor R & D Inc., Malvern, PA, USA, and Schering Plough Corp., Keniworth, NJ, USA."	30	202	203	0	5	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"DEC"	2009	65	12	1211	1228	"NA"	"10.1007/s00228-009-0718-4"	18	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"521UH"	"WOS:000271949400007"	19756557	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-01"
"J"	"Savic, R; Lavielle, M"	"Savic, Radojka; Lavielle, Marc"	"NA"	"M"	"Performance in population models for count data, part II: A new SAEM algorithm"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Nonlinear mixed effects model; Count data; Maximum likelihood estimation; Fischer information matrix; SAEM algorithm; MONOLIX"	"NONMEM; PARAMETERS; SOFTWARE"	"Analysis of count data from clinical trials using mixed effect analysis has recently become widely used. However, algorithms available for the parameter estimation, including LAPLACE and Gaussian quadrature (GQ), are associated with certain limitations, including bias in parameter estimates and the long analysis runtime. The stochastic approximation expectation maximization (SAEM) algorithm has proven to be a very efficient and powerful tool in the analysis of continuous data. The aim of this study was to implement and investigate the performance of a new SAEM algorithm for application to count data. A new SAEM algorithm was implemented in MATLAB for estimation of both, parameters and the Fisher information matrix. Stochastic Monte Carlo simulations followed by re-estimation were performed according to scenarios used in previous studies (part I) to investigate properties of alternative algorithms (Plan et al., 2008, Abstr 1372 [http://wwwpage-meetingorg/?abstract=1372]). A single scenario was used to explore six probability distribution models. For parameter estimation, the relative bias was less than 0.92% and 4.13% for fixed and random effects, for all models studied including ones accounting for over- or under-dispersion. Empirical and estimated relative standard errors were similar, with distance between them being < 1.7% for all explored scenarios. The longest CPU time was 95 s for parameter estimation and 56 s for SE estimation. The SAEM algorithm was extended for analysis of count data. It provides accurate estimates of both, parameters and standard errors. The estimation is significantly faster compared to LAPLACE and GQ. The algorithm is implemented in Monolix 3.1, (beta-version available in July 2009)."	"[Savic, Radojka] Univ Paris 07, INSERM, UMR 738, F-75018 Paris, France; [Lavielle, Marc] INRIA Saclay, Math Lab, F-91400 Orsay, France; [Lavielle, Marc] Univ Paris 11, F-91400 Orsay, France"	"Savic, R (corresponding author), Univ Paris 07, INSERM, UMR 738, 16 Rue Henri Huchard, F-75018 Paris, France."	"radojka.savic@inserm.fr; Marc.Lavielle@math.u-psud.fr"	"NA"	"NA"	"Swedish Academy of Pharmaceutical Sciences"	"Radojka Savic was financially supported by a Postdoc grant from the Swedish Academy of Pharmaceutical Sciences (Apotekarsocieteten). We thank Dr. Shasha Jumbe for valuable comments on the manuscript."	19	15	15	0	0	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"NA"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"AUG"	2009	36	4	367	379	"NA"	"10.1007/s10928-009-9127-7"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"484WL"	"WOS:000269079600005"	19680795	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Chhun, S; Jullien, V; Rey, E; Dulac, O; Chiron, C; Pons, G"	"Chhun, Stephanie; Jullien, Vincent; Rey, Elisabeth; Dulac, Olivier; Chiron, Catherine; Pons, Gerard"	"NA"	"A"	"Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy"	"EPILEPSIA"	"English"	"Article"	"Levetiracetam; Children; Dosing recommendation; Population pharmacokinetics; Body weight"	"PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; CLINICAL PHARMACOKINETICS; THERAPY; CARBAMAZEPINE; SEIZURES; INFANTS"	"To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children. LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration-time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults. LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6-20 mg/L target range for the trough concentration. Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations."	"[Chhun, Stephanie; Jullien, Vincent; Rey, Elisabeth; Pons, Gerard] Univ Paris 05, AP HP, Grp Hosp Cochin St Vincent Paul, Serv Pharmacol Clin, F-75674 Paris 14, France; [Chhun, Stephanie; Jullien, Vincent; Rey, Elisabeth; Dulac, Olivier; Chiron, Catherine; Pons, Gerard] INSERM, U663, Paris, France; [Dulac, Olivier; Chiron, Catherine] Univ Paris 05, AP HP, Serv Neuropediat, Hop Necker, F-75674 Paris 14, France"	"Chhun, S (corresponding author), Univ Paris 05, AP HP, Grp Hosp Cochin St Vincent Paul, Serv Pharmacol Clin, 74-82 Ave Denfert Rochereau, F-75674 Paris 14, France."	"stephanie.chhun@svp.aphp.fr"	"Chiron, Catherine/E-8506-2016"	"Chiron, Catherine/0000-0002-9096-1694"	"Fondation Francaise pour la Recherche sur l'Epilepsie (FFRE)"	"The authors are grateful to the Fondation Francaise pour la Recherche sur l'Epilepsie (FFRE) for their financial support and are indebted to the investigators for their precious work throughout the entire study. We confirm that we have read the Journal's position on issues involved in ethical publication and state that this report is consistent with those guidelines.; Disclosure of conflicts interest: Stephanie Chhun was a recipient of a fellowship from the FEdEration Hospitaliere de France and from the Chancellerie des UniversitEs de Paris.; The authors have no conflict interest directly relevant to the content of this study."	23	25	33	0	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0013-9580"	"1528-1167"	"NA"	"EPILEPSIA"	"Epilepsia"	"MAY"	2009	50	5	1150	1157	"NA"	"10.1111/j.1528-1167.2008.01974.x"	8	"Clinical Neurology"	"Neurosciences & Neurology"	"441LG"	"WOS:000265770000024"	19175400	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Chenel, M; Bouzom, F; Cazade, F; Ogungbenro, K; Aarons, L; Mentre, F"	"Chenel, Marylore; Bouzom, Francois; Cazade, Fanny; Ogungbenro, Kayode; Aarons, Leon; Mentre, France"	"NA"	"M"	"Drug-drug interaction predictions with PBPK models and optimal multiresponse sampling time designs: application to midazolam and a phase I compound. Part 2: clinical trial results"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Optimal multiresponse experimental design; Midazolam; Physiologically based pharmacokinetic models; MONOLIX; NONMEM; Drug-drug interaction"	"MIXED-EFFECTS MODELS; PARAMETERS"	"Purpose To compare results of population PK analyses obtained with a full empirical design (FD) and an optimal sparse design (MD) in a Drug-Drug Interaction (DDI) study aiming to evaluate the potential CYP3A4 inhibitory effect of a drug in development, SX, on a reference substrate, midazolam (MDZ). Secondary aim was to evaluate the interaction of SX on MDZ in the in vivo study. Methods To compare designs, real data were analysed by population PK modelling technique using either FD or MD with NONMEM FOCEI for SX and with NONMEM FOCEI and MONOLIX SAEM for MDZ. When applicable a Wald test was performed to compare model parameter estimates, such as apparent clearance (CL/F), across designs. To conclude on the potential interaction of SX on MDZ PK, a Student paired test was applied to compare the individual PK parameters (i.e. log(AUC) and log(C-max)) obtained either by a non-compartmental approach (NCA) using FD or from empirical Bayes estimates (EBE) obtained after fitting the model separately on each treatment group using either FD or MD. Results For SX, whatever the design, CL/F was well estimated and no statistical differences were found between CL/F estimated values obtained with FD (CL/F = 8.2 l/h) and MD (CL/F = 8.2 l/h). For MDZ, only MONOLIX was able to estimate CL/F and to provide its standard error of estimation with MD. With MONOLIX, whatever the design and the administration setting, MDZ CL/F was well estimated and there were no statistical differences between CL/F estimated values obtained with FD (72 l/h and 40 l/h for MDZ alone and for MDZ with SX, respectively) and MD (77 l/h and 45 l/h for MDZ alone and for MDZ with SX, respectively). Whatever the approach, NCA or population PK modelling, and for the latter approach, whatever the design, MD or FD, comparison tests showed that there was a statistical difference (P < 0.0001) between individual MDZ log(AUC) obtained after MDZ administration alone and co-administered with SX. Regarding C-max, there was a statistical difference (P < 0.05) between individual MDZ log(C-max) obtained under the 2 administration settings in all cases, except with the sparse design with MONOLIX. However, the effect on C-max was small. Finally, SX was shown to be a moderate CYP3A4 inhibitor, which at therapeutic doses increased MDZ exposure by a factor of 2 in average and almost did not affect the C-max. Conclusion The optimal sparse design enabled the estimation of CL/F of a CYP3A4 substrate and inhibitor when co-administered together and to show the interaction leading to the same conclusion as the full empirical design."	"[Chenel, Marylore; Cazade, Fanny] Inst Rech Int Servier, F-92415 Courbevoie, France; [Bouzom, Francois] Technol Servier, F-45007 Orleans 1, France; [Ogungbenro, Kayode; Aarons, Leon] Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester M13 9PL, Lancs, England; [Ogungbenro, Kayode; Aarons, Leon] Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England; [Mentre, France] INSERM, U738, Paris, France; [Mentre, France] Univ Paris Diderot, Paris, France"	"Chenel, M (corresponding author), Inst Rech Int Servier, 6 Pl Pleiades, F-92415 Courbevoie, France."	"marylore.chenel@fr.netgrs.com"	"Ogungbenro, Kayode/G-1825-2015"	"Ogungbenro, Kayode/0000-0003-2446-6895"	"CAPKR"	"We would like to acknowledge the Centre for Applied Pharmacokinetic Research (the CAPKR is supported by the following consortium members: Eli Lilly, GlaxoSmithKline, Novartis, Pfizer and Servier)."	22	9	9	0	3	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"DEC"	2008	35	6	661	681	"NA"	"10.1007/s10928-008-9105-5"	21	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"397YX"	"WOS:000262699400004"	19130187	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Semmar, N; Urien, S; Bruguerolle, B; Simon, N"	"Semmar, Nabil; Urien, Saik; Bruguerolle, Bernard; Simon, Nicolas"	"NA"	"M"	"Independent-model diagnostics for a priori identification and interpretation of outliers from a full pharmacokinetic database: correspondence analysis, Mahalanobis distance and Andrews curves"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"outliers; variability analysis; independent-model diagnostics; full pharmacokinetic database; correspondence analysis; Mahalanobis distance; Andrews curves"	"NA"	"Population pharmacokinetic (PK) (or pharmacodynamic (PD)) modelling aims to analyse the variability of drug kinetics (or dynamics) between numerous subjects belonging to a population. Such variability includes inter- and intra-individual sources leading to important differences between the variation ranges, the relative concentrations and the global shapes of PK profiles. These various sources of variability suggest that the distance metrics between the subjects can be examined under different aspects. Some subjects are so distant from the majority that they tend to be atypical or outliers. This paper presents three multivariate statistical methods to diagnose the outliers within a full population PK dataset, prior to any modelling step. Each method combined all the concentration-time variables to analyse the differences between patients by referring to a distance criterion: (a) Correspondence analysis (CA) used the chi-square distance to highlight the most atypical profiles in terms of relative concentrations; (b) Mahalanobis distance was calculated to extract PK profiles showing atypical shapes due to atypical variations in concentration; (c) Andrews method combined all the concentration variables into a Fourier transformation to give sine-cosine curves showing the clustering behaviours of subjects under the Euclidean distance criterion. After identification of outlier subjects, these methods can also be used to extract the concentration values which cause the atypical states of the patients. Therefore, the outliers will incorporate different variability sources of the PK dataset according to each method and independently of any PK modelling. Finally, a significant positive trend was found between the number of times outlier concentrations were detected (by one, two or three diagnostics) and the NPDE metrics of these concentrations (after a PK modelling): NPDE were highest when the corresponding concentration was detected by more diagnostics a priori. The application of a priori outlier diagnostics is illustrated here on two PK datasets: stimulated cortisol by synacthen and capecitabine administrated orally."	"[Semmar, Nabil; Bruguerolle, Bernard; Simon, Nicolas] Med Sch Marseilles, Lab Clin Pharmacol, EA 3784, Marseille, France; [Semmar, Nabil] ISSBAT, Tunis, Tunisia; [Urien, Saik] Ctr Rene Huguenin, Dept Pharmacol, St Cloud, France; [Urien, Saik] INSERM, Paris, France"	"Semmar, N (corresponding author), Med Sch Marseilles, Lab Clin Pharmacol, EA 3784, Marseille, France."	"nabilsemmar@yahoo.fr"	"Simon, Nicolas/B-1235-2016; SEMMAR, Nabil/J-8398-2018; Urien, Saik/G-3240-2013"	"Simon, Nicolas/0000-0003-4393-2257; SEMMAR, Nabil/0000-0002-3296-1557"	"NA"	"NA"	35	2	2	0	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"APR"	2008	35	2	159	183	"NA"	"10.1007/s10928-007-9082-0"	25	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"303BC"	"WOS:000256013500002"	18293065	"NA"	"NA"	"NA"	"2020-10-01"
"J"	"Comets, E; Verstuyft, C; Lavielle, M; Jaillon, P; Becquemont, L; Mentre, F"	"Comets, Emmanuelle; Verstuyft, Celine; Lavielle, Marc; Jaillon, Patrice; Becquemont, Laurent; Mentre, France"	"NA"	"A"	"Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"digoxin; pharmacogenetics; P-glycoprotein; population pharmacokinetics"	"SINGLE-NUCLEOTIDE POLYMORPHISMS; TRANSPLANT RECIPIENTS; MAXIMUM-LIKELIHOOD; EM ALGORITHM; NONMEM; GENE; PHARMACOGENETICS; REGRESSION"	"Objectives: Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the multi-drug-resistance 1 (MDR1) gene coding for P-glycoprotein. Methods: Thirty-two healthy volunteers were recruited in three pharmacokinetic drug interaction studies. The data after a single oral administration of digoxin alone were pooled. All subjects were genotyped for the MDR1 C3435T and G2677T/A genotypes. The concentration-time profile of digoxin was established using 12-16 blood samples taken between 15 min and 72 h after administration. We modelled the pharmacokinetics of digoxin using non-linear mixed-effect models. Parameter estimation was performed using the stochastic approximation EM method (SAEM). We used three methods to select the covariate model: selection from a full model using Wald tests, forward inclusion using the log-likelihood ratio test and model selection using the Bayesian Information Criterion. Results: The three covariate inclusion methods led to the same final model. Carriers of two T alleles for the C3435T polymorphism in exon 26 of MDR1 had a lower apparent volume of distribution than carriers of a C allele. The only other covariate effect was a shorter absorption time-lag in women. Conclusion: The apparent volume of distribution of digoxin is lower in TT subjects, probably reflecting differences in bioavailability. Non-linear mixed-effect models can be useful for detecting the influence of covariates on pharmacokinetic parameters."	"Univ Paris 07, UFR Med, F-75018 Paris, France; INSERM, U738, Paris, France; Hop Bicetre, Fac Med Paris Sud, CIB, APHP, Le Kremlin Bicetre, France; Univ Paris Sud, Fac Med, Dept Pharmacol, F-94275 Le Kremlin Bicetre, France; Univ Paris Sud, Dept Math, Paris, France; Univ Paris 05, IUT, Paris, France; Univ Paris 06, Fac Med Pierre & Marie Curie, Dept Pharmacol, Paris, France; APHP, URC, Fac Med Paris Sud, F-94275 Le Kremlin Bicetre, France; Hop Bichat Claude Bernard, APHP, Dept Epidemiol Biostat & Rech Clin, F-75877 Paris, France; Hop St Antoine, APHP, F-75571 Paris, France"	"Comets, E (corresponding author), Univ Paris 07, UFR Med, Site Bichat,16 Rue Henri Huchard, F-75018 Paris, France."	"emmanuelle.comets@bichat.inserm.fr"	"Comets, Emmanuelle/C-9328-2017"	"NA"	"NA"	"NA"	42	18	20	0	3	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"MAY"	2007	63	5	437	449	"NA"	"10.1007/s00228-007-0269-5"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"153JM"	"WOS:000245428900003"	17404720	"Green Accepted"	"NA"	"NA"	"2020-10-01"
"J"	"Rekic, D; Johansson, S; Leander, J"	"Rekic, Dinko; Johansson, Susanne; Leander, Jacob"	"NA"	"A"	"Higher Febuxostat Exposure Observed in Asian Compared with Caucasian Subjects Independent of Bodyweight"	"CLINICAL PHARMACOKINETICS"	"English"	"Article; Early Access"	"NA"	"XANTHINE-OXIDASE; PHARMACOKINETICS; MODEL; PHARMACODYNAMICS; VERINURAD; INHIBITOR"	"Background and Objective Febuxostat is a xanthine oxidase inhibitor indicated for gout and hyperuricemia. This work investigates potential clinically relevant covariates for febuxostat pharmacokinetics with a special focus on Asian race and bodyweight. Methods Febuxostat plasma concentrations from 141 male subjects were obtained from two phase II studies in patients with hyperuricemia/gout (NCT02246673, NCT02317861) and one study in healthy volunteers (NCT01883167). Subjects were administered febuxostat oral doses from 10 to 80 mg. The pharmacokinetics of febuxostat was analyzed using non-linear mixed-effects modeling as implemented in NONMEM 7.3.0. The dataset consisted of racially diverse subjects, 40% being Japanese, 10% of unknown Asian origin, 39% Caucasian, and 10% Black. Most subjects (n = 92, 63%) had normal creatinine clearance (90 mL/min), while 52 subjects (36%) had mild renal impairment (creatinine clearance > 60 to < 90) at baseline. The effect of disease state, body weight, and creatinine clearance on febuxostat pharmacokinetics was investigated using stepwise covariate modeling. Results Febuxostat pharmacokinetics was well described by a two-compartment disposition model. Asian race was the only covariate resulting in a potentially clinically important increase in febuxostat area under the curve (1.64-fold, 90% confidence interval 1.48-1.79) compared with Caucasian individuals. The difference in body weight between Asian and Caucasian subjects did not explain the difference in febuxostat exposure. Absorption was modeled as a sequential zero- to first-order process with lag-time. Conclusions In this pooled analysis of three studies, we show that Asian individuals have a 1.64-fold higher febuxostat exposure than Caucasians, independent of bodyweight or other investigated covariates. These findings may be of importance when selecting starting febuxostat doses in Asian patients."	"[Rekic, Dinko; Johansson, Susanne; Leander, Jacob] AstraZeneca AB R&D Gothenburg, Clin Pharmacol & Quantitat Pharmacol, Clin Pharmacol & Safety Sci, Pepparedsleden 1, S-43153 Molndal, Sweden"	"Rekic, D (corresponding author), AstraZeneca AB R&D Gothenburg, Clin Pharmacol & Quantitat Pharmacol, Clin Pharmacol & Safety Sci, Pepparedsleden 1, S-43153 Molndal, Sweden."	"Dinko.rekic@astrazeneca.com"	"NA"	"Leander, Jacob/0000-0002-7411-2967"	"AstraZenecaAstraZeneca"	"This work was funded by AstraZeneca."	32	0	0	0	0	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40262-020-00943-6"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NQ8FL"	"WOS:000571103600001"	32951150	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Snelder, N; Hoefman, S; Garcia-Hernandez, A; Onkels, H; Larsson, TE; Bergmann, KR"	"Snelder, Nelleke; Hoefman, Sven; Garcia-Hernandez, Alberto; Onkels, Hartmut; Larsson, Tobias E.; Bergmann, Kirsten R."	"NA"	"A"	"Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article; Early Access"	"VAP-1 inhibition; Albuminuria; Diabetic kidney disease; Population pharmacokinetic modeling"	"BINDING; OXIDASE; VAP-1"	"ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function."	"[Snelder, Nelleke; Hoefman, Sven] LAP&P Consultants BV, Archimedesweg 31, NL-2333 CM Leiden, Netherlands; [Garcia-Hernandez, Alberto; Onkels, Hartmut; Larsson, Tobias E.; Bergmann, Kirsten R.] Astellas Pharma Europe BV, Global Dev, Sylviusweg 62, NL-2333 BE Leiden, Netherlands"	"Snelder, N (corresponding author), LAP&P Consultants BV, Archimedesweg 31, NL-2333 CM Leiden, Netherlands."	"n.snelder@lapp.nl"	"NA"	", Nelleke/0000-0003-1302-678X"	"AstellasAstellas Pharmaceuticals"	"This study was supported by Astellas."	28	0	0	0	0	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s10928-020-09717-w"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NO5UV"	"WOS:000569556800001"	32930923	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Perez-Pitarch, A; Gottipati, G; Uppoor, R; Mehta, M; Sabarinath, S"	"Perez-Pitarch, Alejandro; Gottipati, Gopichand; Uppoor, Ramana; Mehta, Mehul; Sabarinath, Sreedharan"	"NA"	"A"	"An Innovative Pharmacometric Approach for the Simultaneous Analysis of Frequency, Duration and Severity of Migraine Events"	"PHARMACEUTICAL RESEARCH"	"English"	"Article"	"Time-to-event; ordered categorical; Markov model; migraine prevention; NONMEM"	"MODEL"	"Purpose To explore the use of a multistate repeated, time-to-categorical event model describing the frequency, severity and duration of migraines. Methods Subject level data from patients in placebo arms from two efficacy trials for migraine-preventive treatments were used. Models were developed using NONMEM 7.3. A survival model was combined with an ordered categorical model to form the repeated-time-to-start of categorical migraine event model, which simultaneously described the time-to-start of migraines and the severity of the starting migraine event. This was linked to a repeated-time-to-end of migraine event model with different hazard functions depending on the severity of the ongoing migraine event. Model performance was internally and externally qualified. Results The successfully qualified model showed that patients responding to placebo had a reduction in migraine incidence rate, and a decreased proportion of severe migraines. There was an increase in moderate migraine duration, an increased proportion of mild migraines and a reduction in proportion of severe migraines. Age was related to migraine duration. Conclusions The model represents an innovative framework for clinical trial modeling and simulation, and successfully describes placebo effect in migraine prevention. This approach can be adapted to investigate exposure-response relationship of drugs and can also be implemented in other therapeutic areas where the rate, duration and severity of disease episodes are relevant to trial outcomes."	"[Perez-Pitarch, Alejandro; Gottipati, Gopichand; Uppoor, Ramana; Mehta, Mehul; Sabarinath, Sreedharan] US FDA, Div Neuropsychiat Pharmacol, Off Clin Pharmacol, 10903 New Hampshire Ave,White Oak Bldg 51,RM 2116, Silver Spring, MD 20993 USA"	"Sabarinath, S (corresponding author), US FDA, Div Neuropsychiat Pharmacol, Off Clin Pharmacol, 10903 New Hampshire Ave,White Oak Bldg 51,RM 2116, Silver Spring, MD 20993 USA."	"Sreedharan.Sabarinath@fda.hhs.gov"	"NA"	"NA"	"NA"	"NA"	29	0	0	0	0	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"0724-8741"	"1573-904X"	"NA"	"PHARM RES-DORDR"	"Pharm. Res."	"SEP 7"	2020	37	10	"NA"	"NA"	189	"10.1007/s11095-020-02907-8"	10	"Chemistry, Multidisciplinary; Pharmacology & Pharmacy"	"Chemistry; Pharmacology & Pharmacy"	"NQ5YC"	"WOS:000570944400001"	32895855	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Kittrell, HC; Mochel, JP; Brown, JT; Forseth, AMK; Hayman, KP; Rajewski, SM; Coetzee, JF; Schneider, BK; Ratliffe, B; Skoland, KJ; Karriker, LA"	"Kittrell, Heather C.; Mochel, Jonathan P.; Brown, Justin T.; Forseth, Anna Marie K.; Hayman, Kristen P.; Rajewski, Suzanne M.; Coetzee, Johann F.; Schneider, Benjamin K.; Ratliffe, Brette; Skoland, Kristin J.; Karriker, Locke A."	"NA"	"A"	"Pharmacokinetics of Intravenous, Intramuscular, Oral, and Transdermal Administration of Flunixin Meglumine in Pre-wean Piglets"	"FRONTIERS IN VETERINARY SCIENCE"	"English"	"Article"	"swine; non-steroidal anti-inflammatory; flunixin meglumine; pain; topical; NLME"	"INHIBITION; BIOAVAILABILITY; PARAMETER; MODEL"	"Castration and tail-docking of pre-wean piglets are common procedures that are known to induce pain and would benefit from pain mitigation. Flunixin meglumine (FM) is a non-steroidal anti-inflammatory drug currently approved in the United States for pyrexia in swine and lameness pain in cattle. The objective of this study was to establish the pharmacokinetic (PK) parameters resulting from intravenous (IV), intramuscular (IM), oral (PO) and transdermal (TD) administration of FM in pre-wean piglets. FM was administered to thirty-nine pre-wean piglets at a target dose of 2.2 mg/kg for IV and IM and 3.3 mg/kg for PO and TD route. Plasma was collected at twenty-seven time points from 0 to 9 days after FM administration and concentrations were determined using ultra-high performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Pharmacokinetic data were analyzed using noncompartmental analysis (NCA) methods and nonlinear mixed-effects (NLME). Initial plasma concentration for IV (C-0) 11,653 mu g/L and mean peak plasma concentrations (C-max) 6,543 mu g/L (IM), 4,883 mu g/L (PO), and 31.5 mu g/L (TD) were measured. The time points of peak FM concentrations (t(max)) were estimated 30 min, 1 h, and 24 h for IM, PO, and TD, respectively. The bioavailability (F) of PO and IM FM was estimated at >99%, while the bioavailability of TD FM was estimated to be 7.8%. The reported C(max)of FM after IM and PO administration is consistent with therapeutic concentration ranges that mitigate pain in other species and adult pigs. However, the low estimated concentration of FM after TD dosing is not expected to mitigate pain in pre-wean piglets. The lowFof TD FM suggests that expanding the surface area of application is unlikely to be sufficient to establish an effective TD dose for pain, while the high bioavailability for PO FM should allow for an effective dose regimen to be established."	"[Kittrell, Heather C.; Brown, Justin T.; Hayman, Kristen P.; Ratliffe, Brette; Skoland, Kristin J.; Karriker, Locke A.] Iowa State Univ, Coll Vet Med, Swine Med Educ Ctr, Ames, IA 50011 USA; [Mochel, Jonathan P.; Schneider, Benjamin K.] Iowa State Univ, SMART Pharmacol, Dept Biomed Sci, Coll Vet Med, Ames, IA USA; [Forseth, Anna Marie K.] Montana Dept Livestock, Div Anim Hlth, Helena, MT USA; [Rajewski, Suzanne M.] Iowa State Univ, Coll Vet Med, Analyt Chem Serv, Ames, IA USA; [Coetzee, Johann F.] Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, Manhattan, KS 66506 USA"	"Karriker, LA (corresponding author), Iowa State Univ, Coll Vet Med, Swine Med Educ Ctr, Ames, IA 50011 USA."	"karriker@iastate.edu"	"NA"	"NA"	"National Pork Board Project [17-082]"	"This work was supported by National Pork Board Project #17-082."	40	0	0	0	0	"FRONTIERS MEDIA SA"	"LAUSANNE"	"AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND"	"NA"	"2297-1769"	"NA"	"FRONT VET SCI"	"Front. Vet. Sci."	"AUG 28"	2020	7	"NA"	"NA"	"NA"	586	"10.3389/fvets.2020.00586"	13	"Veterinary Sciences"	"Veterinary Sciences"	"NP9EY"	"WOS:000570474500001"	"NA"	"DOAJ Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Gupta, N; Wang, XH; Offman, E; Prohn, M; Narasimhan, N; Kerstein, D; Hanley, MJ; Venkatakrishnan, K"	"Gupta, Neeraj; Wang, Xiaohui; Offman, Elliot; Prohn, Marita; Narasimhan, Narayana; Kerstein, David; Hanley, Michael J.; Venkatakrishnan, Karthik"	"NA"	"A"	"Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer"	"CLINICAL PHARMACOKINETICS"	"English"	"Article; Early Access"	"NA"	"MODEL; INHIBITOR; RESISTANCE; AP26113; POTENT; DRUGS"	"Background and objectives Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. Methods Plasma concentration-time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). Results Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. Conclusions Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib."	"[Gupta, Neeraj; Hanley, Michael J.; Venkatakrishnan, Karthik] Millennium Pharmaceut Inc, Quantitat Clin Pharmacol, 40 Landsdowne St, Cambridge, MA 02139 USA; [Wang, Xiaohui; Offman, Elliot] Certara, Princeton, NJ USA; [Prohn, Marita] qPharmetra, Nijmegen, Netherlands; [Narasimhan, Narayana; Kerstein, David] ARIAD Pharmaceut Inc, Cambridge, MA 02139 USA; [Narasimhan, Narayana] Verastem Oncol, Needham, MA USA; [Kerstein, David] Anchiano Therapeut, Cambridge, MA USA; [Venkatakrishnan, Karthik] EMD Serono Res & Dev Inst, Billerica, MA USA"	"Gupta, N (corresponding author), Millennium Pharmaceut Inc, Quantitat Clin Pharmacol, 40 Landsdowne St, Cambridge, MA 02139 USA."	"Neeraj.Gupta@takeda.com"	"NA"	"NA"	"ARIAD Pharmaceuticals, Inc."	"The authors thank the patients, their families, and their caregivers; the study investigators and their team members at each study site; and colleagues from Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA and funded by ARIAD Pharmaceuticals, Inc."	32	0	0	1	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40262-020-00929-4"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NC5NI"	"WOS:000561261400001"	32816246	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Adjei, AL; Chaudhary, I; Kollins, SH; Padilla, A"	"Adjei, Akwete L.; Chaudhary, Inder; Kollins, Scott H.; Padilla, Americo"	"NA"	"A"	"A Pharmacokinetic Study of Methylphenidate Hydrochloride Multilayer Extended-Release Capsules (Aptensio XR(R)) in Preschool-Aged Children with Attention-Deficit/Hyperactivity Disorder"	"PEDIATRIC DRUGS"	"English"	"Article; Early Access"	"NA"	"DEFICIT-HYPERACTIVITY DISORDER; MULTIPLE-LAYER BEADS; ADHD TREATMENT; EFFICACY; FORMULATIONS; DIAGNOSIS; TABLETS; SAFETY"	"Objective This was a single-dose, one-period, multicenter, pharmacokinetic (PK) study to evaluate the PK of methylphenidate (MPH) hydrochloride multilayer extended-release capsules (MPH-MLR) in preschool children aged 4 to < 6 years, previously diagnosed with attention-deficit/hyperactivity disorder (ADHD), and on a stable dose of MPH. Methods Preschool-aged children (N = 10) received a single oral dose of MPH-MLR (10, 15, or 20 mg) sprinkled over applesauce; a dose equivalent to their pre-enrollment daily dose of MPH. Blood samples for the measurement of MPH concentrations were obtained pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-dose. No structural model was assumed in the derivation of PK values for analysis. Maximum plasma concentration (C-max), area under the concentration-time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (V-d) data were compared with a historical group of older children aged 6-11 years (N = 11) and analyzed by bodyweight. Safety (adverse event monitoring, vital signs, electrocardiogram, clinical laboratory testing, physical examination) was assessed. Results Mean dose-normalizedC(max)and area under the curve to the last measurable observation (AUC(0-t)) values were similar across dose groups, ranging from 0.67 ng/mL/mg (MPH 15 mg) to 0.81 ng/mL/mg (MPH 10 mg) forC(max)/dose, and from 7.80 h x ng/mL/mg (MPH 20 mg) to 8.92 h x ng/mL/mg (MPH 10 mg) for AUC(0-t)/dose. PK results were integrated into a previously described pharmacostatistical population PK model. Visual predictive check plots showed greater variability in the 6- to 11-year-old group than the 4- to < 6-year-old group, and CL increased with increasing body weight in a greater than dose-proportional manner. Mean CL, normalized for body weight, was constant for all dose groups, ranging from 4.88 L/h/kg to 5.80 L/h/kg. Median time toC(max)ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalizedC(max)concentrations indicated greater systemic exposures of MPH-MLR in preschool children aged 4 to < 6 years compared with children aged 6-11 years. Children aged 4 to < 6 years had a lowerV(d)than children aged 6-11 years. There were no unexpected safety signals. Conclusion The PK of MPH-MLR in preschool children demonstrated the biphasic absorption profile described earlier in older children, and the PK profile in children with ADHD aged 4 to < 6 years was similar to the profile in those aged 6-11 years, apart from a lowerV(d)and relatively higher systemic MPH levels for children in the preschool group."	"[Adjei, Akwete L.; Chaudhary, Inder] Rhodes Pharmaceut LP, 498 Washington St, Coventry, RI 02816 USA; [Kollins, Scott H.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA; [Padilla, Americo] Nicklaus Childrens Hosp, Dept Pediat Psychiat, Miami, FL USA"	"Adjei, AL (corresponding author), Rhodes Pharmaceut LP, 498 Washington St, Coventry, RI 02816 USA."	"akwete.adjei@rhodespharma.com"	"NA"	"Adjei, Akwete L./0000-0001-5772-7866; Kollins, Scott/0000-0001-6847-6935"	"Rhodes Pharmaceuticals L.P."	"This study was funded by Rhodes Pharmaceuticals L.P."	25	0	0	0	0	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"1174-5878"	"1179-2019"	"NA"	"PEDIATR DRUGS"	"Pediatr. Drugs"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40272-020-00409-z"	10	"Pediatrics; Pharmacology & Pharmacy"	"Pediatrics; Pharmacology & Pharmacy"	"MX4YL"	"WOS:000557730100001"	32776159	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Tangden, T; Lundberg, CV; Friberg, LE; Huttner, A"	"Tangden, Thomas; Lundberg, Carina Vingsbo; Friberg, Lena E.; Huttner, Angela"	"NA"	"M"	"How preclinical infection models help define antibiotic doses in the clinic"	"INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS"	"English"	"Article"	"Antibiotics; Pharmacokinetics/pharmacodynamics; In vitro models; Animal infection models; Mathematical modeling"	"CRITICALLY-ILL PATIENTS; POLYMYXIN DERIVATIVES; PHARMACODYNAMICS; PHARMACOKINETICS; RESISTANCE; KILL; CLEARANCE; IMPACT; MICE"	"Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes. (C) 2020 The Authors. Published by Elsevier B.V."	"[Tangden, Thomas] Uppsala Univ, Dept Med Sci, Uppsala, Sweden; [Lundberg, Carina Vingsbo] Statens Serum Inst, Dept Bacteria Parasites & Fungi, Copenhagen, Denmark; [Friberg, Lena E.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Huttner, Angela] Geneva Univ Hosp, Div Infect Dis, Geneva, Switzerland"	"Tangden, T (corresponding author), Uppsala Univ Hosp, Dept Infect Dis, Entr 34, SE-75185 Uppsala, Sweden."	"thomas.tangden@medsci.uu.se"	"NA"	"Friberg, Lena/0000-0002-2979-679X"	"Swedish Research CouncilSwedish Research Council [2019-05911, 2018-03296]"	"This work was supported by the Swedish Research Council grant no. 2019-05911 (TT) and 2018-03296 (LF)."	36	0	0	0	0	"ELSEVIER"	"AMSTERDAM"	"RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS"	"0924-8579"	"1872-7913"	"NA"	"INT J ANTIMICROB AG"	"Int. J. Antimicrob. Agents"	"AUG"	2020	56	2	"NA"	"NA"	106008	"10.1016/j.ijantimicag.2020.106008"	5	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"MU2XY"	"WOS:000555538400004"	32389722	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Esdonk, MJ; Burggraaf, J; van der Graaf, PH; Stevens, J"	"Esdonk, Michiel J.; Burggraaf, Jacobus; van der Graaf, Piet H.; Stevens, Jasper"	"NA"	"A"	"Model informed quantification of the feed-forward stimulation of growth hormone by growth hormone-releasing hormone"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"GH; Growth hormone; growth hormone-releasing hormone; kinetics; NLME model; stimulation test"	"BODY-FAT DISTRIBUTION; SECRETION; PLASMA; SOMATOSTATIN; CONSTRUCT; VOLUME; AXIS"	"Aims Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH-releasing hormone (GHRH). Methods Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 mu g recombinant human GH dose. The next day, a bolus injection of 100 mu g GHRH was given to stimulate GH secretion. Results The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60-kg subject to 32.1 L/h for a 100-kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%). Conclusion The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans."	"[Esdonk, Michiel J.; Burggraaf, Jacobus; van der Graaf, Piet H.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Esdonk, Michiel J.; Burggraaf, Jacobus] Ctr Human Drug Res, Leiden, Netherlands; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England; [Stevens, Jasper] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands"	"Burggraaf, J (corresponding author), Zernikedreef 8, NL-2333 CL Leiden, Netherlands."	"kb@chdr.nl"	"Stevens, Jasper/G-6118-2017"	"Stevens, Jasper/0000-0003-1601-9008"	"NA"	"NA"	41	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"AUG"	2020	86	8	1575	1584	"NA"	"10.1111/bcp.14265"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MN1CD"	"WOS:000550583000014"	32087619	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Betts, A; Clark, T; Jasper, P; Tolsma, J; van der Graaf, PH; Graziani, EI; Rosfjord, E; Sung, M; Ma, DS; Barletta, F"	"Betts, Alison; Clark, Tracey; Jasper, Paul; Tolsma, John; van der Graaf, Piet H.; Graziani, Edmund, I; Rosfjord, Edward; Sung, Matthew; Ma, Dangshe; Barletta, Frank"	"NA"	"A"	"Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"HER2; Antibody drug conjugate; Translational modeling; Tumor static concentration; Pharmacokinetics; PK; PD; Oncology"	"ANTIBODY-DRUG CONJUGATE; EMTANSINE T-DM1; BREAST-CANCER; PHARMACOKINETIC MODEL; SERUM HER-2/NEU; RESISTANCE; DISPOSITION; MECHANISMS; DISCOVERY; EFFICACY"	"A modeling and simulation approach was used for quantitative comparison of a new generation HER2 antibody drug conjugate (ADC, PF-06804103) with trastuzumab-DM1 (T-DM1). To compare preclinical efficacy, the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of PF-06804103 and T-DM1 was determined across a range of mouse tumor xenograft models, using a tumor growth inhibition model. The tumor static concentration was assigned as the minimal efficacious concentration. PF-06804103 was concluded to be more potent than T-DM1 across cell lines studied. TSCs ranged from 1.0 to 9.8 mu g/mL (n = 7) for PF-06804103 and from 4.7 to 29 mu g/mL (n = 5) for T-DM1. Two experimental models which were resistant to T-DM1, responded to PF-06804103 treatment. A mechanism-based target mediated drug disposition (TMDD) model was used to predict the human PK of PF-06804103. This model was constructed and validated based on T-DM1 which has non-linear PK at doses administered in the clinic, driven by binding to shed HER2. Non-linear PK is predicted for PF-06804103 in the clinic and is dependent upon circulating HER2 extracellular domain (ECD) concentrations. The models were translated to human and suggested greater efficacy for PF-06804103 compared to T-DM1. In conclusion, a fit-for-purpose translational PK/PD strategy for ADCs is presented and used to compare a new generation HER2 ADC with T-DM1."	"[Betts, Alison] Pfizer Inc, Dept Biomed Design, 610 Main St, Cambridge, MA 02139 USA; [Clark, Tracey] Pfizer Inc, Worldwide Res Procurement, Eastern Point Rd, Groton, CT 06340 USA; [Jasper, Paul; Tolsma, John] RES Grp Inc, 75 Second Ave, Needham, MA 02494 USA; [Betts, Alison; van der Graaf, Piet H.] Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, NL-2300 RA Leiden, Netherlands; [Graziani, Edmund, I] Apertor Labs Inc, 828 Contra Costa Ave, Berkeley, CA 94707 USA; [Rosfjord, Edward; Sung, Matthew; Barletta, Frank] Pfizer Inc, Oncol Res & Dev, 401 N Middletown Rd, Pearl River, NY 10965 USA; [Ma, Dangshe] Regeneron, Dept Therapeut Prot, Tarrytown, NY 10591 USA; [Betts, Alison] Appl Biomath, 561 Virginia Rd,Suite 220, Concord, MA 01742 USA; [Barletta, Frank] Design Pfizer Inc, Dept Biomed, Pearl River, NY 10965 USA"	"Betts, A (corresponding author), Pfizer Inc, Dept Biomed Design, 610 Main St, Cambridge, MA 02139 USA.; Betts, A (corresponding author), Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, NL-2300 RA Leiden, Netherlands.; Barletta, F (corresponding author), Pfizer Inc, Oncol Res & Dev, 401 N Middletown Rd, Pearl River, NY 10965 USA.; Betts, A (corresponding author), Appl Biomath, 561 Virginia Rd,Suite 220, Concord, MA 01742 USA.; Barletta, F (corresponding author), Design Pfizer Inc, Dept Biomed, Pearl River, NY 10965 USA."	"alison.betts@appliedbiomath.com; frank.barletta@pfizer.com"	"NA"	"NA"	"NA"	"NA"	44	0	0	0	0	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"OCT"	2020	47	5	513	526	"NA"	"10.1007/s10928-020-09702-3"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"NT4KC"	"WOS:000552174200002"	32710210	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Sanchez-Hernandez, JG; Perez-Blanco, JS; Rebollo, N; Munoz, F; Prieto, V; Calvo, MV"	"German Sanchez-Hernandez, Jose; Samuel Perez-Blanco, Jonas; Rebollo, Noemi; Munoz, Fernando; Prieto, Vanessa; Victoria Calvo, Maria"	"NA"	"A"	"Biomarkers of disease activity and other factors as predictors of adalimumab pharmacokinetics in inflammatory bowel disease"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"NA"	"CROHNS-DISEASE; FECAL CALPROTECTIN; ENDOSCOPIC ACTIVITY; ANTIBODIES; COHORT; IMMUNOGLOBULIN; INFLIXIMAB; CONSENSUS; SCORE"	"NA"	"[German Sanchez-Hernandez, Jose; Rebollo, Noemi; Victoria Calvo, Maria] Univ Hosp Salamanca, Pharm Serv, Paseo San Vicente 58-182, Salamanca 37007, Spain; [German Sanchez-Hernandez, Jose; Samuel Perez-Blanco, Jonas; Rebollo, Noemi; Victoria Calvo, Maria] Univ Salamanca, Fac Pharm, Dept Pharmaceut Sci, Salamanca, Spain; [German Sanchez-Hernandez, Jose; Samuel Perez-Blanco, Jonas; Rebollo, Noemi; Munoz, Fernando; Prieto, Vanessa; Victoria Calvo, Maria] Biomed Res Inst Salamanca IBSAL, Salamanca, Spain; [Munoz, Fernando; Prieto, Vanessa] Univ Hosp Salamanca, Gastroenterol Serv, Salamanca, Spain"	"Sanchez-Hernandez, JG (corresponding author), Univ Hosp Salamanca, Pharm Serv, Paseo San Vicente 58-182, Salamanca 37007, Spain."	"jgermansanchez@saludcastillayleon.es"	"NA"	"Perez-Blanco, Jonas Samuel/0000-0002-1232-1763"	"NA"	"NA"	53	0	0	4	4	"ELSEVIER"	"AMSTERDAM"	"RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"JUL 1"	2020	150	"NA"	"NA"	"NA"	105369	"10.1016/j.ejps.2020.105369"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LZ8GT"	"WOS:000541459800003"	32416256	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Wang, Y; Marier, JF; Lavigne, J; Kassir, N; Martin, P"	"Wang, Yi; Marier, Jean-Francois; Lavigne, Jean; Kassir, Nastya; Martin, Patrick"	"NA"	"A"	"Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), in Patients With Ulcerative Colitis or Crohn's Disease"	"JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Crohn's disease; ulcerative colitis; pharmacokinetics; pharmacodynamics; ontamalimab; MAdCAM-1"	"PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PF-00547659; NATALIZUMAB; BINDING; MODEL"	"Ontamalimab (SHP647) is a fully human, immunoglobulin G(2), antihuman mucosal addressin cell adhesion molecule-1 (MAdCAM-1) monoclonal antibody being developed for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). A population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted using clinical phase 2 study data to evaluate the PK and PD of ontamalimab following subcutaneous administrations of 7.5, 22.5, 75, and 225 mg every 4 weeks in patients with moderate to severe UC or CD. A total of 440 patients with UC (n = 249; 56.6%) or CD (n = 191; 43.4%) were included in the analysis. A 2-compartment model with parallel linear and nonlinear elimination adequately characterized concentration-time profiles of ontamalimab. The apparent clearance and volume of distribution were 0.0127 L/h (0.305 L/day) and 6.53 L, respectively. Apparent clearance and volume of distribution were mainly dependent on baseline albumin and body weight, respectively. No differences in the PK properties of ontamalimab were observed between patients with UC or CD. The presence of antidrug antibodies did not impact the PK of ontamalimab. Nonlinear elimination occurred at very low concentrations and was unlikely to contribute to the elimination half-life under steady-state conditions. A linear PK/PD model described the relationship between ontamalimab and free MAdCAM-1. Minimum concentrations of ontamalimab at steady state following 75 mg every 4 weeks were associated with >95% suppression of circulating free MAdCAM-1. The PK/PD properties characterized support phase 3 testing in UC and CD."	"[Wang, Yi; Martin, Patrick] Shire, Cambridge, MA USA; [Marier, Jean-Francois; Lavigne, Jean; Kassir, Nastya] Certara Strateg Consulting, Princeton, NJ USA; [Marier, Jean-Francois; Kassir, Nastya] Amer Coll Clin Pharmacol FCP, Ashburn, VA USA"	"Wang, Y (corresponding author), Shire, Global Clin Pharmacol & Pharmacokinet, 650 East Kendall St, Cambridge, MA 02142 USA."	"yi.wang1@takeda.com"	"NA"	"Marier, Jean Francois/0000-0001-9820-5116"	"Shire Human Genetic Therapies Inc., a member of the Takeda group of companies Funding Source: Medline; Shire International GmbH, a member of the Takeda group of companies Funding Source: Medline"	"NA"	19	0	0	0	2	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0091-2700"	"1552-4604"	"NA"	"J CLIN PHARMACOL"	"J. Clin. Pharmacol."	"JUL"	2020	60	7	903	914	"NA"	"10.1002/jcph.1590"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LZ4CF"	"WOS:000541173700012"	32119128	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Xie, FF; Li, SW; Cheng, ZN"	"Xie, Feifan; Li, Sanwang; Cheng, Zeneng"	"NA"	"A"	"Population pharmacokinetics and dosing considerations of daptomycin in critically ill patients undergoing continuous renal replacement therapy"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"BACTEREMIA; PHARMACODYNAMICS; DELIVERY; MODEL"	"Objectives: The dosing regimen of daptomycin for critically ill patients undergoing continuous renal replacement therapy (CRRT) remains controversial. The goal of this study was to provide guidance for optimal daptomycin therapy in CRRT patients with Staphylococcus aureus infections. Methods: Individual concentration data of 32 CRRT subjects pooled frompreviously published studies were used to construct the population pharmacokinetic model for daptomycin. Model-based simulations were performed to evaluate the efficacy and risk of toxicity for daptomycin doses of 4, 6 and 8 mg/kg, q24h or q48h, under CRRT doses of 25, 30 and 35 mL/h/kg. Efficacy was assessed by the bacteriostatic and bactericidal AUC/MIC targets and drug exposure-based efficacy references. Toxicity was estimated by safety exposure references and the trough concentration threshold. Results: A two-compartment model adequately described the pharmacokinetics of daptomycin. Efficacy analysis demonstrated that q48h dosing is associated with an extremely low probability of bactericidal target attainment on every second day after dosing and q24h dosing is preferred for a high probability of bactericidal target attainment. Toxicity evaluation showed that 8 mg/kg q24h has a high probability for reaching the toxicity-related concentration threshold, while 6 mg/kg q24h gives a satisfactory risk-benefit balance. The studied CRRT doses had a limited impact on efficacy and a CRRT dose of 30-35 mL/h/kg may lower the risk of toxicity. Conclusions: The model predicted that the combination of 6 mg/kg q24h daptomycin dose and CRRT dose of 30-35 mL/h/kg would achieve the best balance of efficacy and safety."	"[Xie, Feifan; Cheng, Zeneng] Cent South Univ, Xiangya Sch Pharmaceut Sci, Div Biopharmaceut & Pharmacokinet, Changsha, Peoples R China; [Li, Sanwang] Hunan Normal Univ, Med Coll, Dept Pharm, Changsha, Peoples R China"	"Xie, FF (corresponding author), Cent South Univ, Xiangya Sch Pharmaceut Sci, Div Biopharmaceut & Pharmacokinet, Changsha, Peoples R China."	"feifan.xie@csu.edu.cn"	"NA"	"NA"	"NA"	"NA"	33	0	0	0	0	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JUN"	2020	75	6	1559	1566	"NA"	"10.1093/jac/dkaa028"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"NL1LR"	"WOS:000567185800029"	32083673	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Ashraf, MW; Uusalo, P; Scheinin, M; Saari, TI"	"Ashraf, Muhammad W.; Uusalo, Panu; Scheinin, Mika; Saari, Teijo, I"	"NA"	"A"	"Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration"	"CLINICAL PHARMACOKINETICS"	"English"	"Article; Early Access"	"NA"	"PERIPHERAL VASOCONSTRICTION; SEDATION; AGONIST; HUMANS"	"Background and Objective Dexmedetomidine is a potent agonist of alpha(2)-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing. Methods Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 mu g/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion. Results The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals. Conclusions Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. ClinicalTrials.org NCT02724098 and EudraCT 2015-004698-34"	"[Ashraf, Muhammad W.; Uusalo, Panu; Saari, Teijo, I] Univ Turku, Dept Anaesthesiol & Intens Care, Kiinamyllynkatu 4-8,11A5,POB 52, Turku 20521, Finland; [Uusalo, Panu; Saari, Teijo, I] Turku Univ Hosp, Div Perioperat Serv Intens Care & Pain Med, Turku, Finland; [Scheinin, Mika] Univ Turku, Inst Biomed, Turku, Finland; [Scheinin, Mika] Turku Univ Hosp, Unit Clin Pharmacol, Turku, Finland"	"Saari, TI (corresponding author), Univ Turku, Dept Anaesthesiol & Intens Care, Kiinamyllynkatu 4-8,11A5,POB 52, Turku 20521, Finland.; Saari, TI (corresponding author), Turku Univ Hosp, Div Perioperat Serv Intens Care & Pain Med, Turku, Finland."	"teisaa@utu.fi"	"NA"	"Ashraf, Muhammad Waqar/0000-0002-9947-1579; Scheinin, Mika/0000-0001-7579-9126; Uusalo, Panu/0000-0001-5120-8854"	"Turku University Foundation; University of Turku Graduate School (University of Turku Drug Research Doctoral Program); Hospital District of South-West Finland, Finland [13821]"	"MWA was supported by a grant from Turku University Foundation, and personal research funding from the University of Turku Graduate School (University of Turku Drug Research Doctoral Program). TIS was supported by a governmental research Grant number 13821 from the Hospital District of South-West Finland, Finland."	39	0	0	1	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1007/s40262-020-00900-3"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MY8JM"	"WOS:000558662900001"	32462542	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Van Wijk, RC; van der Sar, AM; Krekels, EHJ; Verboom, T; Spaink, HP; Simonsson, USH; van der Graaf, PH"	"Van Wijk, Rob C.; van der Sar, Astrid M.; Krekels, Elke H. J.; Verboom, Theo; Spaink, Herman P.; Simonsson, Ulrika S. H.; van der Graaf, Piet H."	"NA"	"A"	"Quantification of Natural Growth of Two Strains of Mycobacterium Marinum for Translational Antituberculosis Drug Development"	"CTS-CLINICAL AND TRANSLATIONAL SCIENCE"	"English"	"Article; Early Access"	"NA"	"TUBERCULOSIS PHARMACOMETRIC MODEL; MULTISTATE TUBERCULOSIS; PATHOGENESIS"	"The zebrafish infected with Mycobacterium marinum (M. marinum) is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis (M. tuberculosis) infections in humans. To translate pharmacological findings from this disease model to higher vertebrates, a quantitative understanding of the natural growth of M. marinum in comparison to the natural growth of M. tuberculosis is essential. Here, the natural growth of two strains of M. marinum, E11 and M-USA, is studied over an extended period using an established model-based approach, the multistate tuberculosis pharmacometric (MTP) model, for comparison to that of M. tuberculosis. Poikilotherm-derived strain E11 and human-derived strain M-USA were grown undisturbed up to 221 days and viability of cultures (colony forming unit (CFU)/mL) was determined by plating at different time points. Nonlinear mixed effects modeling using the MTP model quantified the bacterial growth, the transfer among fast, slow, and non-multiplying states, and the inoculi. Both strains showed initial logistic growth, reaching a maximum after 20-25 days for E11 and M-USA, respectively, followed by a decrease to a new plateau. Natural growth of both E11 and M-USA was best described with Gompertz growth functions. For E11, the inoculum was best described in the slow-multiplying state, for M-USA in the fast-multiplying state. Natural growth of E11 was most similar to that of M. tuberculosis, whereas M-USA showed more aggressive growth behavior. Characterization of natural growth of M. marinum and quantitative comparison with M. tuberculosis brings the zebrafish tuberculosis disease model closer to the quantitative translational pipeline of antituberculosis drug development."	"[Van Wijk, Rob C.; Krekels, Elke H. J.; van der Graaf, Piet H.] Leiden Univ, Leiden Acad Ctr Drug Res, Syst Biomed & Pharmacol, Leiden, Netherlands; [van der Sar, Astrid M.; Verboom, Theo] Vrije Univ Amsterdam Med Ctr, Dept Med Microbiol & Infect Control, Amsterdam, Netherlands; [Spaink, Herman P.] Leiden Univ, Inst Biol Leiden, Div Anim Sci & Hlth, Leiden, Netherlands; [Simonsson, Ulrika S. H.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England"	"van der Graaf, PH (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Syst Biomed & Pharmacol, Leiden, Netherlands.; Simonsson, USH (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden.; van der Graaf, PH (corresponding author), Certara QSP, Canterbury, Kent, England."	"ulrika.simonsson@farmbio.uu.se; p.vandergraaf@lacdr.leidenuniv.nl"	"Simonsson, Ulrika/D-6024-2018"	"Simonsson, Ulrika/0000-0002-3424-9686; van Wijk, Rob Christiaan/0000-0001-7247-1360; Spaink, Herman/0000-0003-4128-9501"	"Innovative Medicines Initiative Joint Undertaking [115337]; European Union's Seventh Framework Programme (FP7/2007-2013)European Union (EU); EFPIA companies"	"The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (www.imi.europe.eu) under grant agreement no 115337, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution."	25	0	0	1	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1752-8054"	"1752-8062"	"NA"	"CTS-CLIN TRANSL SCI"	"CTS-Clin. Transl. Sci."	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"NA"	"10.1111/cts.12793"	5	"Medicine, Research & Experimental"	"Research & Experimental Medicine"	"LK9FL"	"WOS:000531163200001"	32267997	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Sou, T; Kukavica-Ibrulj, I; Levesque, RC; Friberg, LE; Bergstrom, CAS"	"Sou, Tomas; Kukavica-Ibrulj, Irena; Levesque, Roger C.; Friberg, Lena E.; Bergstrom, Christel A. S."	"NA"	"A"	"Model-Informed Drug Development in Pulmonary Delivery: Semimechanistic Pharmacokinetic-Pharmacodynamic Modeling for Evaluation of Treatments against Chronic Pseudomonas aeruginosa Lung Infections"	"MOLECULAR PHARMACEUTICS"	"English"	"Article"	"PK/PD modeling; pharmacokinetics; pharmacodynamics; pulmonary drug delivery; absorption; simulations; infection"	"NEBULIZED ANTIMICROBIAL AGENTS; QUORUM SENSING INHIBITORS; BIOPHARMACEUTICAL CHARACTERIZATION; COLISTIN METHANESULFONATE; MULTISTATE TUBERCULOSIS; ANTIBIOTIC-RESISTANCE; PHARMACOMETRIC MODEL; ANIMAL-MODELS; TOBRAMYCIN; RATS"	"Antibiotic resistance is a major public health threat worldwide, and among others, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. Novel treatment strategies are therefore urgently needed. For lung infections, direct delivery of treatments to the site of action in the airway can achieve a higher local concentration with minimal systemic exposure and hence avoid risks of unwanted systemic adverse effects. Previously, a rat preclinical disease model for PA chronic lung infections has been reported. However, the role of this disease model in the development of new treatment has not been thoroughly evaluated. In this study, tobramycin (TOB) was used as a model antibiotic to evaluate the application of this preclinical disease model for PA treatments. The obtained data were used for pharmacokinetic-pharmacodynamic (PKPD) modeling. Plasma samples following pulmonary delivery of TOB via different dosing methods as well as growth and efficacy data from the chronic lung infection disease model following TOB treatments were collected for analysis and modeling. The developed PKPD model incorporates a semimechanistic description on biofilm development in chronic infections to allow the evaluation of drug action on bacteria in different states (i.e., planktonic, biofilm, and latent) and describes the available data from the efficacy study. The PKPD model can be used to support the application of the preclinical lung infection disease model by providing a quantitative description of the drug exposure-response relationship and a mechanistic platform to integrate all available PK and PKPD data with predictive capacity. With the support of appropriate experimental designs, the model can be further extended for other applications to, for instance, study the transition of bacteria between states and describe drug actions on biofilms."	"[Sou, Tomas; Bergstrom, Christel A. S.] Uppsala Univ, Dept Pharm, Drug Delivery Grp, Uppsala 75123, Sweden; [Bergstrom, Christel A. S.] Uppsala Univ, Dept Pharm, Swedish Drug Delivery Forum, Uppsala 75123, Sweden; [Sou, Tomas; Friberg, Lena E.] Uppsala Univ, Dept Pharmaceut Biosci, Pharmacometr Grp, Uppsala 75105, Sweden; [Kukavica-Ibrulj, Irena; Levesque, Roger C.] Univ Laval, Inst Biol Integrat & Syst, Quebec City, PQ G1V 0A6, Canada"	"Bergstrom, CAS (corresponding author), Uppsala Univ, Dept Pharm, Drug Delivery Grp, Uppsala 75123, Sweden.; Bergstrom, CAS (corresponding author), Uppsala Univ, Dept Pharm, Swedish Drug Delivery Forum, Uppsala 75123, Sweden."	"christel.bergstrom@farmaci.uu.se"	"NA"	"Bergstrom, Christel/0000-0002-8917-2612; Friberg, Lena/0000-0002-2979-679X"	"Joint Programming Initiative on Antimicrobial Resistance (JPIAMR, Swedish Research Council)Swedish Research Council [2014-7513, 2015-06826]"	"This work was supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR, Swedish Research Council grants 2014-7513 and 2015-06826). The authors would like to acknowledge XenoGesis (Nottingham, UK) for their assistance in the in vivo studies."	51	0	0	12	12	"AMER CHEMICAL SOC"	"WASHINGTON"	"1155 16TH ST, NW, WASHINGTON, DC 20036 USA"	"1543-8384"	"NA"	"NA"	"MOL PHARMACEUT"	"Mol. Pharm."	"MAY 4"	2020	17	5	1458	1469	"NA"	"10.1021/acs.molpharmaceut.9b00968"	12	"Medicine, Research & Experimental; Pharmacology & Pharmacy"	"Research & Experimental Medicine; Pharmacology & Pharmacy"	"LK2BV"	"WOS:000530663800003"	31951139	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"van Esdonk, MJ; Burggraaf, J; Dehez, M; van der Graaf, PH; Stevens, J"	"van Esdonk, Michiel J.; Burggraaf, Jacobus; Dehez, Marion; van der Graaf, Piet H.; Stevens, Jasper"	"NA"	"A"	"Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Growth hormone; Deconvolution; Prolactin; Population PKPD; Dopastatin"	"ANTAGONIST INTERACTION-MODEL; REMOXIPRIDE; OCTREOTIDE; RELEASE; SYSTEM"	"A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [E-MAX] = - 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (E-MAX = - 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065."	"[van Esdonk, Michiel J.; Burggraaf, Jacobus; van der Graaf, Piet H.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [van Esdonk, Michiel J.; Burggraaf, Jacobus; Stevens, Jasper] Ctr Human Drug Res, Leiden, Netherlands; [Dehez, Marion] Ipsen Innovat, Les Ulis, France; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England; [Stevens, Jasper] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands"	"van Esdonk, MJ (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands.; van Esdonk, MJ (corresponding author), Ctr Human Drug Res, Leiden, Netherlands."	"mvesdonk@chdr.nl"	"; Stevens, Jasper/G-6118-2017"	"Burggraaf, Jacobus/0000-0001-7912-0918; Stevens, Jasper/0000-0003-1601-9008"	"Ipsen"	"This study was sponsored by Ipsen."	24	0	0	0	0	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2020	47	3	229	239	"NA"	"10.1007/s10928-020-09683-3"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LY0GN"	"WOS:000523402600002"	32248329	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Baker, B; Schaeffler, B; Beliveau, M; Rubets, I; Pederson, S; Trinh, M; Smith, J; Latham, J"	"Baker, Brian; Schaeffler, Barbara; Beliveau, Martin; Rubets, Igor; Pederson, Susan; Trinh, MyMy; Smith, Jeff; Latham, John"	"NA"	"A"	"Population pharmacokinetic and exposure-response analysis of eptinezumab in the treatment of episodic and chronic migraine"	"PHARMACOLOGY RESEARCH & PERSPECTIVES"	"English"	"Article"	"calcitonin gene-related peptide; CGRP; drug dose-response relationship; eptinezumab; intravenous administration; migraine disorders; monoclonal antibody; pharmacokinetics"	"GENE-RELATED PEPTIDE; MONOCLONAL-ANTIBODIES; DOUBLE-BLIND; ERENUMAB; HEADACHE; PREVENTION; HEALTHY; TRIAL"	"Eptinezumab is a humanized mAb that targets calcitonin gene-related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose- and exposure-response analyses, were performed using patient-level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. Exposure-response analysis explored the relationship between eptinezumab exposure metrics and efficacy parameters including monthly migraine days. The pharmacokinetic profile of eptinezumab was characterized by rapid attainment of maximum plasma concentration (ie, end of IV administration) and a terminal half-life of 27 days. Covariate analysis found that patient characteristics had no clinically significant effects on pharmacokinetic parameters and were insufficient to influence dosing. Dose- and exposure-response analyses found exposure with single doses >= 100 mg was associated with greater efficacy compared with doses <= 30 mg and a plateau of effect between 100 and 300 mg. A saturable inhibitory E-max model found the exposure over 12 weeks produced by single-dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC90). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100- or 300-mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab."	"[Baker, Brian; Schaeffler, Barbara; Pederson, Susan; Smith, Jeff; Latham, John] Lundbeck Seattle BioPharmaceut, 11804 North Creek Pkwy South, Bothell, WA 98011 USA; [Beliveau, Martin; Rubets, Igor; Trinh, MyMy] Certara Strateg Consulting, Montreal, PQ, Canada"	"Baker, B (corresponding author), Lundbeck Seattle BioPharmaceut, 11804 North Creek Pkwy South, Bothell, WA 98011 USA."	"BRAK@lundbeck.com"	"NA"	"NA"	"The Medicine Group, LLC; Lundbeck Seattle BioPharmaceuticals, Inc"	"The Medicine Group, LLC; Lundbeck Seattle BioPharmaceuticals, Inc"	35	0	0	2	2	"JOHN WILEY & SONS LTD"	"CHICHESTER"	"THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND"	"2052-1707"	"NA"	"NA"	"PHARMACOL RES PERSPE"	"Pharmacol. Res. Perspect."	"APR"	2020	8	2	"NA"	"NA"	"e00567"	"10.1002/prp2.567"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"LJ7LK"	"WOS:000530342100014"	32155317	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Campagne, O; Zhong, B; Nair, S; Lin, T; Huang, J; Onar-Thomas, A; Robinson, G; Gajjar, A; Stewart, CF"	"Campagne, Olivia; Zhong, Bo; Nair, Sreenath; Lin, Tong; Huang, Jie; Onar-Thomas, Arzu; Robinson, Giles; Gajjar, Amar; Stewart, Clinton F."	"NA"	"A"	"Exposure-Toxicity Association of Cyclophosphamide and Its Metabolites in Infants and Young Children with Primary Brain Tumors: Implications for Dosing"	"CLINICAL CANCER RESEARCH"	"English"	"Article"	"NA"	"HIGH-DOSE CYCLOPHOSPHAMIDE; POPULATION PHARMACOKINETICS; NONLINEAR PHARMACOKINETICS; PHOSPHORAMIDE MUSTARD; CHEMOTHERAPY; MODEL; THIOTEPA; PLASMA; 4-HYDROXYCYCLOPHOSPHAMIDE; TRANSPLANTATION"	"Purpose: To characterize the population pharmacokinetics of cyclophosphamide, active 4-hydroxy-cyclophosphamide (4OH-CTX), and inactive carboxyethylphosphoramide mustard (CEPM), and their associations with hematologic toxicities in infants and young children with brain tumors. Touse this information to provide cyclophosphamide dosing recommendations in this population. Patients and Methods: Patients received four cycles of a 1-hour infusion of 1.5 g/m(2) cyclophosphamide. Serial samples were collected to measure cyclophosphamide, 4OH-CTX, and CEPM plasma concentrations. Population pharmacokinetic modeling was performed to identify the patient characteristics influencing drug disposition. Associations between drug exposures and metrics reflecting druginduced neutropenia, erythropenia, and thrombocytopenia were investigated. A Bayesian approach was developed to predict 4OH-CTX exposure using only cyclophosphamide and CEPM plasma concentrations. Results: Data from 171 patients (0.07-4.9 years) were adequately fitted by a two-compartment (cyclophosphamide) and one-compartment model (metabolites). Young infants (<6 months) exhibited higher mean 4OH-CTX exposure than did young children (138.4 vs. 107.2 mu mol/L.h, P < 0.0001). No genotypes exhibited clinically significant influence on drug exposures. Worse toxicity metrics were significantly associated with higher 4OH-CTX exposures. Dosing simulations suggested decreased cyclophosphamide dosage to 1.2 g/m(2) for young infants versus 1.5 g/m(2) for children to attain similar 4OH-CTX exposure. Bayesian-modeled 4OH-CTX exposure predictions were precise (mean absolute prediction error 14.8% � 4.2%) and had low bias (mean prediction error 4.9% � 5.1%). Conclusions: A 4OH-CTX exposure-toxicity association was established, and a decreased cyclophosphamide dosage for young infants was suggested to reduce toxicity in this population. Bayesian modeling to predict 4OH-CTX exposure may reduce clinical processing-related costs and provide insights into further exposure-response associations."	"[Campagne, Olivia; Zhong, Bo; Nair, Sreenath; Stewart, Clinton F.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA; [Lin, Tong; Huang, Jie; Onar-Thomas, Arzu] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA; [Robinson, Giles; Gajjar, Amar] St Jude Childrens Res Hosp, Dept Oncol, Div Neurooncol, 332 N Lauderdale St, Memphis, TN 38105 USA"	"Stewart, CF (corresponding author), St Jude Childrens Res Hosp, 262 Danny Thomas Pl,Mail Stop 313, Memphis, TN 38105 USA."	"clinton.stewart@stjude.org"	"Robinson, Giles/N-8095-2018; Nair, Sreenath/N-9843-2018"	"Robinson, Giles/0000-0001-7441-9486; Nair, Sreenath/0000-0003-1286-4554"	"NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA154619]; St. Jude Children's Research Hospital Comprehensive Cancer Center Support (CORE) [CA21765]; American Lebanese Syrian Associated Charities at St. Jude Children's Research HospitalAmerican Lebanese Syrian Associated Charities (ALSAC)"	"We thank the clinical pharmacists, pharmacokinetic nurses, and nursing team at St. Jude for their assistance in this study; the Stewart laboratory for bedside collection and processing of the samples; and the Hartwell Center for performing Illumina Chip. We also thank Drs. Carl Panetta, Mike Tagen, Yogesh Patel, and Vinay Daryani for their contributions in the population pharmacokinetic and covariate analyses. This work was supported by grants from the NCI (R01CA154619; C.F. Stewart), St. Jude Children's Research Hospital Comprehensive Cancer Center Support (CORE; CA21765), and the American Lebanese Syrian Associated Charities at St. Jude Children's Research Hospital."	46	1	1	3	3	"AMER ASSOC CANCER RESEARCH"	"PHILADELPHIA"	"615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA"	"1078-0432"	"1557-3265"	"NA"	"CLIN CANCER RES"	"Clin. Cancer Res."	"APR"	2020	26	7	1563	1573	"NA"	"10.1158/1078-0432.CCR-19-2685"	11	"Oncology"	"Oncology"	"KY8PB"	"WOS:000522837300005"	31796512	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Goodchild, CS; Serrao, JM; Sear, JW; Anderson, BJ"	"Goodchild, Colin S.; Serrao, Juliet M.; Sear, John W.; Anderson, Brian J."	"NA"	"A"	"Pharmacokinetic and Pharmacodynamic Analysis of Alfaxalone Administered as a Bolus Intravenous Injection of Phaxan in a Phase 1 Randomized Trial"	"ANESTHESIA AND ANALGESIA"	"English"	"Article"	"NA"	"BISPECTRAL INDEX; MODEL; PROPOFOL; ALTHESIN; ALPHAXALONE; FORMULATION; MODULATION; PARAMETERS; ETOMIDATE; KETAMINE"	"BACKGROUND: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers. METHODS: A dose of 0.5 mg/kg (0.42-0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (E-MAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t(1/2)keo). RESULTS: A 3-compartment model used to fit PK data with an additional compartment, linked by t(1/2)keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87-1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53-2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32-1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19-1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79-10.7 L (median; 95% CI) and V3: 19.1 L; 8.61-37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated E-MAX: 0.94; 0.71-0.99 (median; 95% CI), a plasma concentration (C-p) for 50% effect (C-50): 0.98 mg/L; 0.83-1.09 mg/L (median; 95% CI), and a Hill coefficient (gamma): 12.1; 6.7-15 (median; 95% CI). The t(1/2)keo was 8 minutes; 4.70-12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes). CONCLUSIONS: After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of t(1/2)keo is relatively high, but the large Hill coefficient contributes to rapid onset and offset of action. This information can inform future studies of this formulation."	"[Goodchild, Colin S.; Serrao, Juliet M.] Drawbridge Pharmaceut Pty Ltd, 23 Milton Parade, Malvern, Vic 3144, Australia; [Sear, John W.] Univ Oxford, Nuffield Dept Anaesthet, Oxford, England; [Anderson, Brian J.] Univ Auckland, Dept Anaesthesiol, Auckland, New Zealand"	"Goodchild, CS (corresponding author), Drawbridge Pharmaceut Pty Ltd, 23 Milton Parade, Malvern, Vic 3144, Australia."	"colin@drawbridgepharmaceuticals.com.au"	"NA"	"NA"	"Drawbridge Pharmaceuticals"	"This work was funded entirely by Drawbridge Pharmaceuticals."	37	1	1	3	3	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0003-2999"	"NA"	"NA"	"ANESTH ANALG"	"Anesth. Analg."	"MAR"	2020	130	3	704	714	"NA"	"10.1213/ANE.0000000000004204"	11	"Anesthesiology"	"Anesthesiology"	"LH5OK"	"WOS:000528834100046"	31124836	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Bue, M; Sou, T; Okkels, ASL; Hanberg, P; Thorsted, A; Friberg, LE; Andersson, TL; Obrink-Hansen, K; Christensen, S"	"Bue, Mats; Sou, Tomas; Okkels, Anna Sophie L.; Hanberg, Pelle; Thorsted, Anders; Friberg, Lena E.; Andersson, Torben L.; Obrink-Hansen, Kristina; Christensen, Steffen"	"NA"	"A"	"Population pharmacokinetics of piperacillin in plasma and subcutaneous tissue in patients on continuous renal replacement therapy"	"INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES"	"English"	"Article"	"PK/PD; Modelling; beta-lactams; Microdialysis; Tissue distribution; Continuous renal replacement therapy"	"CRITICALLY-ILL PATIENTS; CONTINUOUS VENOVENOUS HEMOFILTRATION; CONTINUOUS-INFUSION; TAZOBACTAM; MICRODIALYSIS; PHARMACODYNAMICS; FAILURE; MODEL; PRINCIPLES; OUTCOMES"	"Objectives: Piperacillin is a beta-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population are limited. A prospective observational study was conducted of free piperacillin concentrations during a single 8-h dosing interval in plasma (8 samples) and subcutaneous tissue (SCT) (13 samples), in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min. Methods: A population pharmacokinetic model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint minimum inhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamics targets: 50% fT > 1 x MIC, 100% fT > 1 x MIC, and 100% fT > 4 x MIC. Results: SCT concentrations were generally lower than plasma concentrations. For the target of 50% free time (fT) > 1 x MIC and 100% fT > 1 x MIC, piperacillin 4 g every 8 h resulted in probability of target attainment (PTA) >90% in both plasma and SCT. PTA > 90% for the target of 100% fT > 4 x MIC was only achieved for continuous infusion. Conclusions: Piperacillin 4 g every 8 h is likely to provide sufficient exposure in both plasma and SCT to treat P.aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT > 1 x MIC or 100% fT > 1 x MIC are adequate. However, if a more aggressive target of 100% fT > 4 x MIC is adopted, continuous infusion is needed. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases."	"[Bue, Mats; Hanberg, Pelle] Horsens Reg Hosp, Dept Orthopaed Surg, Sundvej 30, DK-8700 Horsens, Denmark; [Bue, Mats; Okkels, Anna Sophie L.; Christensen, Steffen] Aarhus Univ Hosp, Dept Anaesthesia & Intens Care Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark; [Bue, Mats; Hanberg, Pelle] Aarhus Univ Hosp, Orthopaed Res Unit, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark; [Sou, Tomas; Thorsted, Anders; Friberg, Lena E.] Uppsala Univ, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden; [Andersson, Torben L.] Aarhus Univ Hosp, Dept Clin Biochem, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark; [Obrink-Hansen, Kristina] Aarhus Univ Hosp, Dept Infect Dis, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark"	"Bue, M (corresponding author), Horsens Reg Hosp, Dept Orthopaed Surg, Sundvej 30, DK-8700 Horsens, Denmark."	"matsbue6@rm.dk; tomas.sou@farmaci.uu.se; asokkels@hotmail.com; pehanb@rm.dk; anders.thorsted@farmbio.uu.se; lena.friberg@farmbio.uu.se; t.l.a@stofanet.dk; kristina.Obrink.Hansen@auh.rm.dk; steffen.christensen@auh.rm.dk"	"NA"	"Bue, Mats/0000-0001-7215-8323; Thorsted, Anders/0000-0003-1804-2703; Friberg, Lena/0000-0002-2979-679X; Hanberg, Pelle/0000-0002-6845-1874"	"Aase & Ejnar Danielsens Foundation"	"This work was supported by unrestricted grants from the Aase & Ejnar Danielsens Foundation."	40	1	1	0	0	"ELSEVIER SCI LTD"	"OXFORD"	"THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND"	"1201-9712"	"1878-3511"	"NA"	"INT J INFECT DIS"	"Int. J. Infect. Dis."	"MAR"	2020	92	"NA"	133	140	"NA"	"10.1016/j.ijid.2020.01.010"	8	"Infectious Diseases"	"Infectious Diseases"	"KT7KI"	"WOS:000519191900023"	31978581	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Mian, P; Allegaert, K; Conings, S; Annaert, P; Tibboel, D; Pfister, M; van Calsteren, K; van den Anker, JN; Dallmann, A"	"Mian, Paola; Allegaert, Karel; Conings, Sigrid; Annaert, Pieter; Tibboel, Dick; Pfister, Marc; van Calsteren, Kristel; van den Anker, John N.; Dallmann, Andre"	"NA"	"A"	"Integration of Placental Transfer in a Fetal-Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"DEVELOPMENTAL EXPRESSION; DRUG; PERMEABILITY; PARACETAMOL; LIVER; SULFOTRANSFERASES; PREDICTION; PREGNANCY; ABSORPTION; TRANSPORT"	"Background and Objective Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal-maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi (R)]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. Conclusion The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure."	"[Mian, Paola; Tibboel, Dick; van den Anker, John N.] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [Mian, Paola; Tibboel, Dick; van den Anker, John N.] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Rotterdam, Netherlands; [Mian, Paola; Pfister, Marc; van den Anker, John N.; Dallmann, Andre] Pediat Pharmacol Pharmacometr Res Ctr, Basel, Switzerland; [Mian, Paola; Pfister, Marc; van den Anker, John N.; Dallmann, Andre] Univ Childrens Hosp Basel UKBB, Basel, Switzerland; [Mian, Paola] Med Spectrum Twente, Dept Clin Pharm, Koningspl 1, NL-7512 KZ Enschede, Netherlands; [Allegaert, Karel; Conings, Sigrid; van Calsteren, Kristel] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Allegaert, Karel] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium; [Allegaert, Karel] Erasmus MC, Dept Clin Pharm, Rotterdam, Netherlands; [Annaert, Pieter] Katholieke Univ Leuven, Drug Delivery & Disposit Lab, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium; [van Calsteren, Kristel] Univ Hosp Leuven, Dept Obstet & Gynecol, Leuven, Belgium; [van den Anker, John N.] Childrens Natl Hosp, Div Clin Pharmacol, Washington, DC USA"	"Mian, P (corresponding author), Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands.; Mian, P (corresponding author), Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Rotterdam, Netherlands.; Mian, P (corresponding author), Pediat Pharmacol Pharmacometr Res Ctr, Basel, Switzerland.; Mian, P (corresponding author), Univ Childrens Hosp Basel UKBB, Basel, Switzerland.; Mian, P (corresponding author), Med Spectrum Twente, Dept Clin Pharm, Koningspl 1, NL-7512 KZ Enschede, Netherlands."	"Paola.Mian@mst.nl"	"; allegaert, karel/C-3611-2016"	"Pfister, Marc/0000-0003-2597-1228; allegaert, karel/0000-0001-9921-5105; Dallmann, Andre/0000-0003-1108-5719"	"Sophia Stichting Wetenschappelijk Onderzoek (SSWO) [S16-08]; Stichting Sophia Kinderziekenhuis; Eramus Trustfonds"	"For this project, P. Mian was supported by the Sophia Stichting Wetenschappelijk Onderzoek (SSWO) (S16-08) and received a Short Term Minor (STM-2017) Grant from the Stichting Sophia Kinderziekenhuis to conduct this research, a travel grant from Eramus Trustfonds, and the Dr. Catharine van Tussenbroek, Mevr. Speleers Pharmacy grant."	59	0	0	0	0	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JUL"	2020	59	7	911	925	"NA"	"10.1007/s40262-020-00861-7"	15	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"MI7DZ"	"WOS:000513049500001"	32052378	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Cheng, QQ; Huang, JH; Xu, L; Li, YF; Li, HF; Shen, YF; Zheng, QS; Li, LJ"	"Cheng, Qingqing; Huang, Jihan; Xu, Ling; Li, Yunfei; Li, Huafang; Shen, Yifeng; Zheng, Qingshan; Li, Lujin"	"NA"	"A"	"Analysis of Time-Course, Dose-Effect, and Influencing Factors of Antidepressants in the Treatment of Acute Adult Patients With Major Depression"	"INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY"	"English"	"Article"	"antidepressant; efficacy; model-based meta-analysis"	"PHARMACOLOGICAL-TREATMENT; NETWORK METAANALYSIS; PLACEBO-RESPONSE; MODEL; DYSFUNCTION; GUIDELINES; DISORDERS"	"Objective: Model-based meta-analysis was used to describe the time-course and dose-effect relationships of antidepressants and also simultaneously investigate the impact of various factors on drug efficacy. Methods: This study is a reanalysis of a published network meta-analysis. Only placebo-controlled trials were included in this study. The change rate in depression rating scale scores from baseline was used as an efficacy indicator because a continuous variable is more likely to reflect subtle differences in efficacy between drugs. Results: A total 230 studies containing 64346 patients were included in the analysis. The results showed that the number of study sites (single or multi-center) and the type of setting (inpatient or noninpatient) are important factors affecting the efficacy of antidepressants. After deducting the placebo effect, the maximum pure drug efficacy value of inpatients was 18.4% higher than that of noninpatients, and maximum pure drug efficacy value of single-center trials was 10.2% higher than that of multi-central trials. Amitriptyline showed the highest drug efficacy. The remaining 18 antidepressants were comparable or had little difference. Within the approved dose range, no significant dose-response relationship was observed. However, the time-course relationship is obvious for all antidepressants. In terms of safety, with the exception of amitriptyline, the dropout rate due to adverse events of other drugs was not more than 10% higher than that of the placebo group. Conclusion: The number of study sites and the type of setting are significant impact factors for the efficacy of antidepressants. Except for amitriptyline, the other 18 antidepressants have little difference in efficacy and safety."	"[Cheng, Qingqing; Huang, Jihan; Xu, Ling; Li, Yunfei; Zheng, Qingshan; Li, Lujin] Shanghai Univ Tradit Chinese Med, Ctr Drug Clin Res, Shanghai, Peoples R China; [Li, Huafang; Shen, Yifeng] Shanghai Mental Hlth Ctr, Shanghai, Peoples R China"	"Cheng, QQ; Zheng, QS (corresponding author), 1200 Cailun Rd, Shanghai 201203, Peoples R China."	"lilujin666@163.com"	"NA"	"SHEN, Yifeng/0000-0002-3298-6682; cheng, qingqing/0000-0001-5351-7538"	"Shanghai Municipal Health Planning Commission [2018YQ48]; Drug Innovation Major Project [2018ZX09734005-001-002, 2018ZX09734005-006, 2018ZX09711001-009-011, 2018ZX09731016, 2017ZX09304003]; Science and Technology Innovation Action Plan of Shanghai [17401970900]"	"This study was funded by the project of Shanghai Municipal Health Planning Commission (2018YQ48), The Drug Innovation Major Project (2018ZX09734005-001-002, 2018ZX09734005-006, 2018ZX09711001-009-011, 2018ZX09731016, 2017ZX09304003), and Science and Technology Innovation Action Plan of Shanghai (17401970900)."	39	3	3	0	0	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"1461-1457"	"1469-5111"	"NA"	"INT J NEUROPSYCHOPH"	"Int. J. Neuropsychopharmacol."	"FEB"	2020	23	2	76	87	"NA"	"10.1093/ijnp/pyz062"	12	"Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry"	"Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry"	"MZ3AJ"	"WOS:000558994700002"	31774497	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Janssen, JM; Dorlo, TPC; Niewerth, D; Wilhelm, AJ; Zwaan, CM; Beijnen, JH; Attarbaschi, A; Baruchel, A; Fagioli, F; Klingebiel, T; De Moerloose, B; Palumbo, G; von Stackelberg, A; Kaspers, GJL; Huitema, ADR"	"Janssen, Julie M.; Dorlo, T. P. C.; Niewerth, D.; Wilhelm, A. J.; Zwaan, C. M.; Beijnen, J. H.; Attarbaschi, A.; Baruchel, A.; Fagioli, F.; Klingebiel, T.; De Moerloose, B.; Palumbo, G.; Von Stackelberg, A.; Kaspers, G. J. L.; Huitema, A. D. R."	"NA"	"A"	"A Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic Model of Bortezomib in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"PROTEASOME INHIBITOR BORTEZOMIB; SOLID TUMORS; PHASE-I"	"Introduction The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia. Methods Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m(2) twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model. Results The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664-0.728) after administration. Conclusion The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib."	"[Janssen, Julie M.; Dorlo, T. P. C.; Beijnen, J. H.; Huitema, A. D. R.] Netherlands Canc Inst, Dept Pharm, Pharmacology, Antoni Leeuwenhoek, Plesmanlaan 121, NL-1066 Amsterdam, CX, Netherlands; [Niewerth, D.; Kaspers, G. J. L.] Univ Med Ctr, Dept Pediat Oncol, Hematol, Amsterdam, Netherlands; [Wilhelm, A. J.] Univ Med Ctr, Dept Clin Pharmacol, Pharm, Amsterdam, Netherlands; [Zwaan, C. M.; Kaspers, G. J. L.] Princess Maxima Ctr Pediat Oncology, Utrecht, Netherlands; [Zwaan, C. M.] MC Sophia Children's Hosp, Dept Pediat Oncol, Hematol, Erasmus, Rotterdam, Netherlands; [Beijnen, J. H.] Univ Utrecht, Utrecht Inst Pharmaceut Sciences, UIPS, Utrecht, Netherlands; [Attarbaschi, A.] Anna Children's Hosp, Dept Pediat Hematol Oncol, St, Vienna, Austria; [Attarbaschi, A.] Med Univ Vienna, Dept Pediat, Adolescent Med, Vienna, Austria; [Baruchel, A.] Hop St Louis, Dept Pediat Hematol, Paris, France; [Fagioli, F.] Univ Torino, Turin, Italy; [Klingebiel, T.] Univ Hosp Frankfurt, Dept Pediat, Frankfurt, Germany; [De Moerloose, B.] Ghent Univ Hosp, Dept Pediat, Ghent, Belgium; [Palumbo, G.] Osped Pediatr Bambino Gesu, Rome, Italy; [Von Stackelberg, A.] Dept Pediat Oncol, Hematol, Charite Universitatsmedizin, Berlin, Germany; [Huitema, A. D. R.] Univ Med Ctr Utrecht, Utrecht Univ, Dept Clin Pharm, Utrecht, Netherlands; [Zwaan, C. M.; Baruchel, A.] ITCC Consortium, Paris, France"	"Janssen, JM (corresponding author), Netherlands Canc Inst, Dept Pharm, Pharmacology, Antoni Leeuwenhoek, Plesmanlaan 121, NL-1066 Amsterdam, CX, Netherlands."	"ju.janssen@nki.nl"	"De㊇ꮖ訬�, Barbara/AAN-3298-2020; Dorlo, Thomas/F-1339-2011"	"Dorlo, Thomas/0000-0003-3076-8435"	"NA"	"NA"	24	0	0	0	1	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"FEB"	2020	59	2	207	216	"NA"	"10.1007/s40262-019-00803-y"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KI8SU"	"WOS:000511628800004"	31313068	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"P?rez-Ruixo, C; P?rez-Blanco, JS; Chien, C; Yu, MG; Ouellet, D; P?rez-Ruixo, JJ; Ackaert, O"	"Perez-Ruixo, Carlos; Perez-Blanco, Jonas Samuel; Chien, Caly; Yu, Margaret; Ouellet, Daniele; Perez-Ruixo, Juan-Jose; Ackaert, Oliver"	"NA"	"A"	"Population Pharmacokinetics of Apalutamide and its Active Metabolite N-Desmethyl-Apalutamide in Healthy and Castration-Resistant Prostate Cancer Subjects"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"ANTIANDROGEN; ARN-509; MODELS"	"Background Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC). Objective The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects. Methods Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed. Results Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-desmethyl-apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-desmethyl-apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-desmethyl-apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-desmethyl-apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%). Conclusions A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-desmethyl-apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-desmethyl-apalutamide pharmacokinetics."	"[Perez-Ruixo, Carlos; Perez-Blanco, Jonas Samuel; Perez-Ruixo, Juan-Jose; Ackaert, Oliver] Janssen Res & Dev, Antwerp, Belgium; [Chien, Caly; Ouellet, Daniele] Janssen Res & Dev, Spring House, PA USA; [Yu, Margaret] Janssen Res & Dev, Los Angeles, CA USA"	"Ackaert, O (corresponding author), Janssen Res & Dev, Antwerp, Belgium."	"oackaert@its.jnj.com"	"Perez-Blanco, Jonas Samuel/AAB-5010-2019; Ruixo, Juan Jose Perez/AAL-2987-2020"	"Perez-Blanco, Jonas Samuel/0000-0002-1232-1763; Ackaert, Oliver/0000-0002-5908-5200"	"NA"	"NA"	23	4	4	3	3	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"FEB"	2020	59	2	229	244	"NA"	"10.1007/s40262-019-00808-7"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KI8SU"	"WOS:000511628800006"	31432469	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Llanos-Paez, CC; Staatz, CE; Lawson, R; Hennig, S"	"Llanos-Paez, C. C.; Staatz, C. E.; Lawson, R.; Hennig, S."	"NA"	"A"	"Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"pediatrics; gentamicin; NONMEM; body composition; normal fat mass; pediatrics"	"BODY-COMPOSITION; AMINOGLYCOSIDE THERAPY; PARAMETER UNCERTAINTY; CHILDREN; MODEL; DISTRIBUTIONS; OBESITY; SIZE; MASS"	"Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size descriptor. Data from 423 oncology and 115 nononcology patients were analyzed. Differences in drug disposition were observed between the oncology and nononcology patients, with oncology patients having a 15% lower central volume of distribution and 32% lower intercompartmental clearance. Simulations based on the population pharmacokinetic model demonstrated low exposure target attainment in all individuals at the current clinical recommended starting dose of 7.5 mg/kg of body weight once daily, with 57.4% of oncology and 35.7% of nononcology subjects achieving a peak concentration (C-max) of >= 25 mg/liter and 64.3% of oncology and 65.6% of nononcology subjects achieving an area under the concentration-time curve at 24 h postdose (AUC(24)) of mg.h/liter after the first dose. Based on simulations, the extent of the impact of differences in drug disposition between the two cohorts appeared to be dependent on the exposure target under examination. Greater differences in achieving a C-max target of >25 mg/liter than an AUC(24) target of >= 70 mg.h/liter between the cohorts was observed. Further investigation into whether differences in the pharmacokinetics of gentamicin between oncology and nononcology patients are a consequence of changes in body composition is required."	"[Llanos-Paez, C. C.; Staatz, C. E.; Hennig, S.] Univ Queensland, Sch Pharm, Brisbane, Qld, Australia; [Lawson, R.] Queensland Childrens Hosp, Brisbane, Qld, Australia; [Llanos-Paez, C. C.] Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden; [Hennig, S.] Certara Strateg Consulting, Princeton, NJ USA"	"Llanos-Paez, CC (corresponding author), Univ Queensland, Sch Pharm, Brisbane, Qld, Australia.; Llanos-Paez, CC (corresponding author), Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden."	"c.llanospaez@uq.edu.au"	"Hennig, Stefanie/E-4426-2011"	"Hennig, Stefanie/0000-0001-5972-3711"	"BECAS-Chile CONICYT scholarship; Humboldt Foundation, GermanyAlexander von Humboldt Foundation"	"C.C.L.-P. acknowledges the BECAS-Chile CONICYT scholarship for supporting her Ph.D. during the time when the manuscript was written. C.C.L.-P., C.E.S., R.L., and S.H. acknowledge the Australian Centre of Pharmacometrics for NONMEM software and hardware. S.H. was partly supported by a fellowship from the Humboldt Foundation, Germany."	32	0	0	0	1	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"FEB"	2020	64	2	"NA"	"NA"	"e01730-19"	"10.1128/AAC.01730-19"	10	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"KG2CG"	"WOS:000509748200025"	31712209	"Green Published, Bronze"	"NA"	"NA"	"2020-10-02"
"J"	"Santana, VM; Sahr, N; Tatevossian, RG; Jia, SJ; Campagne, O; Sykes, A; Stewart, CF; Furman, WL; McGregor, LM"	"Santana, Victor M.; Sahr, Natasha; Tatevossian, Ruth G.; Jia, Sujuan; Campagne, Olivia; Sykes, April; Stewart, Clinton F.; Furman, Wayne L.; McGregor, Lisa M."	"NA"	"A"	"A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors"	"CANCER"	"English"	"Article"	"bevacizumab; clinical oncology; everolimus; pediatrics"	"YOUNG-ADULTS; I RECEPTOR; GROWTH; COMBINATION; RAPAMYCIN; INHIBITION; TEMSIROLIMUS; SORAFENIB; PATHWAY"	"Background The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors. Methods In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. Results Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m(2) of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m(2) of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline. Conclusions The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m(2) of everolimus in a 4-week cycle for children with recurrent solid tumors. (c) 2020 American Cancer Society."	"[Santana, Victor M.; Furman, Wayne L.] St Jude Childrens Res Hosp, Dept Oncol, Danny Thomas Pl,MS-281, Memphis, TN 38105 USA; [Santana, Victor M.; Furman, Wayne L.] Comprehens Canc Ctr, Memphis, TN USA; [Sahr, Natasha; Sykes, April] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA; [Tatevossian, Ruth G.; Jia, Sujuan] St Jude Childrens Res Hosp, Dept Pathol, Diagnost Biomarkers Shared Resource, 332 N Lauderdale St, Memphis, TN 38105 USA; [Campagne, Olivia; Stewart, Clinton F.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA; [McGregor, Lisa M.] Penn State Univ, Coll Med, Dept Pediat, Hershey, PA USA"	"Santana, VM (corresponding author), St Jude Childrens Res Hosp, Dept Oncol, Danny Thomas Pl,MS-281, Memphis, TN 38105 USA."	"victor.santana@stjude.org"	"Sykes, April D/N-4407-2018; Tatevossian, Ruth/G-6377-2016"	"Sykes, April D/0000-0002-7667-8155; Tatevossian, Ruth/0000-0002-1653-3026"	"Novartis Oncology; National Cancer Institute (St. Jude Cancer Center Support [CORE]) [P30 CA21765]; American Lebanese Syrian Associated Charities (ALSAC)American Lebanese Syrian Associated Charities (ALSAC)"	"Supported by an investigator clinical trial award to Lisa M. McGregor from Novartis Oncology (the original grant was awarded to St. Jude when Dr Lisa McGregor was the principal investigator of the study; when Dr. McGregor left St. Jude, the grant remained on site), the National Cancer Institute (St. Jude Cancer Center Support [CORE] under grant P30 CA21765), and the American Lebanese Syrian Associated Charities (ALSAC)."	31	0	0	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0008-543X"	"1097-0142"	"NA"	"CANCER-AM CANCER SOC"	"Cancer"	"APR 15"	2020	126	8	1749	1757	"NA"	"10.1002/cncr.32722"	9	"Oncology"	"Oncology"	"KX1OB"	"WOS:000508505300001"	31967673	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Campagne, O; Davis, A; Maharaj, AR; Zhong, B; Stripay, J; Farmer, D; Roussel, MF; Stewart, CF"	"Campagne, Olivia; Davis, Abigail; Maharaj, Anil R.; Zhong, Bo; Stripay, Jennifer; Farmer, Dana; Roussel, Martine F.; Stewart, Clinton F."	"NA"	"A"	"CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Prexasertib; Cerebral microdialysis; Pharmacokinetic modeling; Non-specific binding; Pediatric brain tumors; Phosphorylated CHK1"	"CHECKPOINT KINASE 1; CANCER; PHARMACOKINETICS; REPLICATION; SIMULATION; BIOMARKER; CHILDREN"	"Prexasertib (LY2606368) is a potent and selective small molecule inhibitor of cell-cycle checkpoint CHK1 and CHK2 protein kinases and is currently under clinical evaluation for treatment of pediatric malignancies. As a candidate therapy for pediatric Group 3 medulloblastoma (G3MB), prexasertib CNS penetration was evaluated in mice using cerebral microdialysis and pharmacokinetic modeling. A plasma pharmacokinetic study with a population-based design was performed in CD1 nude mice bearing G3MB orthotopically implanted in the brain and receiving a single dose of prexasertib (10 mg/kg, subcutaneously) to characterize prexasertib disposition and to establish a limited plasma sampling model for the microdialysis studies. The microdialysis studies were performed in both non-tumor bearing mice and in mice bearing G3MB receiving 10 mg/kg prexasertib subcutaneously, for up to 24 h post-dose. Plasma and extracellular fluid (ECF) concentrations were quantified using validated LC MS/MS methods, and analyzed using a population pharmacokinetic model. Model-derived prexasertib tumor/ECF to plasma partition coefficient K-p,K-uu (ratio of tumor/brain ECF to unbound plasma AUC(0-24) (h)) was significantly greater in G3MB tumor-bearing mice (0.17 � 0.08) compared to non-tumor bearing mice (0.09 � 0.04, p = 0.04). A pharmacodynamic study was then performed in mice bearing G3MB (20 mg/kg, IV) to evaluate prexasertib-induced target engagement after a single dose. Phosphorylated CHK1 serine 345 (pCHK1 S345), phosphorylated Histone 2A variant (gamma-H2AX), and cleaved caspase-3 were quantified in mouse G3MB tumor tissues by immunohistochemistry at different time points up to 24 h post-dose. The induction of pCHK1 S345 and gamma-H2AX peaked at 2 h after the dose and was elevated above baseline for at least 6 h, reflecting relevant CHK1 inhibition and DNA damage. Cleaved caspase-3 levels increased at 24 h suggesting initiation of cell apoptosis. Adequate unbound prexasertib exposure reached the brain tumor site relative to target engagement in G3MB tumor bearing mice at a clinically relevant dosage. These results support further preclinical and clinical development of prexasertib to treat children with medulloblastoma."	"[Campagne, Olivia; Davis, Abigail; Maharaj, Anil R.; Zhong, Bo; Stewart, Clinton F.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 262 Danny Thomas Pl, Memphis, TN 38105 USA; [Stripay, Jennifer; Farmer, Dana; Roussel, Martine F.] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, 262 Danny Thomas Pl, Memphis, TN 38105 USA; [Maharaj, Anil R.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA"	"Stewart, CF (corresponding author), St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 262 Danny Thomas Pl, Memphis, TN 38105 USA."	"clinton.stewart@stjude.org"	"NA"	"NA"	"Eli LillyEli Lilly; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA21765, CA096832]; American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children's Research HospitalAmerican Lebanese Syrian Associated Charities (ALSAC)"	"This work was supported in part by grants from Eli Lilly, the National Cancer Institute (CA21765 (MFR; CFS) and CA096832 (MFR)), and the American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children's Research Hospital."	39	0	0	2	3	"ELSEVIER"	"AMSTERDAM"	"RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"JAN 15"	2020	142	"NA"	"NA"	"NA"	105106	"10.1016/j.ejps.2019.105106"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"JZ6CK"	"WOS:000505188900005"	31669383	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Michelet, R; Dossche, L; Van Herzeele, C; De Bruyne, P; Gasthuys, E; Van Bocxlaer, J; Vande Walle, J; Vermeulen, A"	"Michelet, Robin; Dossche, Lien; Van Herzeele, Charlotte; De Bruyne, Pauline; Gasthuys, Elke; Van Bocxlaer, Jan; Vande Walle, Johan; Vermeulen, An"	"NA"	"A"	"An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"ORAL DESMOPRESSIN; PHARMACOKINETICS; CHILDREN; FORMULATION; TABLET; SIZE; FOOD"	"Introduction The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age. Methods Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies. Results The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 mu g is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects. Conclusions Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed."	"[Michelet, Robin; Van Bocxlaer, Jan; Vermeulen, An] Univ Ghent, Fac Pharmaceut Sci, Dept Bioanal, Lab Med Biochem & Clin Anal, Ghent, Belgium; [Michelet, Robin] Free Univ Berlin, Inst Pharm, Dept Clin Pharm & Biochem, Berlin, Germany; [Dossche, Lien; Van Herzeele, Charlotte; De Bruyne, Pauline; Gasthuys, Elke; Vande Walle, Johan] Ghent Univ Hosp, Dept Paediat Nephrol, Ghent, Belgium; [Van Herzeele, Charlotte] Gen Hosp Sint Jan Bruges Ostend, Dept Clin Psychol, Brugge, Belgium; [Dossche, Lien; De Bruyne, Pauline; Vande Walle, Johan] Univ Ghent, Dept Internal Med & Paediat, Fac Med & Hlth Sci, Ghent, Belgium; [Gasthuys, Elke] Univ Ghent, Dept Pharmacol Toxicol & Biochem, Fac Vet Med, Ghent, Belgium"	"Vermeulen, A (corresponding author), Univ Ghent, Fac Pharmaceut Sci, Dept Bioanal, Lab Med Biochem & Clin Anal, Ghent, Belgium."	"AnMC.Vermeulen@UGent.be"	"De Bruyne, Pauline/J-2055-2017; Michelet, Robin/AAM-7991-2020"	"De Bruyne, Pauline/0000-0002-3090-9755; Michelet, Robin/0000-0002-5485-607X; Dossche, Lien/0000-0003-1030-9848"	"NA"	"NA"	28	1	1	1	2	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"JAN"	2020	59	1	81	96	"NA"	"10.1007/s40262-019-00798-6"	16	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KI7XC"	"WOS:000511564400005"	31347012	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Campagne, O; Davis, A; Zhong, B; Nair, S; Haberman, V; Patel, YT; Janke, L; Roussel, MF; Stewart, CF"	"Campagne, Olivia; Davis, Abigail; Zhong, Bo; Nair, Sreenath; Haberman, Victoria; Patel, Yogesh T.; Janke, Laura; Roussel, Martine F.; Stewart, Clinton F."	"NA"	"A"	"CNS Penetration of Cyclophosphamide and Metabolites in Mice Bearing Group 3 Medulloblastoma and Non-Tumor Bearing Mice"	"JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES"	"English"	"Article"	"NA"	"DOSE CYCLOPHOSPHAMIDE; CLINICAL-PHARMACOLOGY; PHARMACOKINETICS; BRAIN; CHILDREN; CHEMOTHERAPY; PLASMA; TUMORS; MODEL; MICRODIALYSIS"	"PURPOSE: Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration of cyclophosphamide (130 mg/kg, IP) and its metabolites [4-hydroxy-cyclophosphamide (40H-CTX) and carboxyethylphosphoramide mustard (CEPM)] in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. METHODS: A plasma pharmacokinetic study was performed in non-tumor-bearing CD1-nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor-bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 40H-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 40H-CTX concentrations were separately measured using different LC-MS/MS methods. RESULTS: All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 40H-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 mu mol.hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (K-p(,uu)) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide K-p(,uu) was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in K-p(,uu) were observed between these groups for 40H-CTX and CEPM (overall mean 0.10 and 0.07). CONCLUSIONS: Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models."	"[Campagne, Olivia; Davis, Abigail; Zhong, Bo; Nair, Sreenath; Haberman, Victoria; Patel, Yogesh T.; Stewart, Clinton F.] St Jude Childrens Res Hosp, Pharmaceut Sci Dept, 262 Danny Thomas Pl, Memphis, TN 38105 USA; [Patel, Yogesh T.] Cognigen Corp, Buffalo, NY USA; [Janke, Laura] St Jude Childrens Res Hosp, Dept Vet Pathol Core, Memphis, TN 38105 USA; [Roussel, Martine F.] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA"	"Stewart, CF (corresponding author), St Jude Childrens Res Hosp, Pharmaceut Sci Dept, 262 Danny Thomas Pl, Memphis, TN 38105 USA."	"clinton.stewart@stjude.org"	"Nair, Sreenath/N-9843-2018"	"Nair, Sreenath/0000-0003-1286-4554"	"National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [CA21765, CA096832, R25CA23944]; American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children's Research HospitalAmerican Lebanese Syrian Associated Charities (ALSAC)"	"We thank Dana Farmer for growing and providing G3MB tumor cells for implantation and the Veterinary Pathology Core. This work was supported by grants from the National Cancer Institute (CA21765 (MFR; CFS), CA096832 (MFR), and R25CA23944), and the American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children's Research Hospital."	37	0	0	0	1	"CANADIAN SOC PHARMACEUTICAL SCIENCES"	"EDMONTON"	"3118 DENTISTRY-PHARMACY CENTRE UNIV ALBERTA CAMPUS, EDMONTON, ALBERTA T6G2N8, CANADA"	"1482-1826"	"NA"	"NA"	"J PHARM PHARM SCI"	"J. Pharm. Pharm. Sci."	"DEC 4"	2019	22	"NA"	612	629	"NA"	"NA"	18	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"KB0MG"	"WOS:000506192600001"	31815662	"DOAJ Gold, Green Accepted"	"NA"	"NA"	"2020-10-02"
"J"	"Lyons, MA"	"Lyons, Michael A."	"NA"	"A"	"Modeling and Simulation of Pretomanid Pharmacodynamics in Pulmonary Tuberculosis Patients"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"pretomanid; PA-824; tuberculosis; pharmacokinetics; pharmacodynamics; mathematical modeling"	"EARLY BACTERICIDAL ACTIVITY; NONREPLICATING MYCOBACTERIUM-TUBERCULOSIS; ANTITUBERCULOSIS DRUGS; NITROIMIDAZOPYRAN PA-824; TUBERCLE-BACILLI; MURINE MODEL; TIME; SPUTUM; PHARMACOKINETICS; CULTURE"	"Pretomanid (PA-824) is a nitroimidazole in clinical testing for the treatment of tuberculosis. A population pharmacodynamic model for pretomanid was developed using a Bayesian analysis of efficacy data from two early bactericidal activity (EBA) studies, PA-824-CL-007 and PA-824-CL-010, conducted in Cape Town, South Africa. The two studies included 122 adult male and female participants with newly diagnosed pulmonary tuberculosis who received once-daily oral pretomanid doses of either 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The structural model described capacity-limited growth and saturable drug-induced bacterial killing with separate rate equations for sputum solid culture CFU counts and liquid culture time to positivity (TTP) that were linked through a time constant. The posterior population geometric means and interindividual variability coefficients of variation were, respectively, 0.152 � 0.013 log(10) CFU/ml sputum/day and 54% � 6% for the maximum kill rate constant, 770 � 140 ng/ml and 48% � 17% for the pretomanid half-maximum effect plasma concentration, and 20.4 � 1.0 h and 20.8% � 0.1% for the time constant of proportionality between the CFU and TTP rate equations. Model simulations showed once-daily pretomanid at 100, 200, and 300 mg attained 58, 73, and 80%, respectively, of an expected maximum 14-day EBA of 0.136 log 10 CFU/ml sputum/day. These results establish a pretomanid exposure-efficacy relationship with dual outcomes for CFU counts and TTP and with potential applications to dose optimization of pretomanid-containing regimens."	"[Lyons, Michael A.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA"	"Lyons, MA (corresponding author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA."	"michael.lyons@colostate.edu"	"NA"	"NA"	"National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), HHS [R01AI125454]"	"The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), HHS, provided funding to M. A. Lyons under grant no. R01AI125454."	72	0	0	0	1	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"DEC"	2019	63	12	"NA"	"NA"	"e00732-19"	"10.1128/AAC.00732-19"	24	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"JP0YE"	"WOS:000497999100041"	31570404	"Green Published, Bronze"	"NA"	"NA"	"2020-10-02"
"J"	"Wang, JZ; Schneider, BK; Xue, J; Sun, P; Qiu, JC; Mochel, JP; Cao, XY"	"Wang, Jianzhong; Schneider, Benjamin K.; Xue, Jiao; Sun, Pan; Qiu, Jicheng; Mochel, Jonathan P.; Cao, Xingyuan"	"NA"	"A"	"Pharmacokinetic Modeling of Ceftiofur Sodium Using Non-linear Mixed-Effects in Healthy Beagle Dogs"	"FRONTIERS IN VETERINARY SCIENCE"	"English"	"Article"	"ceftiofur sodium; pharmacokinetics; NLME; monte carlo simulations; dogs"	"CRYSTALLINE-FREE ACID; MULTIPLE INTRAMUSCULAR ADMINISTRATIONS; SINGLE; METABOLITES; PLASMA; HYDROCHLORIDE; ROBENACOXIB; DISPOSITION; SIMULATION"	"Ceftiofur (CEF) sodium is a third-generation broad-spectrum cephalosporin commonly used in an extra-label manner in dogs for the treatment of respiratory and urinary system infections. To contribute to the literature supporting CEF use in companion animals, we have developed a compartmental, non-linear mixed-effects (NLME) model of CEF pharmacokinetics in dogs (PK). We then used the mathematical model to predict (via Monte Carlo simulation) the duration of time for which plasma concentrations of CEF and its pharmacologically active metabolites remained above minimum inhibitory concentrations (respiratory tract Escherichia coli spp.). Twelve healthy beagle dogs were administered either 2.2 mg/kg ceftiofur-sodium (CEF-Na) intravenously (I.V) or 2.2 mg/kg CEF-Na subcutaneously (S.C). Plasma samples were collected over a period of 72 h post-administration. To produce a measurement of total CEF, both CEF and CEF metabolites were derivatized into desfuroylceftiofur acetamide (DCA) before analysis by UPLC-MS/MS. No adverse effects were reported after I.V or S.C dosing. The NLME PK models were parameterized using the stochastic approximation expectation maximization algorithm as implemented in Monolix 2018R2. A two-compartment mamillarymodel with first-order elimination and first-order S.C absorption best described the available kinetic data. Final parameter estimates indicate that CEF has a low systemic clearance (0.25 L/h/kg) associated with a low global extraction ratio E = 0.02) and a moderate volume of distribution (2.97 L/kg) in dogs. The absolute bioavailability after S.C administration was high (93.7%). Gender was determined to be a significant covariate in explaining the variability of S.C absorption. Our simulations predicted that a dose of 2.2 mg/kg CEF-Na S.C would produce median plasma concentrations of CEF of at least 0.5 mu g/mL (MIC50) for similar to 30 h."	"[Wang, Jianzhong; Xue, Jiao; Sun, Pan; Qiu, Jicheng; Cao, Xingyuan] China Agr Univ, Coll Vet Med, Dept Vet Pharmacol & Toxicol, Beijing, Peoples R China; [Wang, Jianzhong; Xue, Jiao; Sun, Pan; Qiu, Jicheng; Cao, Xingyuan] Minist Agr & Rural Affairs, Lab Qual & Safety Risk Assessment Anim Prod Chem, Beijing, Peoples R China; [Wang, Jianzhong; Schneider, Benjamin K.; Mochel, Jonathan P.] Iowa State Univ, SMART Pharmacol, Biomed Sci, Coll Vet Med, Ames, IA 50011 USA; [Cao, Xingyuan] Minist Agr & Rural Affairs, Lab Detect Vet Drug Residues & Illegal Addit, Beijing, Peoples R China"	"Cao, XY (corresponding author), China Agr Univ, Coll Vet Med, Dept Vet Pharmacol & Toxicol, Beijing, Peoples R China.; Cao, XY (corresponding author), Minist Agr & Rural Affairs, Lab Qual & Safety Risk Assessment Anim Prod Chem, Beijing, Peoples R China.; Mochel, JP (corresponding author), Iowa State Univ, SMART Pharmacol, Biomed Sci, Coll Vet Med, Ames, IA 50011 USA.; Cao, XY (corresponding author), Minist Agr & Rural Affairs, Lab Detect Vet Drug Residues & Illegal Addit, Beijing, Peoples R China."	"jmochel@iastate.edu; cxy@cau.edu.cn"	"NA"	"Mochel, Jonathan/0000-0002-0997-3111"	"National Science & Technology Pillar Program during the Thirteenth Five-Year Plan Period [2016YFD0501309-1]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31672599]"	"This work was supported by the National Science & Technology Pillar Program during the Thirteenth Five-Year Plan Period (2016YFD0501309-1) and the National Natural Science Foundation of China (No. 31672599)."	38	2	2	1	2	"FRONTIERS MEDIA SA"	"LAUSANNE"	"AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND"	"2297-1769"	"NA"	"NA"	"FRONT VET SCI"	"Front. Vet. Sci."	"OCT 17"	2019	6	"NA"	"NA"	"NA"	363	"10.3389/fvets.2019.00363"	10	"Veterinary Sciences"	"Veterinary Sciences"	"JO3SL"	"WOS:000497500600001"	31681816	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Salinger, DH; Subramoney, V; Everitt, D; Nedelman, JR"	"Salinger, David H.; Subramoney, Vishak; Everitt, Daniel; Nedelman, Jerry R."	"NA"	"A"	"Population Pharmacokinetics of the Antituberculosis Agent Pretomanid"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"Mycobacterium tuberculosis; antibiotic resistance; multidrug resistance; tuberculosis"	"EARLY BACTERICIDAL ACTIVITY; PA-824; PYRAZINAMIDE; SAFETY; MOXIFLOXACIN; COMBINATIONS; TRIAL; MODEL"	"A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months. Pretomanid pharmacokinetic behavior was described by a one-compartment model that at a given dose was linear in its absorption and clearance processes but where the rate of absorption and extent of bioavailability changed with dose. Clearance and volume of distribution scaled allometrically with weight. Apparent clearance in females was 18% less than in males. Among HIV-positive subjects, absent the effect of CYP3A4-inducing antiretrovirals, apparent clearance was 6% higher. Some effects of total bilirubin and albumin were found, but the impacts on exposure were small. Bioavailability in the fasted condition was about half that in the fed condition. Relative bioavailability decreased with increasing dose in the fasted condition, but not for doses of <= 200 mg in the fed condition. HIV-positive subjects taking efavirenz and lopinavir/ritonavir had exposures that were reduced by 46 and 17%, respectively. There was little evidence for noteworthy effects of regimen partners on pretomanid. Standard diagnostics indicated that the model described the voluminous, diverse data well, so that the model could be used to generate exposure metrics for exposure/response analyses to be reported elsewhere."	"[Salinger, David H.; Subramoney, Vishak] Certara Inc, Princeton, NJ USA; [Everitt, Daniel; Nedelman, Jerry R.] TB Alliance, New York, NY 10005 USA"	"Nedelman, JR (corresponding author), TB Alliance, New York, NY 10005 USA."	"Jerry.Nedelman@tbaliance.org"	"NA"	"NA"	"TB Alliance; Australia's Department of Foreign Affairs and Trade; Bill and Melinda Gates FoundationBill & Melinda Gates Foundation; Germany's Federal Ministry of Education and Research through KfW; Irish Aid; Netherlands Ministry of Foreign Affairs; United Kingdom Department for International Development; United Kingdom Department of Health; United States Agency for International DevelopmentUnited States Agency for International Development (USAID)"	"This study was supported by TB Alliance with support from Australia's Department of Foreign Affairs and Trade, the Bill and Melinda Gates Foundation, Germany's Federal Ministry of Education and Research through KfW, Irish Aid, Netherlands Ministry of Foreign Affairs, United Kingdom Department for International Development, United Kingdom Department of Health, and the United States Agency for International Development."	24	1	1	1	4	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"OCT"	2019	63	10	"NA"	"NA"	"e00907-19"	"10.1128/AAC.00907-19"	10	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"IZ7ZN"	"WOS:000487320100051"	31405856	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Van Wijk, RC; Krekels, EHJ; Kantae, V; Ordas, A; Kreling, T; Harms, AC; Hankemeier, T; Spaink, HP; van der Graaf, PH"	"Van Wijk, Rob C.; Krekels, Elke H. J.; Kantae, Vasudev; Ordas, Anita; Kreling, Thijs; Harms, Amy C.; Hankemeier, Thomas; Spaink, Herman P.; van der Graaf, Piet H."	"NA"	"A"	"Mechanistic and Quantitative Understanding of Pharmacokinetics in Zebrafish Larvae through Nanoscale Blood Sampling and Metabolite Modeling of Paracetamol"	"JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS"	"English"	"Article"	"NA"	"ACETAMINOPHEN; ENZYMES"	"Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically studied and quantified pharmacokinetics in zebrafish larvae, and compared this to higher vertebrates, using paracetamol (acetaminophen) as a paradigm compound. A method was developed to sample blood from zebrafish larvae 5 days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulfate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analyzed through nonlinear mixed-effects modeling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein, with a median volume (interquartile range) of 1.12 nl (0.676-1.66 nl) per blood sample. Samples were pooled (n = 15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulfate was the major metabolite, and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well with reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development. SIGNIFICANCE STATEMENT In early phases of drug development, new compounds are increasingly screened in zebrafish larvae, but the internal drug exposure is often not taken into consideration. We developed innovative experimental and computational methods, including a blood-sampling technique, to measure the paradigm drug paracetamol (acetaminophen) and its major metabolites and quantify pharmacokinetics (absorption, distribution, elimination) in zebrafish larvae of 5 days post fertilization with a total volume of only 300 nl. These parameter values were scaled to higher vertebrates, including humans."	"[Van Wijk, Rob C.; Krekels, Elke H. J.; Kantae, Vasudev; Kreling, Thijs; Harms, Amy C.; Hankemeier, Thomas; van der Graaf, Piet H.] Leiden Univ, Syst Biomed & Pharmacol, Leiden Acad Ctr Drug Res, Leiden, Netherlands; [Ordas, Anita; Spaink, Herman P.] Leiden Univ, Anim Sci & Hlth, Inst Biol Leiden, Leiden, Netherlands; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England; [Kantae, Vasudev] AstraZeneca, Mechanist Biol & Profiling, Discovery Sci, BioPharmaceut R&D, Cambridge, England"	"van der Graaf, PH (corresponding author), Leiden Univ, POB 9502, NL-2300 RA Leiden, Netherlands."	"piet.vandergraaf@certara.com"	"NA"	"Krekels, Elke/0000-0001-6006-1567; Spaink, Herman/0000-0003-4128-9501; Kantae, Vasudev/0000-0001-8541-0882; Hankemeier, Thomas/0000-0001-7871-2073; Ordas, Anita/0000-0001-7833-5669"	"Leiden University Fund"	"This work was supported by the Leiden University Fund (A.O. and H.P.S.)."	45	1	1	0	3	"AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS"	"BETHESDA"	"9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA"	"0022-3565"	"1521-0103"	"NA"	"J PHARMACOL EXP THER"	"J. Pharmacol. Exp. Ther."	"OCT 1"	2019	371	1	15	24	"NA"	"10.1124/jpet.119.260299"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IX7OT"	"WOS:000485874600002"	31371482	"Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Kim, JH; Han, N; Kim, MG; Kim, YW; Jang, H; Yun, HY; Yu, MY; Kim, IW; Kim, YS; Oh, JM"	"Kim, Jae Hyun; Han, Nayoung; Kim, Myeong Gyu; Kim, Young Won; Jang, Hayoung; Yun, Hwi-Yeol; Yu, Mi-Yeon; Kim, In-Wha; Kim, Yon Su; Oh, Jung Mi"	"NA"	"A"	"Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients"	"SCIENTIFIC REPORTS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; BAYESIAN-ESTIMATION; ACID EXPOSURE; POLYMORPHISMS; CHINESE; IMPACT; PREDICTION; GUIDELINES; RISK"	"This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients."	"[Kim, Jae Hyun; Han, Nayoung; Kim, Myeong Gyu; Kim, Young Won; Jang, Hayoung; Kim, In-Wha; Oh, Jung Mi] Seoul Natl Univ, Coll Pharm, Seoul, South Korea; [Kim, Myeong Gyu] CHA Univ, Grad Sch Clin Pharm, Pochon, South Korea; [Yun, Hwi-Yeol] Chungnam Natl Univ, Coll Pharm, Daejeon, South Korea; [Yu, Mi-Yeon] Hanyang Univ, Dept Internal Med, Guri Hosp, Guri, South Korea; [Kim, Yon Su] Seoul Natl Univ, Kidney Res Inst, Coll Med, Seoul, South Korea; [Kim, Yon Su] Seoul Natl Univ, Coll Med, Dept Med Sci, Seoul, South Korea"	"Oh, JM (corresponding author), Seoul Natl Univ, Coll Pharm, Seoul, South Korea.; Kim, YS (corresponding author), Seoul Natl Univ, Kidney Res Inst, Coll Med, Seoul, South Korea.; Kim, YS (corresponding author), Seoul Natl Univ, Coll Med, Dept Med Sci, Seoul, South Korea."	"yonsukim@snu.ac.kr; jmoh@snu.ac.kr"	"NA"	"Oh, JungMi/0000-0002-1836-1707"	"Ministry of Food and Drug SafetyMinistry of Food & Drug Safety (MFDS) [15182MFDS504]"	"This research was supported by a grant (15182MFDS504) from Ministry of Food and Drug Safety in 2015 and the 2018 Brain Korea (BK) 21 Plus."	48	0	0	0	0	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"2045-2322"	"NA"	"NA"	"SCI REP-UK"	"Sci Rep"	"AUG 13"	2019	9	"NA"	"NA"	"NA"	11740	"10.1038/s41598-019-47876-0"	9	"Multidisciplinary Sciences"	"Science & Technology - Other Topics"	"IQ1NH"	"WOS:000480517100020"	31409869	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Morse, J; Hannam, JA; Cortinez, LI; Allegaert, K; Anderson, BJ"	"Morse, James; Hannam, Jacqueline A.; Ignacio Cortinez, Luis; Allegaert, Karel; Anderson, Brian J."	"NA"	"A"	"A manual propofol infusion regimen for neonates and infants"	"PEDIATRIC ANESTHESIA"	"English"	"Article"	"anesthetic techniques; anesthetics; infants; infusion; intravenous; neonates; pediatrics; propofol; TIVA"	"BISPECTRAL INDEX; CHILDREN; PHARMACOKINETICS; ANESTHESIA; INTUBATION; PREDICTION; PAEDFUSOR; MODELS; SIZE"	"Aims Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age-specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens. Methods Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0-3 years. Simulated steady state concentrations were 6-8 mu g.mL(-1) in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady-state concentration of 3 mu g.mL(-1) was determined using a heuristic approach. Results A manual dosing regimen predicted to achieve steady-state plasma concentration of 3 mu g.mL(-1) comprised a loading dose of 2 mg.kg(-1) followed by an infusion rate of 9 mg.kg(-1).h(-1) for the first 15 minutes, 7 mg.kg(-1).h(-1) from 15 to 30 minutes, 6 mg.kg(-1).h(-1) from 30 to 60 minutes, 5 mg.kg(-1).h(-1) from 1 to 2 hours in neonates (38-44 weeks postmenstrual age). Dose increased with age in those aged 1-2 years with a loading dose of 2.5 mg.kg(-1) followed by an infusion rate of 13 mg.kg(-1).h(-1) for the first 15 minutes, 12 mg.kg(-1).h(-1) from 15 to 30 minutes, 11 mg.kg(-1).h(-1) from 30 to 60 minutes, and 10 mg.kg(-1).h(-1) from 1 to 2 hours. Conclusion Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg(-1)) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data."	"[Morse, James; Hannam, Jacqueline A.] Auckland Univ, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand; [Ignacio Cortinez, Luis] Pontificia Univ Catolica Chile, Escuela Med, Div Anestesiol, Santiago, Chile; [Allegaert, Karel] Erasmus MC Sophia Childrens Hosp, Div Neonatol, Dept Pediat, Rotterdam, Netherlands; [Allegaert, Karel] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Anderson, Brian J.] Univ Auckland, Dept Anaesthesiol, Auckland, New Zealand"	"Anderson, BJ (corresponding author), Auckland Childrens Hosp, PICU, Pk Rd,Private Bag 92024, Auckland, New Zealand."	"briana@adhb.govt.nz"	"Morse, James/AAI-9377-2020; allegaert, karel/C-3611-2016"	"Morse, James/0000-0001-7500-0062; allegaert, karel/0000-0001-9921-5105"	"NA"	"NA"	33	7	7	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1155-5645"	"1460-9592"	"NA"	"PEDIATR ANESTH"	"Pediatr. Anesth."	"SEP"	2019	29	9	907	914	"NA"	"10.1111/pan.13706"	8	"Anesthesiology; Pediatrics"	"Anesthesiology; Pediatrics"	"IY9JJ"	"WOS:000480681800001"	31325395	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"van Esdonk, MJ; Stevens, J; Stuurman, FE; de Boon, WMI; Dehez, M; van der Graaf, PH; Burggraaf, J"	"van Esdonk, Michiel Joost; Stevens, Jasper; Stuurman, Frederik E.; de Boon, Wadim M. I.; Dehez, Marion; van der Graaf, Piet Hein; Burggraaf, Jacobus"	"NA"	"A"	"The Pharmacodynamic Effects of a Dopamine-Somatostatin Chimera Agonist on the Cardiovascular System"	"JOURNAL OF CARDIOVASCULAR PHARMACOLOGY"	"English"	"Article"	"rate-pressure product; neuroendocrine tumors; acromegaly; PK/PD modeling; phase I clinical trial"	"RATE-PRESSURE PRODUCT; CIRCADIAN-RHYTHM; RECEPTORS; EXERCISE; HEART"	"The quantification of the effect of pharmacological treatment on the cardiovascular system is complicated because of the high level of interindividual and circadian variability. Recently, a dopamine-somatostatin chimera, BIM23B065, was under investigation to concurrently target the somatostatin and dopamine D-2 receptors for the treatment of neuroendocrine tumors. However, both dopamine and somatostatin interact with different components of the cardiovascular system. This study established the response of the heart rate and the systolic blood pressure after administration of BIM23B065 in healthy male volunteers by analysis of the ratepressure product (RPP), in a model-informed analysis. The RPP in the supine position of placebo-treated subjects showed a clear circadian component, best described by 2 cosine functions. The pharmacokinetics of BIM23B065 and its metabolite were best described using 2-compartment models with different forms of elimination kinetics. The administration of BIM23B065 gave a statistically significant reduction in the RPP, after which the effect diminished because of the tolerance to the cardiovascular effects after prolonged exposure to BIM23B065. This model provided insight in the circadian rhythm of the RPP in the supine position and the level of interindividual variability in healthy male volunteers. The developed population pharmacokinetic/pharmacodynamic model quantified the interaction between BIM23B065 and the RPP, informing on the clinical pharmacological properties of BIM23B065."	"[van Esdonk, Michiel Joost; van der Graaf, Piet Hein; Burggraaf, Jacobus] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [van Esdonk, Michiel Joost; Stuurman, Frederik E.; de Boon, Wadim M. I.; Burggraaf, Jacobus] Ctr Human Drug Res, Zernikedreef 8, NL-2333 CL Leiden, Netherlands; [Stevens, Jasper] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands; [Dehez, Marion] Ipsen Innovat, Les Ulis, France; [van der Graaf, Piet Hein] Certara QSP, Canterbury, Kent, England"	"Burggraaf, J (corresponding author), Ctr Human Drug Res, Zernikedreef 8, NL-2333 CL Leiden, Netherlands."	"kb@chdr.nl"	"Stevens, Jasper/G-6118-2017"	"Stevens, Jasper/0000-0003-1601-9008"	"Ipsen"	"This study was funded by Ipsen."	24	1	1	0	0	"LIPPINCOTT WILLIAMS & WILKINS"	"PHILADELPHIA"	"TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA"	"0160-2446"	"1533-4023"	"NA"	"J CARDIOVASC PHARM"	"J. Cardiovasc. Pharmacol."	"AUG"	2019	74	2	128	136	"NA"	"10.1097/FJC.0000000000000695"	9	"Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy"	"Cardiovascular System & Cardiology; Pharmacology & Pharmacy"	"KC9LU"	"WOS:000507493600006"	31306369	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Harun, SN; Holford, NHG; Grimwood, K; Wainwright, CE; Hennig, S"	"Harun, Sabariah Noor; Holford, Nicholas H. G.; Grimwood, Keith; Wainwright, Claire E.; Hennig, Stefanie"	"Australasian Cystic Fibrosis Bron"	"A"	"Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis"	"THORAX"	"English"	"Article"	"NA"	"ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; BRONCHOALVEOLAR LAVAGE; OROPHARYNGEAL CULTURES; LUNG-FUNCTION; INFECTION; COLONIZATION; FUMIGATUS; TOBRAMYCIN; PATHOGENS; INFANTS"	"Background While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. Aim To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. Methods Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. Results Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. Conclusion In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus."	"[Harun, Sabariah Noor] USM, School Pharmaceut Sci, George Town, Malaysia; [Harun, Sabariah Noor; Hennig, Stefanie] Univ Queensland, Sch Pharm, Brisbane, Qld 4072, Australia; [Holford, Nicholas H. G.] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand; [Grimwood, Keith] Griffith Univ, Menzies Hlth Inst Queensland, Gold Coast, Qld, Australia; [Grimwood, Keith] Gold Coast Univ Hosp, Gold Coast, Qld, Australia; [Wainwright, Claire E.] Lady Cilento Childrens Hosp, Resp & Sleep Med, South Brisbane, Qld, Australia; [Wainwright, Claire E.] Univ Queensland, Child Hlth Res Ctr, Brisbane, Qld, Australia"	"Hennig, S (corresponding author), Univ Queensland, Sch Pharm, Brisbane, Qld 4072, Australia."	"s.hennig@uq.edu.au"	"harun, sabariah noor/E-5102-2012; Hennig, Stefanie/E-4426-2011; Wainwright, Claire/G-4218-2013"	"harun, sabariah noor/0000-0001-8476-7425; Grimwood, Keith/0000-0003-3174-9834; Hennig, Stefanie/0000-0001-5972-3711; Wainwright, Claire/0000-0001-8389-3809"	"National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [9937868, 351541]; Children's Hospital Foundation Queensland, Australia; Children's Hospital Foundation Brisbane; Queensland Health Research Fellowship; Alexander von Humboldt Foundation, GermanyAlexander von Humboldt Foundation"	"The original ACFBAL study was supported by the National Health and Medical Research Council (grants 9937868 and 351541) and the Children's Hospital Foundation Queensland, Australia. The tobramycin inhalation solution and delivery system used throughout the AC FBAL study was supplied by Pathogenesis Corporation, Chiron Corporation, and Novartis Pharmaceuticals Inc. CW was supported by a project grant from the Children's Hospital Foundation Brisbane and a Queensland Health Research Fellowship. SH was supported by a fellowship from the Alexander von Humboldt Foundation, Germany during part of the study."	39	4	4	1	2	"BMJ PUBLISHING GROUP"	"LONDON"	"BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND"	"0040-6376"	"1468-3296"	"NA"	"THORAX"	"Thorax"	"AUG"	2019	74	8	740	748	"NA"	"10.1136/thoraxjnl-2018-211548"	9	"Respiratory System"	"Respiratory System"	"IT5CD"	"WOS:000482879000004"	31203197	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Wang, JZ; Schneider, BK; Sun, P; Gong, XH; Qiu, JC; Li, J; Seo, YJ; Mochel, JP; Cao, XY"	"Wang, Jianzhong; Schneider, Benjamin K.; Sun, Pan; Gong, Xiaohui; Qiu, Jicheng; Li, Jing; Seo, Yeon-Jung; Mochel, Jonathan P.; Cao, Xingyuan"	"NA"	"A"	"Nonlinear mixed-effects pharmacokinetic modeling of the novel COX-2 selective inhibitor vitacoxib in dogs"	"JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS"	"English"	"Article"	"NA"	"POPULATION PHARMACOKINETICS; ROBENACOXIB; MAVACOXIB"	"The objective of this study was to develop a nonlinear mixed-effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two-compartment mamillary model with first-order elimination and first-order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low-to-moderate systemic clearance (0.35 L hr(-1) kg(-1)) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs."	"[Wang, Jianzhong; Sun, Pan; Gong, Xiaohui; Qiu, Jicheng; Cao, Xingyuan] China Agr Univ, Coll Vet Med, Dept Vet Pharmacol & Toxicol, Beijing, Peoples R China; [Wang, Jianzhong; Sun, Pan; Gong, Xiaohui; Qiu, Jicheng; Cao, Xingyuan] Minist Agr & Rural Affairs Peoples Republ China, Lab Qual & Safety Risk Assessment Anim Prod Chem, Beijing, Peoples R China; [Wang, Jianzhong; Schneider, Benjamin K.; Seo, Yeon-Jung; Mochel, Jonathan P.] Iowa State Univ, Coll Vet Med, SMART Pharmacol, Biomed Sci, Ames, IA USA; [Li, Jing] Beijing Orbiepharm Co Ltd, Beijing, Peoples R China; [Cao, Xingyuan] Minist Agr & Rural Affairs Peoples Republ China, Key Lab Detect Vet Drug Residues & Illegal Addit, Beijing, Peoples R China"	"Mochel, JP (corresponding author), Iowa State Univ, Coll Vet Med, Pharmacol, 2448 Lloyd,1809 S Riverside Dr, Ames, IA 50011 USA.; Cao, XY (corresponding author), China Agr Univ, Dept Pharmacol & Toxicol, Coll Vet Med, Yuanmingyuan West Rd 2, Beijing 100193, Peoples R China."	"jmochel@iastate.edu; jmochel@iastate.edu"	"NA"	"Mochel, Jonathan/0000-0002-0997-3111"	"Projects in the National Science & Technology Pillar Program during the Thirteenth Five-Year Plan Period [2016YFD0501309-1]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31672599]"	"This work was supported by the Projects in the National Science & Technology Pillar Program during the Thirteenth Five-Year Plan Period (2016YFD0501309-1) and National Natural Science Foundation of China (No. 31672599)."	26	3	3	0	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0140-7783"	"1365-2885"	"NA"	"J VET PHARMACOL THER"	"J. Vet. Pharmacol. Ther."	"SEP"	2019	42	5	530	540	"NA"	"10.1111/jvp.12802"	11	"Pharmacology & Pharmacy; Veterinary Sciences"	"Pharmacology & Pharmacy; Veterinary Sciences"	"IY6KV"	"WOS:000479827800001"	31369157	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Faisal, M; Cawello, W; Burckhardt, BB; de Hoon, J; Laer, S; van Hecken, A; Herbort, M; Breitkreutz, J; Wiedey, W; Klingmann, I; Spatenkova, L; Lagler, F; Moder, A; Khalil, F"	"Faisal, Muhammad; Cawello, Willi; Burckhardt, Bjoern B.; de Hoon, Jan; Laer, Stephanie; van Hecken, Anne; Herbort, Marissa; Breitkreutz, Joerg; Wiedey, Wolfgang; Klingmann, Ingrid; Spatenkova, Lucie; Lagler, Florian; Moder, Angelika; Khalil, Feras"	"LENA Consortium"	"A"	"Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets"	"FRONTIERS IN PEDIATRICS"	"English"	"Article"	"enalapril; enalaprilat; heart failure; population pharmacokinetics modeling analysis; NONMEM; orodispersible mini-tablets; child appropriate dosage forms"	"CONVERTING ENZYME-INHIBITORS; HEART-FAILURE; DRUG; DISPOSITION; FORMULATION; ABSORPTION; ETIOLOGY; TRANSIT"	"Enalapril is recommended as the first line of therapy and is proven to improve survival rates for treatment of Pediatric Heart Failure; however, an approved drug and child appropriate dosage formulation is still absent. The present analysis was conducted to perform a detailed model informed population pharmacokinetic analysis of prodrug enalapril and its active metabolite enalaprilat in serum and urine. Further, a model informed dosage form population-pharmacokinetic analysis was conducted to evaluate differences in pharmacokinetics of enalapril and its active metabolite enalaprilat when prodrug was administered to 24 healthy adults in a crossover, two periods, two treatments, phase I clinical trial using child-appropriate orodispersible mini-tablets (ODMT) and reference (Renitec (R)) dosage formulation. A simultaneous semi-mechanistic population-pharmacokinetic model was developed using NONMEM software, which predicted full profile serum and urine concentrations of enalapril and enalaprilat. First-order conditional estimation with interaction was used for parameter estimation. Transit compartments added using Erlang distribution method to predicted enalapril absorption and enalaprilat formation phases. Normalized body weight was identified as covariate related to enalapril volume of distribution. Visual predictive check (VPC) plots and conducted bootstrap analysis validated the model. The data from the two formulations were pooled for population-pharmacokinetic analysis and covariate effect of the formulation was found on mean transit time (MTT1) of enalapril absorption. In addition, data of each formulation were modeled separately and the estimated parameters of each individual administered both formulations were correlated using paired samples Wilcoxon rank test (p < 0.05 = significant) which also showed only a significant difference (p = 0.03) in MTT1 i.e., 5min early appearance of enalapril from ODMT compared to reference tablets. No difference in the pharmacokinetics of active enalaprilat was found from the ODMT compared to the reference formulation. The population pharmacokinetic analysis provided detailed information about the pharmacokinetics of enalapril and enalaprilat, which showed that the ODMT formulation might have similar pharmacodynamic response compared to the reference formulation."	"[Faisal, Muhammad; Cawello, Willi; Burckhardt, Bjoern B.; Laer, Stephanie] Heinrich Heine Univ Dusseldorf, Inst Clin Pharm & Pharmacotherapy, Dusseldorf, Germany; [de Hoon, Jan] Katholieke Univ Leuven, Univ Hosp Leuven, Ctr Clin Pharmacol, Leuven, Belgium; [van Hecken, Anne; Herbort, Marissa] Katholieke Univ Leuven, Ctr Clin Pharmacol, Leuven, Belgium; [Breitkreutz, Joerg; Wiedey, Wolfgang] Ethicare GmbH, Haltern Am See, Germany; [Klingmann, Ingrid; Spatenkova, Lucie] Pharmaplex Bvba, Brussels, Belgium; [Lagler, Florian; Moder, Angelika] Med Privatuniv PMU, Salzburg, Austria; [Khalil, Feras] Heinrich Heine Univ, Dusseldorf, Germany"	"Faisal, M (corresponding author), Heinrich Heine Univ Dusseldorf, Inst Clin Pharm & Pharmacotherapy, Dusseldorf, Germany."	"muhammad.faisal@HHU.de"	"NA"	"NA"	"European UnionEuropean Union (EU) [602295]; Higher Education Commission (HEC), PakistanHigher Education Commission of Pakistan; German Academic Exchange Program (DAAD), GermanyDeutscher Akademischer Austausch Dienst (DAAD)"	"The research work was a part of project LENA which is funded by a European Union Seventh Framework Program (FP7/2007-2013) under the grant agreement no 602295. The research work was also supported by a scholarship from the Higher Education Commission (HEC), Pakistan in collaboration with the German Academic Exchange Program (DAAD), Germany."	44	0	0	0	1	"FRONTIERS MEDIA SA"	"LAUSANNE"	"AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND"	"2296-2360"	"NA"	"NA"	"FRONT PEDIATR"	"Front. Pediatr."	"JUL 9"	2019	7	"NA"	"NA"	"NA"	281	"10.3389/fped.2019.00281"	11	"Pediatrics"	"Pediatrics"	"IH8WS"	"WOS:000474788100003"	31338356	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Tardivon, C; Desmee, S; Kerioui, M; Bruno, R; Wu, B; Mentre, F; Mercier, F; Guedj, J"	"Tardivon, Coralie; Desmee, Soline; Kerioui, Marion; Bruno, Rene; Wu, Benjamin; Mentre, France; Mercier, Francois; Guedj, Jeremie"	"NA"	"A"	"Association Between Tumor Size Kinetics and Survival in Patients With Urothelial Carcinoma Treated With Atezolizumab: Implication for Patient Follow-Up"	"CLINICAL PHARMACOLOGY & THERAPEUTICS"	"English"	"Article"	"NA"	"TIME-TO-EVENT; DYNAMIC PREDICTION; RESPONSE METRICS; MODELS; CANCER; CHEMOTHERAPY; PEMBROLIZUMAB; BIOMARKERS; CISPLATIN; VERSION"	"We characterized the association between tumor size kinetics and survival in patients with advanced urothelial carcinoma treated with atezolizumab (anti-programmed death-ligand 1, Tecentriq) using a joint model. The model, developed on data from 309 patients of a phase II clinical trial, identified the time-to-tumor growth and the instantaneous changes in tumor size as the best on-treatment predictors of survival. On the validation dataset containing data from 457 patients from a phase III study, the model predicted individual survival probability using 3-month or 6-month tumor size follow-up data with an area under the receptor-occupancy curve between 0.75 and 0.84, as compared with values comprised between 0.62 and 0.75 when the model included only information available at treatment initiation. Including tumor size kinetics in a relevant statistical framework improves the prediction of survival probability during immunotherapy treatment and may be useful to identify most-at-risk patients in real-time."	"[Tardivon, Coralie; Kerioui, Marion; Mentre, France; Guedj, Jeremie] Univ Paris, INSERM, IAME, F-75018 Paris, France; [Desmee, Soline; Kerioui, Marion] Univ Tours, Univ Nantes, UMR 1246, Inserm SPHERE, Tours, France; [Bruno, Rene] Roche Genentech, Clin Pharmacol, Marseille, France; [Wu, Benjamin] Genentech Inc, Clin Pharmacol, San Francisco, CA 94080 USA; [Mercier, Francois] Roche Innovat Ctr, Clin Pharmacol, Basel, Switzerland"	"Guedj, J (corresponding author), Univ Paris, INSERM, IAME, F-75018 Paris, France."	"jeremie.guedj@inserm.fr"	"; guedj, Jeremie/A-6842-2017"	"Bruno, Rene/0000-0003-0200-039X; Mercier, Francois/0000-0002-5685-1408; Mentre, france/0000-0002-7045-1275; guedj, Jeremie/0000-0002-5534-5482"	"NA"	"NA"	45	5	5	1	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0009-9236"	"1532-6535"	"NA"	"CLIN PHARMACOL THER"	"Clin. Pharmacol. Ther."	"OCT"	2019	106	4	810	820	"NA"	"10.1002/cpt.1450"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"IX9CJ"	"WOS:000474177000001"	30985002	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Kloprogge, F; Hill, LF; Booth, J; Klein, N; Irwin, AD; Dixon, G; Standing, JF"	"Kloprogge, Frank; Hill, Louise F.; Booth, John; Klein, Nigel; Irwin, Adam D.; Dixon, Garth; Standing, Joseph F."	"NA"	"A"	"Revising Pediatric Vancomycin Dosing Accounting for Nephrotoxicity in a Pharmacokinetic-Pharmacodynamic Model"	"ANTIMICROBIAL AGENTS AND CHEMOTHERAPY"	"English"	"Article"	"pharmacodynamics; pharmacokinetics; population pharmacokinetics"	"BLOOD-STREAM INFECTIONS; CRITICALLY-ILL CHILDREN; POPULATION PHARMACOKINETICS; MORTALITY; FAILURE; AREA"	"This study aimed to suggest an initial pediatric vancomycin dose regimen through population pharmacokinetic-pharmacodynamic modeling. A population pharmacokinetic approach was used to analyze vancomycin concentration-time data from a large pediatric cohort. Pharmacokinetic target attainment for patients with bloodstream isolates was compared with clinical outcome using logistic regression and classification and regression trees. Change in serum creatinine during treatment was used as an indicator of acute nephrotoxicity. Probability of acute kidney injury (50% increase from baseline) or kidney failure (75% increase from baseline) was evaluated using logistic regression. An initial dosing regimen was derived, personalized by age, weight, and serum creatinine, using stochastic simulations. Data from 785 hospitalized pediatric patients (1 day to 21 years of age) with suspected Gram-positive infections were collected. Estimated (relative standard error) typical clearance, volume of distribution 1, intercompartmental clearance, and volume of distribution 2 were (standardized to 70 kg) 4.84 (2.38) liters/h, 39.9 (8.15) liters, 3.85 (17.3) liters/h, and 37.8 (10.2) liters, respectively. While cumulative vancomycin exposure correlated positively with the development of nephrotoxicity (713 patients), no clear relationship between vancomycin area under the plasma concentration-time curve and efficacy was found (102 patients). Predicted probability of acute kidney injury and kidney failure with the optimized dosing regimen at day 5 was 10 to 15% and 5 to 10%, increasing by approximately 50% on day 7 and roughly 100% on day 10 across all age groups. This study presents the first data-driven pediatric dose selection to date accounting for nephrotoxicity, and it indicates that cumulative vancomycin exposure best describes risk of acute kidney injury and acute kidney failure."	"[Kloprogge, Frank] UCL, Inst Global Hlth, London, England; [Hill, Louise F.; Klein, Nigel; Irwin, Adam D.; Dixon, Garth; Standing, Joseph F.] UCL, Great Ormond St Inst Child Hlth, London, England; [Hill, Louise F.] St Georges Univ London, Inst Infect & Immun, London, England; [Booth, John; Klein, Nigel; Irwin, Adam D.; Dixon, Garth; Standing, Joseph F.] Great Ormond St Hosp Sick Children, London, England; [Irwin, Adam D.] Univ Queensland, Ctr Clin Res, Herston, Qld, Australia"	"Kloprogge, F (corresponding author), UCL, Inst Global Hlth, London, England."	"f.kloprogge@ucl.ac.uk"	"Irwin, Adam/D-7551-2017; Hill, Louise/L-9863-2015"	"Irwin, Adam/0000-0001-8974-6789; Hill, Louise/0000-0001-9912-3593; Kloprogge, Frank/0000-0001-7213-4559"	"Medical Research CouncilMedical Research Council UK (MRC) [MR/P014534/1, MR/M008665/1]; National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust; National Institute for Health Research Biomedical Research Center at Great Ormond Street Hospital for Children NHS Foundation Trust; University College London"	"No specific funding was received for this study. F.K. (MR/P014534/1) and J.F.S. (MR/M008665/1) have conducted the research as part of their Medical Research Council fellowships. The Medical Research Council had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Support at the institutional level came from the National Institute for Health Research Biomedical Research Center at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. L.F.H. is supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We have no competing interests to declare."	41	2	2	2	3	"AMER SOC MICROBIOLOGY"	"WASHINGTON"	"1752 N ST NW, WASHINGTON, DC 20036-2904 USA"	"0066-4804"	"1098-6596"	"NA"	"ANTIMICROB AGENTS CH"	"Antimicrob. Agents Chemother."	"MAY"	2019	63	5	"NA"	"NA"	"e00067-19"	"10.1128/AAC.00067-19"	12	"Microbiology; Pharmacology & Pharmacy"	"Microbiology; Pharmacology & Pharmacy"	"HU8SQ"	"WOS:000465561100011"	30833429	"Green Published, Green Accepted, Bronze"	"NA"	"NA"	"2020-10-02"
"J"	"Zhang, L; Wicha, WW; Bhavnani, SM; Rubino, CM"	"Zhang, Li; Wicha, Wolfgang W.; Bhavnani, Sujata M.; Rubino, Christopher M."	"NA"	"A"	"Prediction of lefamulin epithelial lining fluid penetration after intravenous and oral administration using Phase 1 data and population pharmacokinetics methods"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"PLEUROMUTILIN; BC-3781"	"Objectives Lefamulin is a semi-synthetic intravenous and oral pleuromutilin antibiotic with activity against pathogens commonly associated with community-acquired bacterial pneumonia. Using data from two Phase 1 studies, a population pharmacokinetics (PPK) model for lefamulin in plasma and epithelial lining fluid (ELF) was constructed. Methods Plasma pharmacokinetic (PK) data from a crossover, bioavailability, food-effect study and plasma and ELF PK data from a tissue penetration study in normal healthy volunteers were used to construct a PPK model for lefamulin. Model development involved refinement of a previous PPK model for intravenous and oral administration, followed by application of the model to plasma and ELF data from the tissue penetration study. The ELF penetration ratio of lefamulin was determined using model-based simulations. Results The PPK analysis data set contained 1103 plasma and 12 ELF lefamulin concentrations from 32 subjects. A three-compartment model with non-linear protein binding and two parallel absorption processes provided precise and unbiased estimated plasma concentration-time profiles. The absorption rate was slower and bioavailability was decreased after a high-fat/high-calorie meal. ELF data were well described using first-order rate constants into and out of the ELF compartment. The median predicted lefamulin total-drug ELF AUC(0-24)/free-drug plasma AUC(0-24) ratio was approximate to 5:1 after intravenous or oral administration. Conclusions The final PPK model allowed precise characterization of plasma and ELF exposures after intravenous and oral administration. The high ELF penetration ratio suggests that the penetration of lefamulin into the effect site is rapid and extensive, irrespective of route of administration."	"[Zhang, Li; Bhavnani, Sujata M.; Rubino, Christopher M.] Inst Clin Pharmacodynam, Schenectady, NY 12305 USA; [Wicha, Wolfgang W.] Nabriva Therapeut GmbH, Vienna, Austria"	"Rubino, CM (corresponding author), Inst Clin Pharmacodynam, Schenectady, NY 12305 USA."	"crubino@icpd.com"	"NA"	"NA"	"Nabriva Therapeutics - Nabriva Therapeutics"	"This work was supported by Nabriva Therapeutics. Copyediting support for this article was funded by Nabriva Therapeutics."	11	5	5	0	2	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"APR"	2019	74	"NA"	27	34	"NA"	"10.1093/jac/dkz088"	8	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"HU2ME"	"WOS:000465104400006"	30949708	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Berger, J; Vigan, M; Pereira, B; Nguyen, TT; Froissart, R; Belmatoug, N; Dalbies, F; Masseau, A; Rose, C; Serratrice, C; Pers, YM; Bertchansky, I; Camou, F; Bengherbia, M; Bourgne, C; Caillaud, C; Pettazzoni, M; Berrahal, A; Stirnemann, J; Mentre, F; Berger, MG"	"Berger, Juliette; Vigan, Marie; Pereira, Bruno; Thu Thuy Nguyen; Froissart, Roseline; Belmatoug, Nadia; Dalbies, Florence; Masseau, Agathe; Rose, Christian; Serratrice, Christine; Pers, Yves-Marie; Bertchansky, Ivan; Camou, Fabrice; Bengherbia, Monia; Bourgne, Celine; Caillaud, Catherine; Pettazzoni, Magali; Berrahal, Amina; Stirnemann, Jerome; Mentre, France; Berger, Marc G."	"NA"	"A"	"Intra-monocyte Pharmacokinetics of Imiglucerase Supports a Possible Personalized Management of Gaucher Disease Type 1"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"ENZYME REPLACEMENT THERAPY; MANNOSE-TERMINAL GLUCOCEREBROSIDASE; ACID-BETA-GLUCOSIDASE; DEFICIENCY; INTERNALIZATION; MANIFESTATIONS; OSTEOPONTIN; BIOMARKER; TURNOVER; ADULTS"	"Background and objectivesIntravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses.MethodsGlucocerebrosidase intra-monocyte activity was studied by flow cytometry. The pharmacokinetics of imiglucerase was analyzed using a population-pharmacokinetic model from a cohort of 31 patients with Gaucher disease type 1 who either started or were receiving long-term treatment with imiglucerase.ResultsA pharmacokinetic analysis of imiglucerase showed a two-compartment model with a high peak followed by a two-phase exponential decay (fast phase half-life: 0.36days; slow phase half-life: 9.7days) leading to a median 1.4-fold increase in glucocerebrosidase intra-monocyte activity from the pre-treatment activity (p=0.04). In patients receiving long-term treatment, for whom the imiglucerase dose per infusion was chosen on the basis of disease aggressiveness/response, imiglucerase clearance correlated with the administered dose. However, the residual glucocerebrosidase intra-monocyte activity value was dose independent, suggesting that the maintenance of imiglucerase residual activity is patient specific. Endogenous pre-treatment glucocerebrosidase intra-monocyte activity was the most informative single parameter for distinguishing patients without (n=10) and with a clinical indication (n=17) for starting enzyme replacement therapy (area under the receiver operating characteristic curve: 0.912; 95% confidence interval 0.8-1; p<0.001), as confirmed also by a factorial analysis of mixed data.ConclusionThis study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness. These findings can potentially improve Gaucher disease type 1 management algorithms and clinical decision making."	"[Berger, Juliette; Bourgne, Celine; Berrahal, Amina; Berger, Marc G.] CHU Estaing, CHU Clermont Ferrand, Hematol Biol, 1 Pl Lucie & Raymond Aubrac, F-63003 Clermont Ferrand 1, France; [Berger, Juliette; Bourgne, Celine; Berger, Marc G.] Univ Clermont Auvergne, CHU Estaing, CHELTER, Equipe Accueil 7453, 1 Pl Lucie & Raymond Aubrac, F-63003 Clermont Ferrand 1, France; [Berger, Juliette; Berger, Marc G.] CHU Estaing, CHU Clermont Ferrand, CRB Auvergne, 1 Pl Lucie & Raymond Aubrac, F-63003 Clermont Ferrand 1, France; [Vigan, Marie; Thu Thuy Nguyen; Mentre, France] INSERM, Paris, France; [Vigan, Marie; Thu Thuy Nguyen; Mentre, France] Univ Paris Diderot, IAME, UMR 1137, Paris, France; [Vigan, Marie; Mentre, France] Hop Xavier Bichat, AP HP, Dept Epidemiol Biostat & Clin Res, F-75018 Paris, France; [Pereira, Bruno] CHU Montpied, CHU Clermont Ferrand, DRCI, 58 Rue Montalembert, F-63003 Clermont Ferrand 1, France; [Froissart, Roseline; Pettazzoni, Magali] Hosp Civils Lyon, Ctr Biol & Pathol Est, Unite Malad Hereditaires Metab & Depistage Neonat, Serv Biochim & Biol Mol Grand Est, F-69677 Bron, France; [Belmatoug, Nadia; Bengherbia, Monia] Hop Beaujon, AP HP, Med Interne, 100 Blvd Gen Leclerc, F-92110 Clichy, France; [Dalbies, Florence] CHRU Brest, Site Hop Morvan, Hematol, 5 Ave Marechal Foch, F-29200 Brest, France; [Masseau, Agathe] CHU Nantes, Hotel Dieu, Med Interne, F-44093 Nantes, France; [Rose, Christian] Hop St Vincent de Paul, Oncohematol, Blvd Belfort, F-59000 Lille, France; [Serratrice, Christine] Hop Trois Chene, Hop Univ Geneve, Dept Med Interne, Chemin Pont Bochet 3, CH-1226 Geneva, Switzerland; [Pers, Yves-Marie] Lapeyronie Univ Hosp, Clin Immunol & Osteoarticular Dis Therapeut Unit, 371 Ave Doyen Gaston Giraud, F-34295 Montpellier, France; [Bertchansky, Ivan] St Eloi Univ Hosp, INSERM, U1183, Montpellier, France; [Camou, Fabrice] CHU Bordeaux, Serv Med Interne & Malad Infect, Grp Hosp Sud, Ave Magellan, F-33604 Pessac, France; [Caillaud, Catherine] Univ Paris 05, Inst Necker Enfants Malades, INSERM, U1151, Paris, France; [Caillaud, Catherine] Hop Univ Necker Enfants Malades, AP HP, Lab Biochim Metabol & Prote, 149 Rue Sevres, F-75005 Paris, France; [Stirnemann, Jerome] Hop Univ Geneve, Dept Med Interne, Gabrielle Perret Gentil 4, CH-1211 Geneva, Switzerland"	"Berger, MG (corresponding author), CHU Estaing, CHU Clermont Ferrand, Hematol Biol, 1 Pl Lucie & Raymond Aubrac, F-63003 Clermont Ferrand 1, France.; Berger, MG (corresponding author), Univ Clermont Auvergne, CHU Estaing, CHELTER, Equipe Accueil 7453, 1 Pl Lucie & Raymond Aubrac, F-63003 Clermont Ferrand 1, France.; Berger, MG (corresponding author), CHU Estaing, CHU Clermont Ferrand, CRB Auvergne, 1 Pl Lucie & Raymond Aubrac, F-63003 Clermont Ferrand 1, France."	"mberger@chu-clermontferrand.fr"	"NA"	"Pers, Yves-Marie/0000-0001-5927-3773; Camou, Fabrice/0000-0003-4715-224X"	"Sanofi-Genzyme [GZ-2010-10458]; Vaincre les Maladies Lysosomales (patient association, Paris, France) [VML S9MBerger]; CHU de Clermont-Ferrand [PHRC2010-AOI MBerger]"	"This study was supported by grants from Genzyme SA then Sanofi-Genzyme (Grant no. GZ-2010-10458) and from Vaincre les Maladies Lysosomales (patient association, Paris, France) (Grant no. VML S9MBerger) and research funding from CHU de Clermont-Ferrand as the promotor establishment, Marc G. Berger being an investigator coordinator (Grant no. PHRC2010-AOI MBerger)."	53	1	1	0	4	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"APR"	2019	58	4	469	482	"NA"	"10.1007/s40262-018-0708-8"	14	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HN3AE"	"WOS:000460055400005"	30128966	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Kashihara, Y; Terao, Y; Yoda, K; Hirota, T; Kubota, T; Kimura, M; Matsuki, S; Hirakawa, M; Irie, S; Ieiri, I"	"Kashihara, Yushi; Terao, Yui; Yoda, Kensaku; Hirota, Takeshi; Kubota, Toshio; Kimura, Miyuki; Matsuki, Shunji; Hirakawa, Masaaki; Irie, Shin; Ieiri, Ichiro"	"NA"	"A"	"Effects of magnesium oxide on pharmacokinetics of L-dopa/carbidopa and assessment of pharmacodynamic changes by a model-based simulation"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"L-Dopa; carbidopa; Magnesium oxide; Interaction; Pharmacokinetics; Model-based meta-analysis"	"O-METHYLTRANSFERASE INHIBITOR; PARKINSONS-DISEASE; L-DOPA; POPULATION PHARMACOKINETICS; HEALTHY-SUBJECTS; DOUBLE-BLIND; LEVODOPA; ENTACAPONE; CARBIDOPA; ACID"	"BackgroundMagnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA).MethodsThe effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa.ResultsIn vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC(0-12) of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa.ConclusionsThis is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required."	"[Kashihara, Yushi; Terao, Yui; Yoda, Kensaku; Hirota, Takeshi; Ieiri, Ichiro] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharmacokinet, Higashi Ku, 3-1-1 Maidashi, Fukuoka, Fukuoka 8128582, Japan; [Yoda, Kensaku; Hirakawa, Masaaki] Fukuoka Tokushukai Med Ctr, Hosp Pharm, Fukuoka, Fukuoka, Japan; [Kubota, Toshio] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharm & Pharmaceut Care, Fukuoka, Fukuoka, Japan; [Kimura, Miyuki; Matsuki, Shunji; Irie, Shin] SOUSEIKAI Fukuoka Mirai Hosp Clin Res Ctr, Fukuoka, Fukuoka, Japan"	"Ieiri, I (corresponding author), Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharmacokinet, Higashi Ku, 3-1-1 Maidashi, Fukuoka, Fukuoka 8128582, Japan."	"ieiri-ttr@umin.ac.jp"	"NA"	"NA"	"Japan Research Foundation for Clinical Pharmacology"	"This study was funded by the Japan Research Foundation for Clinical Pharmacology."	39	0	0	0	5	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"MAR"	2019	75	3	351	361	"NA"	"10.1007/s00228-018-2568-4"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HM0VN"	"WOS:000459165800008"	30382297	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"van Wijk, RC; Krekels, EHJ; Kantae, V; Harms, AC; Hankemeier, T; van der Graaf, PH; Spaink, HP"	"van Wijk, Rob C.; Krekels, Elke H. J.; Kantae, Vasudev; Harms, Amy C.; Hankemeier, Thomas; van der Graaf, Piet H.; Spaink, Herman P."	"NA"	"A"	"Impact of post-hatching maturation on the pharmacokinetics of paracetamol in zebrafish larvae"	"SCIENTIFIC REPORTS"	"English"	"Article"	"NA"	"LIFE STAGES; KINETICS"	"Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, is driving observed effects. Moreover, as the zebrafish larva is a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like the absorption and elimination of exogenous compounds, influencing the interpretation of observations and conclusions drawn from experiments at different larval ages. Here, using paracetamol as paradigm compound, mathematical modelling is used to quantify absorption and elimination rates from internal exposure over time profiles after waterborne treatment, as well as changes in these parameters in post-hatching larvae of 3, 4, and 5 days post fertilisation (dpf). An increase of 106% in absorption rate was observed between 3 and 4 dpf, but no further increase at 5 dpf, and an increase of 17.5% in elimination rate for each dpf. Paracetamol clearance, determined from elimination rate constants and reported total larval volumes of 253, 263, and 300 nL at 3, 4, and 5 dpf respectively, correlates best with higher vertebrates at 5 dpf. This suggests that when studying direct effects of exogenous compounds, experiments with zebrafish larvae are best performed at 5 dpf."	"[van Wijk, Rob C.; Krekels, Elke H. J.; Kantae, Vasudev; Harms, Amy C.; Hankemeier, Thomas; van der Graaf, Piet H.] Leiden Univ, LACDR, Syst Biomed & Pharmacol, Leiden, Netherlands; [van der Graaf, Piet H.] Certara OSP, Canterbury Innovat House, Canterbury, Kent, England; [Spaink, Herman P.] Leiden Univ, IBL, Anim Sci & Hlth, Leiden, Netherlands"	"Spaink, HP (corresponding author), Leiden Univ, IBL, Anim Sci & Hlth, Leiden, Netherlands."	"h.p.spaink@biology.leidenuniv.nl"	"van Wijk, Rob Christiaan/AAS-9679-2020; Spaink, Herman P./S-3586-2017; Hankemeier, Thomas/V-5407-2019"	"van Wijk, Rob Christiaan/0000-0001-7247-1360; Spaink, Herman P./0000-0003-4128-9501; Hankemeier, Thomas/0000-0001-7871-2073; Kantae, Vasudev/0000-0001-8541-0882; Krekels, Elke/0000-0001-6006-1567"	"NA"	"NA"	36	4	4	0	0	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"2045-2322"	"NA"	"NA"	"SCI REP-UK"	"Sci Rep"	"FEB 15"	2019	9	"NA"	"NA"	"NA"	2149	"10.1038/s41598-019-38530-w"	9	"Multidisciplinary Sciences"	"Science & Technology - Other Topics"	"HL5FS"	"WOS:000458752600001"	30770889	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Marshall, S; Madabushi, R; Manolis, E; Krudys, K; Staab, A; Dykstra, K; Visser, SAG"	"Marshall, Scott; Madabushi, Rajanikanth; Manolis, Efthymios; Krudys, Kevin; Staab, Alexander; Dykstra, Kevin; Visser, Sandra A. G."	"NA"	"M"	"Model-Informed Drug Discovery and Development: Current Industry Good Practice and Regulatory Expectations and Future Perspectives"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"METAANALYSIS; IMPACT"	"Good practices around model-informed drug discovery and development (MID3) aim to improve the implementation, standardization, and acceptance of these approaches within drug development and regulatory review. A survey targeted to clinical pharmacology and pharmacometric colleagues across industry, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) was conducted to understand current and future roles of MID3. The documented standards were generally affirmed as a good match to current industry practice and regulatory expectations, with some identified gaps that are discussed. All have seen at least a modest step forward in MID3 implementation associated with greater organizational awareness and share the expectation for a future wider use and impact. The priority within organizations was identified as a limitation with respect to the future of MID3. Finally, potential solutions, including a global overarching MID3 regulatory guideline, to facilitate greater acceptance by industry and regulatory decision makers are discussed."	"[Marshall, Scott] Pfizer R&D UK Ltd, Pharmacometr, Clin Pharmacol, Sandwich, Kent, England; [Madabushi, Rajanikanth; Krudys, Kevin] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, Silver Spring, MD USA; [Manolis, Efthymios] EMA, London, England; [Staab, Alexander] Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Biberach, Germany; [Dykstra, Kevin] qPharmetra LLC, Andover, MA USA; [Visser, Sandra A. G.] GlaxoSmithKline, Clin Pharmacol Modeling & Simulat, Philadelphia, PA USA"	"Marshall, S (corresponding author), Pfizer R&D UK Ltd, Pharmacometr, Clin Pharmacol, Sandwich, Kent, England."	"Scott.Marshall@pfizer.com"	"NA"	"NA"	"NA"	"NA"	35	9	9	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"FEB"	2019	8	2	87	96	"NA"	"10.1002/psp4.12372"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HM7DH"	"WOS:000459637000004"	30411538	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Xu, HM; Tong, X; Mugundu, G; Scott, ML; Cook, C; Arfvidsson, C; Pease, E; Zhou, DS; Lyne, P; Al-Huniti, N"	"Xu, Hongmei; Tong, Xiao; Mugundu, Ganesh; Scott, Martin L.; Cook, Carl; Arfvidsson, Cecilia; Pease, Elizabeth; Zhou, Diansong; Lyne, Paul; Al-Huniti, Nidal"	"NA"	"A"	"Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Dosing strategy; Population PK; Oncology"	"DOSE SELECTION; OLIGONUCLEOTIDES; SAFETY"	"Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4mg/kg as monotherapy or in combination with durvalumab, most at 3mg/kg (n=70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis revealed ideal body weight was not a significant covariate on the PK of danvatirsen; nor was age, sex or race. The model-based simulation suggested that steady state weekly AUC and Cmax were very similar between 3mg/kg and 200mg flat dosing (geometric mean of AUC: 62.5 vs. 63.4mgh/L and Cmax: 26.2 vs. 26.5mg/L for two dose groups) with slightly less overall between-subject variability in the flat dosing regimen. The switch to flat dosing was approved by multiple regulatory agencies, including FDA, EMA, PMDA and ANSM. Several ongoing studies have been evaluating flat dosing. Interim analysis from an ongoing study (D5660C00016, NCT03421353) has shown the observed steady state concentration from 200mg flat dose is in agreement with the model predictions. The population PK model could be further utilized in subsequent exposure-response efficacy and safety modelling."	"[Xu, Hongmei; Tong, Xiao; Mugundu, Ganesh; Zhou, Diansong; Al-Huniti, Nidal] AstraZeneca, IMED Biotech Unit, Early Clin Dev, Quantitat Clin Pharmacol, Boston, MA 02130 USA; [Scott, Martin L.; Cook, Carl; Lyne, Paul] AstraZeneca, IMED Biotech Unit, Oncol, Boston, MA USA; [Arfvidsson, Cecilia] AstraZeneca, IMED Biotech Unit, Early Clin Dev, Clin Sample & Bioanalyt Sci, Gothenburg, Sweden; [Pease, Elizabeth] AstraZeneca, IMED Biotech Unit, Oncol, Cambridge, England; [Mugundu, Ganesh] AstraZeneca, 35 Gatehouse Dr, Waltham, MA 02451 USA"	"Mugundu, G (corresponding author), AstraZeneca, IMED Biotech Unit, Early Clin Dev, Quantitat Clin Pharmacol, Boston, MA 02130 USA.; Mugundu, G (corresponding author), AstraZeneca, 35 Gatehouse Dr, Waltham, MA 02451 USA."	"Ganesh.Mugundu@astrazeneca.com"	"NA"	"NA"	"NA"	"NA"	15	0	0	1	2	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"FEB"	2019	46	1	65	74	"NA"	"10.1007/s10928-019-09619-6"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HL5RT"	"WOS:000458788400006"	30661177	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Olmos, I; Ibarra, M; Vazquez, M; Maldonado, C; Fagiolino, P; Giachetto, G"	"Olmos, Ismael; Ibarra, Manuel; Vazquez, Marta; Maldonado, Cecilia; Fagiolino, Pietro; Giachetto, Gustavo"	"NA"	"A"	"Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia"	"BIOMED RESEARCH INTERNATIONAL"	"English"	"Article"	"NA"	"PLASMA CLOZAPINE; ATYPICAL ANTIPSYCHOTICS; SERUM CONCENTRATIONS; MAJOR METABOLITES; GENERIC CLOZAPINE; MODEL; SMOKING; DRUGS; BIOEQUIVALENCE; CYP1A2"	"Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex (R)) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina (R)). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean � standard deviation for CZP and NCZP concentration was 421 � 262 ng/mL and 275 � 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting."	"[Olmos, Ismael] Vilardebo Hosp, Dept Pharm, Ave Millan 2515, Montevideo 11800, Uruguay; [Ibarra, Manuel; Vazquez, Marta; Maldonado, Cecilia; Fagiolino, Pietro] Univ Republica, Fac Chem, Pharmaceut Sci Dept, Ave Gen Flores 2124,POB 1157, Montevideo 11800, Uruguay; [Giachetto, Gustavo] Univ Republica, Fac Med, Pereira Rossell Hosp, Pediat Clin C, Bulevar Gral Artigas 1550, Montevideo 11600, Uruguay"	"Vazquez, M (corresponding author), Univ Republica, Fac Chem, Pharmaceut Sci Dept, Ave Gen Flores 2124,POB 1157, Montevideo 11800, Uruguay."	"ismaelolmos@gmail.com; mibarra@fq.edu.uy; mvazquez@fq.edu.uy; cmaldonado@fq.edu.uy; pfagioli@fq.edu.uy; ggiachet@gmail.com"	"NA"	"Ibarra, Manuel/0000-0002-0484-6367; Olmos, Ismael/0000-0002-3074-7637; Fagiolino, Pietro/0000-0001-6756-1601; Maldonado, Cecilia/0000-0002-9452-2111"	"NA"	"NA"	54	6	6	1	4	"HINDAWI LTD"	"LONDON"	"ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND"	"2314-6133"	"2314-6141"	"NA"	"BIOMED RES INT"	"Biomed Res. Int."	"NA"	2019	2019	"NA"	"NA"	"NA"	3163502	"10.1155/2019/3163502"	10	"Biotechnology & Applied Microbiology; Medicine, Research & Experimental"	"Biotechnology & Applied Microbiology; Research & Experimental Medicine"	"HP3VA"	"WOS:000461604600001"	30956977	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Gregoire, N; Marchand, S; Ferrandiere, M; Lasocki, S; Seguin, P; Vourc'h, M; Barbaz, M; Gaillard, T; Launey, Y; Asehnoune, K; Couet, W; Mimoz, O"	"Gregoire, Nicolas; Marchand, Sandrine; Ferrandiere, Martine; Lasocki, Sigismond; Seguin, Philippe; Vourc'h, Mickael; Barbaz, Mathilde; Gaillard, Thomas; Launey, Yoann; Asehnoune, Karim; Couet, William; Mimoz, Olivier"	"NA"	"A"	"Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment"	"JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY"	"English"	"Article"	"NA"	"PROTEIN-BINDING; PLASMA; PENETRATION; INFECTIONS; EXPOSURE; MODEL"	"Objectives: The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Methods: Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin (R)) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) >= 30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUC(u)/MIC >40 or >80) or toxicity (C-min >24.3 mg/L) targets. Results: Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (f(u)) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Conclusions: Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR >= 30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function."	"[Gregoire, Nicolas; Marchand, Sandrine; Couet, William; Mimoz, Olivier] INSERM, U1070, Pole Biol Sante, 1 Rue Georges Bonnet, F-86000 Poitiers, France; [Gregoire, Nicolas; Marchand, Sandrine; Couet, William; Mimoz, Olivier] Univ Poitiers, UFR Med Pharm, 6 Rue Mil, F-86000 Poitiers, France; [Marchand, Sandrine; Couet, William] CHU Poitiers, Serv Toxicol Pharmacocinet, 2 Rue Mil, F-86000 Poitiers, France; [Ferrandiere, Martine; Barbaz, Mathilde] CHU Tours, Serv Anesthesie & Reanimat, 2 Blvd Tonnelle, F-37044 Tours 9, France; [Lasocki, Sigismond; Gaillard, Thomas] CHU Angers, Serv Anesthesie & Reanimat, 4 Rue Larrey, F-49100 Angers, France; [Seguin, Philippe; Launey, Yoann] CHU Rennes, Serv Reanimat Chirurg, 2 Rue Henri Le Guilloux, F-35000 Rennes, France; [Vourc'h, Mickael; Asehnoune, Karim] CHU Nantes, Serv Anesthesie & Reanimat, Hotel Dieu, 1 Pl Alexis Ricordeau, F-44000 Nantes, France; [Mimoz, Olivier] CHU Poitiers, Serv Urgences, SAMU 86, SMUR, 2 Rue Mil, F-86000 Poitiers, France"	"Gregoire, N (corresponding author), INSERM, U1070, Pole Biol Sante, 1 Rue Georges Bonnet, F-86000 Poitiers, France.; Gregoire, N (corresponding author), Univ Poitiers, UFR Med Pharm, 6 Rue Mil, F-86000 Poitiers, France."	"nicolas.gregoire@univ-poitiers.fr"	"Launey, Yoann/AAN-7176-2020; lasocki, sigismond/G-9443-2016"	"Launey, Yoann/0000-0001-9105-8862; Gregoire, Nicolas/0000-0001-6436-3757"	"NovartisNovartis"	"This work was funded by an unrestricted grant from Novartis."	31	4	4	0	4	"OXFORD UNIV PRESS"	"OXFORD"	"GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND"	"0305-7453"	"1460-2091"	"NA"	"J ANTIMICROB CHEMOTH"	"J. Antimicrob. Chemother."	"JAN"	2019	74	1	117	125	"NA"	"10.1093/jac/dky374"	9	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"Infectious Diseases; Microbiology; Pharmacology & Pharmacy"	"HN8TU"	"WOS:000460469900017"	30295740	"Bronze"	"NA"	"NA"	"2020-10-02"
"J"	"Goulooze, SC; Krekels, EHJ; Hankemeier, T; Knibbe, CAJ"	"Goulooze, Sebastiaan C.; Krekels, Elke H. J.; Hankemeier, Thomas; Knibbe, Catherijne A. J."	"NA"	"M"	"Covariates in Pharmacometric Repeated Time-to-Event Models: Old and New (Pre)Selection Tools"	"AAPS JOURNAL"	"English"	"Article"	"covariate model building; empirical Bayes estimate; non-linear mixed effects modeling; repeated time-to-event"	"PHARMACOLOGY"	"During covariate modeling in pharmacometrics, computational time can be reduced by using a fast preselection tool to identify a subset of promising covariates that are to be tested with the more computationally demanding likelihood ratio test (LRT), which is considered to be the standard for covariate selection. There is however a lack of knowledge on best practices for covariate (pre)selection in pharmacometric repeated time-to-event (RTTE) models. Therefore, we aimed to systematically evaluate the performance of three covariate (pre)selection tools for RTTE models: the likelihood ratio test (LRT), the empirical Bayes estimates (EBE) test, and a novel Schoenfeld-like residual test. This was done in simulated datasets with and without a true time-constant covariate, and both in the presence and absence of high EBE shrinkage. In scenarios with a true covariate effect, all tools had comparable power to detect this effect. In scenarios without a true covariate effect, the false positive rates of the LRT and the Schoenfeld-like residual test were slightly inflated to 5.7% and 7.2% respectively, while the EBE test had no inflated false positive rate. The presence of high EBE shrinkage (>40%) did not affect the performance of any of the covariate (pre)selection tools. We found the EBE test to be a fast and accurate tool for covariate preselection in RTTE models. The novel Schoenfeld-like residual test proposed here had a similar performance in the tested scenarios and might be applied more readily to time-varying covariates, such as drug concentration and dynamic biomarkers."	"[Goulooze, Sebastiaan C.; Krekels, Elke H. J.; Hankemeier, Thomas; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Room 0-2-11,Einsteinweg 55, NL-2333 CC Leiden, Netherlands; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands"	"Knibbe, CAJ (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Room 0-2-11,Einsteinweg 55, NL-2333 CC Leiden, Netherlands.; Knibbe, CAJ (corresponding author), St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands."	"c.knibbe@antoniusziekenhuis.nl"	"Hankemeier, Thomas/V-5407-2019"	"Hankemeier, Thomas/0000-0001-7871-2073; Knibbe, Catherijne Annette Jantine/0000-0001-9893-4415; Goulooze, Sebastiaan/0000-0003-3369-6107"	"NA"	"NA"	21	0	0	0	2	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"JAN"	2019	21	1	"NA"	"NA"	11	"10.1208/s12248-018-0278-6"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HF0DR"	"WOS:000453829100002"	30565031	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Mian, P; van Esdonk, MJ; Olkkola, KT; de Winter, BCM; Liukas, A; Spriet, I; Tibboel, D; Petrovic, M; Koch, BCP; Allegaert, K"	"Mian, P.; van Esdonk, M. J.; Olkkola, K. T.; de Winter, B. C. M.; Liukas, A.; Spriet, I.; Tibboel, D.; Petrovic, M.; Koch, B. C. P.; Allegaert, K."	"NA"	"A"	"Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"acetaminophen; aging; elderly; geriatric; pharmacokinetics; variability"	"ACETAMINOPHEN; MANAGEMENT; PLASMA; PAIN; METABOLITES; AGE"	"Aims Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean) of 10 mg l(-1) as target for effective analgesia. Methods A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. Results A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a C-ss of 9.2 mg l(-1) and 7.2 mg l(-1), for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in C-ss above 5.4 and 4.1 mg l(-1), respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. Conclusions The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed."	"[Mian, P.; Tibboel, D.; Allegaert, K.] Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands; [Mian, P.; Tibboel, D.; Allegaert, K.] Erasmus MC Sophia Childrens Hosp, Dept Paediat Surg, Rotterdam, Netherlands; [van Esdonk, M. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [van Esdonk, M. J.] Ctr Human Drug Res, Leiden, Netherlands; [Olkkola, K. T.] Univ Helsinki, Dept Anaesthesiol Intens Care & Pain Med, Helsinki, Finland; [Olkkola, K. T.] Univ Helsinki, Cent Hosp, Helsinki, Finland; [de Winter, B. C. M.; Koch, B. C. P.] Erasmus MC, Dept Hosp Pharm, Rotterdam, Netherlands; [Liukas, A.] Turku Univ Hosp, Dept Anaesthesiol, Turku, Finland; [Spriet, I.] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Clin Pharmacol & Pharmacotherapy, Leuven, Belgium; [Spriet, I.] Univ Hosp Leuven, Dept Pharm, Leuven, Belgium; [Petrovic, M.] Ghent Univ Hosp, Dept Geriatr, Ghent, Belgium; [Allegaert, K.] Katholieke Univ Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Allegaert, K.] Erasmus MC Sophia Childrens Hosp, Div Neonatol, Dept Paediat, Rotterdam, Netherlands"	"Mian, P (corresponding author), Erasmus MC Sophia Childrens Hosp, Room NA-1523,Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands."	"p.mian@erasmusmc.nl"	"Mian, Paola/Y-1481-2019; van Esdonk, Michiel Joost/Y-7595-2019; allegaert, karel/C-3611-2016"	"van Esdonk, Michiel Joost/0000-0001-8159-0273; allegaert, karel/0000-0001-9921-5105; Olkkola, Klaus/0000-0001-7872-8665"	"NA"	"NA"	26	2	2	1	4	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"JAN"	2019	85	1	126	135	"NA"	"10.1111/bcp.13770"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"HF2WA"	"WOS:000454096200011"	30321459	"Bronze, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Valade, E; Valenzuela, B; Kakuda, TN; Westland, C; McClure, MW; Ouwerkerk-Mahadevan, S; Perez-Ruixo, JJ; Ackaert, O"	"Valade, Elodie; Valenzuela, Belen; Kakuda, Thomas N.; Westland, Christopher; McClure, Matthew W.; Ouwerkerk-Mahadevan, Sivi; Perez-Ruixo, Juan Jose; Ackaert, Oliver"	"NA"	"A"	"Characterizing the Pharmacokinetic Interaction Between Simeprevir and Odalasvir in Healthy Volunteers Using a Population Modeling Approach"	"AAPS JOURNAL"	"English"	"Article"	"drug-drug interaction; hepatitis C infection; odalasvir; pharmacokinetics; simeprevir"	"VIRUS"	"The aim of this study was to characterize the pharmacokinetic drug-drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach. Previous pharmacokinetic models developed to characterize the pharmacokinetics for each drug were used as starting point. The dual effect of simeprevir and odalasvir on their pharmacokinetic parameters was explored. Simulations were performed to assess the impact of the DDI on exposure parameters. In presence of odalasvir, the relative bioavailability of simeprevir increased by 26% and the apparent clearance was reduced following competitive inhibition depending on odalasvir plasma concentrations, with an inhibitory constant (K-i) estimated to be 1610ng/mL. The apparent odalasvir clearance was reduced by simeprevir plasma concentrations following an I-max model, characterized by a maximum inhibitory effect of 46.7% and an IC50 of 257ng/mL. Model-based simulations indicated that both C-max and AUC(24h) increased for both drugs, when co-administered. The pharmacokinetic model adequately describes the time course of plasma concentrations and their variability when simeprevir and/or odalasvir were orally administered. This model can be used as a first step to predict the exposures of concomitant administration of simeprevir and odalasvir in HCV-infected subjects. Data from study AL355-602 (NCT02512562) were used for this analysis."	"[Valade, Elodie; Ouwerkerk-Mahadevan, Sivi; Perez-Ruixo, Juan Jose; Ackaert, Oliver] Global Clin Pharmacol, Janssen Res & Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium; [Valenzuela, Belen] SGS Exprimo NV, Mechelen, Belgium; [Kakuda, Thomas N.; Westland, Christopher; McClure, Matthew W.] Alios BioPharma Inc, San Francisco, CA USA; [McClure, Matthew W.] Second Genome, San Francisco, CA USA"	"Ackaert, O (corresponding author), Global Clin Pharmacol, Janssen Res & Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium."	"oackaert@ITS.JNJ.com"	"Ruixo, Juan Jose Perez/AAF-3160-2020; Ruixo, Juan Jose Perez/AAL-2987-2020"	"PEREZ RUIXO, JUAN JOSE/0000-0001-9890-745X"	"NA"	"NA"	24	0	0	0	4	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"NOV"	2018	20	6	"NA"	"NA"	111	"10.1208/s12248-018-0271-0"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GX8XT"	"WOS:000448080000002"	30350297	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Jamsen, KM; Patel, K; Nieforth, K; Kirkpatrick, CMJ"	"Jamsen, Kris M.; Patel, Kashyap; Nieforth, Keith; Kirkpatrick, Carl M. J."	"NA"	"M"	"A Regression Approach to Visual Predictive Checks for Population Pharmacometric Models"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"MIXED EFFECT MODELS; QUANTIFICATION; SELECTION; LIMIT"	"A visual predictive check (VPC) is a common diagnostic procedure for population pharmacometric models. Typically, VPCs are generated by specifying intervals, or bins, of an independent variable (e.g., time). However, bin specification is not always straightforward and the choice of bins may affect the appearance, and possibly conclusions, of VPCs. The objective of this work was to demonstrate how regression techniques can be used to derive VPCs and prediction-corrected VPCs (pcVPCs) for population pharmacometric models. This alternative approach negates the need for empirical bin selection. The proposed method utilizes local and additive quantile regression. Implementation is straightforward and computationally acceptable. This work provides support for deriving VPCs and pcVPCs via regression techniques."	"[Jamsen, Kris M.; Patel, Kashyap; Nieforth, Keith] Certara Inc, Princeton, NJ 08540 USA; [Jamsen, Kris M.; Patel, Kashyap; Kirkpatrick, Carl M. J.] Monash Univ, Ctr Med Use & Safety, Fac Pharm & Pharmaceut Sci, Parkville, Vic, Australia"	"Jamsen, KM (corresponding author), Certara Inc, Princeton, NJ 08540 USA.; Jamsen, KM (corresponding author), Monash Univ, Ctr Med Use & Safety, Fac Pharm & Pharmaceut Sci, Parkville, Vic, Australia."	"kris.jamsen@monash.edu"	"Kirkpatrick, Carl MJ/F-1222-2010"	"Kirkpatrick, Carl/0000-0002-5715-1534"	"NA"	"NA"	29	3	3	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"OCT"	2018	7	10	678	686	"NA"	"10.1002/psp4.12319"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GY7KE"	"WOS:000448788100008"	30058222	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Ashraf, MW; Peltoniemi, MA; Olkkola, KT; Neuvonen, PJ; Saari, TI"	"Ashraf, Muhammad W.; Peltoniemi, Marko A.; Olkkola, Klaus T.; Neuvonen, Pertti J.; Saari, Teijo I."	"NA"	"A"	"Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"CLINICAL PHARMACOKINETICS; PARAMETER UNCERTAINTY; N-DEMETHYLATION; IN-VITRO; INHIBITION; PHARMACODYNAMICS; DISTRIBUTIONS; INACTIVATION; CYP2B6; VALUES"	"Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo. A pharmacokinetic model was developed with gut wall and hepatic clearances for S-ketamine, its primary metabolite norketamine, and ticlopidine. Nonlinear mixed effects modeling approach was used (NONMEM version 7.3.0), and the final model was evaluated with visual predictive checks and the sampling-importance-resampling procedure. Our final model produces biologically plausible output and demonstrates that ticlopidine is a strong inhibitor of CYP2B6 mediated S-ketamine metabolism. Simulations from our model may be used to evaluate chronic pain therapy with S-ketamine."	"[Ashraf, Muhammad W.; Peltoniemi, Marko A.; Saari, Teijo I.] Univ Turku, Dept Anesthesiol & Intens Care, Turku, Finland; [Peltoniemi, Marko A.; Saari, Teijo I.] Turku Univ Hosp, Div Perioperat Serv Intens Care & Pain Med, Turku, Finland; [Olkkola, Klaus T.] Univ Helsinki, Dept Anesthesiol Intens Care & Pain Med, Helsinki, Finland; [Olkkola, Klaus T.; Neuvonen, Pertti J.] Helsinki Univ Hosp, Helsinki, Finland; [Neuvonen, Pertti J.] Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland"	"Saari, TI (corresponding author), Univ Turku, Dept Anesthesiol & Intens Care, Turku, Finland.; Saari, TI (corresponding author), Turku Univ Hosp, Div Perioperat Serv Intens Care & Pain Med, Turku, Finland."	"teisaa@utu.fi"	"Neuvonen, Pertti J/G-4675-2011; Neuvonen, Pertti/Z-4818-2019"	"Neuvonen, Pertti/0000-0003-3631-9411; Ashraf, Muhammad Waqar/0000-0002-9947-1579; Olkkola, Klaus/0000-0001-7872-8665"	"Turku University Foundation; University of Turku Graduate School (University of Turku Drug Research Doctoral Program); Hospital District of South-West Finland, Finland [13821]"	"M.W. Ashraf was supported by a grant from Turku University Foundation, and personal research funding from the University of Turku Graduate School (University of Turku Drug Research Doctoral Program). T.I. Saari was supported by governmental research grant number 13821 from the Hospital District of South-West Finland, Finland."	45	9	11	0	1	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"OCT"	2018	7	10	687	697	"NA"	"10.1002/psp4.12346"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GY7KE"	"WOS:000448788100009"	30091858	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Cortinez, LI; Anderson, BJ"	"Ignacio Cortinez, Luis; Anderson, Brian J."	"NA"	"A"	"Modeling the pharmacokinetics and pharmacodynamics of sevoflurane using compartment models in children and adults"	"PEDIATRIC ANESTHESIA"	"English"	"Article"	"allometry; bispectral index; compartment models; pharmacodynamics; pharmacometrics"	"END-TIDAL SEVOFLURANE; MINIMUM ALVEOLAR CONCENTRATIONS; MAINTAINING BISPECTRAL INDEX; SPECTRAL EDGE FREQUENCY; DYNAMIC RELATIONSHIP; INHALATION ANESTHESIA; PEDIATRIC ANESTHESIA; SYSTEM MODEL; AGE; ISOFLURANE"	"BackgroundSevoflurane pharmacokinetics have been traditionally described using physiological models, while pharmacodynamics employed the use of minimal alveolar concentration. AimsThe integrated pharmacokinetic-pharmacodynamic relationship of sevoflurane in both adults and children was reviewed using compartment models. We wished to delineate age-related changes in both pharmacokinetics and pharmacodynamics. MethodsThe bispectral index and sevoflurane endtidal concentration were continuously measured in 50 patients, aged 3-71years, scheduled for minor surgery. During maintenance of anesthesia and after stable bispectral index values of 60-65 were obtained, the inspired concentration of sevoflurane was increased to 5 vol % for 5minutes or until BIS 40 and then decreased. Data were analyzed using mammillary compartments with nonlinear mixed effects population modeling. The covariate effects of age and size were investigated. ResultsA three-compartment PK model adequately described sevoflurane pharmacokinetics. Size standardization using allometry explained clearance and volume changes with age. The equilibration half-time (1.48minutes) increased with age, but could be predicted using allometry in those under 40years. The effect site concentration eliciting half the maximum response at age 40years was 1.3% (95%CI 1.22, 1.42) decreased with age from 1.6% at 3years to 1.1% at 70years. ConclusionPharmacokinetic compartment models offer an alternative method to describe inhalation anesthetic drug disposition and effects."	"[Ignacio Cortinez, Luis] Pontificia Univ Catolica Chile, Escuela Med, Div Anestesiol, Santiago, Chile; [Anderson, Brian J.] Univ Auckland, Dept Anesthesiol, Auckland, New Zealand"	"Anderson, BJ (corresponding author), Auckland Childrens Hosp, PICU, Pk Rd,Private Bag 92024, Auckland, New Zealand."	"briana@adhb.govt.nz"	"NA"	"NA"	"NA"	"NA"	32	4	4	1	7	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1155-5645"	"1460-9592"	"NA"	"PEDIATR ANESTH"	"Pediatr. Anesth."	"OCT"	2018	28	10	834	840	"NA"	"10.1111/pan.13465"	7	"Anesthesiology; Pediatrics"	"Anesthesiology; Pediatrics"	"GW3WN"	"WOS:000446839900002"	30117213	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Hannam, JA; Anderson, BJ; Potts, A"	"Hannam, Jacqueline A.; Anderson, Brian J.; Potts, Amanda"	"NA"	"A"	"Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy"	"PEDIATRIC ANESTHESIA"	"English"	"Article"	"drug interactions; drugs; pharmacodynamics; pharmacokinetics; response surface models"	"CONTROL FOLLOWING TONSILLECTOMY; VS. SEQUENTIAL-ANALYSIS; FIXED-DOSE COMBINATION; POSTOPERATIVE PAIN; DOUBLE-BLIND; DENTAL PAIN; CHILDREN; PHARMACOKINETICS; PARACETAMOL; RELIEF"	"BackgroundThe impact of tramadol in children given acetaminophen-ibuprofen combination therapy is uncertain in acute pediatric pain management. A model describing the interaction between these three drugs would be useful to understand the role of supplemental analgesic therapy. MethodsChildren undergoing tonsillectomy were given oral paracetamol and ibuprofen perioperatively. Blood was taken for paracetamol and ibuprofen drug assay on up to six occasions over 6h after the initial dose. Tramadol was administered by caregivers for unacceptable postoperative pain. Pain was measured using the Parent's Postoperative Pain Measurement rating two hourly on the first postoperative day. A first-order absorption, one-compartment linear model with first-order elimination was used to describe acetaminophen and ibuprofen disposition. Analgesia was described using an E-MAX model extended for three drugs, assuming additive effects. Curve fitting was performed using nonlinear mixed effects models. ResultsPharmacodynamic parameter estimates, expressed using fractional Hill equation, were maximum effect (E-MAX) 0.65 (95%CI 0.54, 0.74), the concentration of acetaminophen associated with 50% of the maximal drug effect (C-50,C-ACET) 7.06 (95%CI 7.03, 7.72) mg/L, and the ibuprofen C-50 (C-50,C-IBU) 3.95 (95%CI 2.57, 7.53) mg/L. The Hill coefficient was 1.48 (95%CI 0.92, 2.62) and an interaction term was fixed at zero (additivity). The half-time (t(1/2)keo) for equilibration between the plasma and effect site was 0.34hour (95%CI 0.23, 1.98) for acetaminophen and 1.04hour (95%CI 0.75, 1.77) for ibuprofen. Tramadol had a C-50,C-TRAM of 0.07 (95%CI 0.048, 1.07) mg/L with a t(1/2)keo,(TRAM) 1.78hour (95%CI 1.06, 1.96). ConclusionIbuprofen has an EC50 for analgesia in children similar to that of adults (3.95mg/L; 95%CI 2.57-7.53, vs 5-10mg/L adults). The maximum effect from combination therapy (ie, 65% reduction in pain score) achieves satisfactory analgesia with commonly used doses but increased dose adds little additional benefit. The addition of tramadol to this analgesic mixture prolongs analgesia duration."	"[Hannam, Jacqueline A.] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand; [Anderson, Brian J.] Univ Auckland, Dept Anaesthesiol, Auckland, New Zealand; [Potts, Amanda] Clin Solut NZ Ltd, Auckland, New Zealand"	"Anderson, BJ (corresponding author), Univ Auckland, Dept Anaesthesiol, Pk Rd, Grafton, New Zealand."	"briana@adhb.govt.nz"	"NA"	"NA"	"AFT Pharmaceuticals Ltd, Auckland, New Zealand"	"The study was sponsored by AFT Pharmaceuticals Ltd, Auckland, New Zealand. Dr Amanda Potts, Clinical Solutions NZ Ltd, received payment from the sponsor to conduct the trial in NZ."	45	8	8	0	6	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1155-5645"	"1460-9592"	"NA"	"PEDIATR ANESTH"	"Pediatr. Anesth."	"OCT"	2018	28	10	841	851	"NA"	"10.1111/pan.13464"	11	"Anesthesiology; Pediatrics"	"Anesthesiology; Pediatrics"	"GW3WN"	"WOS:000446839900003"	30117229	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Madelain, V; Baize, S; Jacquot, F; Reynard, S; Fizet, A; Barron, S; Solas, C; Lacarelle, B; Carbonnelle, C; Mentre, F; Raoul, H; de Lamballerie, X; Guedj, J"	"Madelain, Vincent; Baize, Sylvain; Jacquot, Frederic; Reynard, Stephanie; Fizet, Alexandra; Barron, Stephane; Solas, Caroline; Lacarelle, Bruno; Carbonnelle, Caroline; Mentre, France; Raoul, Herve; de Lamballerie, Xavier; Guedj, Jeremie"	"NA"	"A"	"Ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies"	"NATURE COMMUNICATIONS"	"English"	"Article"	"NA"	"T-705 FAVIPIRAVIR; ANIMAL-MODELS; INFECTION; DISEASE; EFFICACY; INTERFERON; MACAQUES; KINETICS; GUINEA; PLASMA"	"Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a similar to 50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFN alpha reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks."	"[Madelain, Vincent; Mentre, France; Guedj, Jeremie] Univ Paris Diderot, Sorbonne Paris Cite Paris, INSERM, IAME,UMR 1137, F-75018 Paris, France; [Baize, Sylvain; Reynard, Stephanie; Fizet, Alexandra] Ctr Int Rech Infectiol, Inst Pasteur, UBIVE, F-69007 Lyon, France; [Jacquot, Frederic; Barron, Stephane; Carbonnelle, Caroline; Raoul, Herve] US003 Inserm, Lab Inserm Jean Merieux P4, F-69365 Lyon, France; [Solas, Caroline; Lacarelle, Bruno] Aix Marseille Univ U105, Lab Pharmacocinet & Toxicol, Hop La Timone, SMARTc CRCM Inserm CNRS UMR1068 UMR7258, F-13005 Marseille, France; [de Lamballerie, Xavier] EPV Aix Marseille Univ, IRD 190, Inserm 1207, UMR Emergence Pathol Virales,EHESP,Inst Hosp,Univ, F-13385 Marseille, France"	"Madelain, V (corresponding author), Univ Paris Diderot, Sorbonne Paris Cite Paris, INSERM, IAME,UMR 1137, F-75018 Paris, France."	"vincent.madelain@inserm.fr"	"Guedj, Jeremie/A-6842-2017"	"Guedj, Jeremie/0000-0002-5534-5482; Madelain, Vincent/0000-0001-6200-0311; REYNARD, Stephanie/0000-0002-8508-5167; Baize, Sylvain/0000-0002-3234-7477"	"European UnionEuropean Union (EU) [666092]; St. Luke's International University (Tokyo, Japan)"	"We would like to thank the team involved in molecular and PK analyses (G. Piorkowski, K. Barthelemy, B. Pastorino, and L. Molina) as well as the teams of the Inserm Jean Merieux BSL4 laboratory for their help, expertise, management (E. Chevillard) and night and day work: animal facility staff (L. Barrot, A. Duthey, M. Langry, and A. Vallve) and in vitro analysis team (A. Bocquin, S. Godard, S. Mely, E. Moissonier, S. Mundweiler, D. Pannetier and D. Thomas). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 666092, and from the St. Luke's International University (Tokyo, Japan) in the framework of Research Program on Emerging and Re-emerging Infectious Diseases of the Japan Agency for Medical Research and Development (AMED)."	64	16	17	5	24	"NATURE PUBLISHING GROUP"	"LONDON"	"MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND"	"2041-1723"	"NA"	"NA"	"NAT COMMUN"	"Nat. Commun."	"OCT 1"	2018	9	"NA"	"NA"	"NA"	4013	"10.1038/s41467-018-06215-z"	11	"Multidisciplinary Sciences"	"Science & Technology - Other Topics"	"GV5AL"	"WOS:000446113000015"	30275474	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Beydon, N; Nguyen, TT; Amsallem, F; Denjean, A; Fenu, G; Seddon, P; Mentre, F; Alberti, C; Lombardi, E"	"Beydon, Nicole; Thu Thuy Nguyen; Amsallem, Francis; Denjean, Andre; Fenu, Grazia; Seddon, Paul; Mentre, France; Alberti, Corinne; Lombardi, Enrico"	"NA"	"A"	"Interrupter resistance to measure dose-response to salbutamol in wheezy preschool children"	"PEDIATRIC PULMONOLOGY"	"English"	"Article"	"asthma & early wheeze; bronchodilation; pharmacodynamic; pulmonary function testing"	"BRONCHODILATOR RESPONSE; AIRWAY-RESISTANCE; YOUNG-CHILDREN; LUNG-FUNCTION; FUNCTION TESTS; ASTHMA; SPIROMETRY; MODELS; REPEATABILITY; POPULATION"	"AimUsing a non-invasive lung function technique (interrupter resistance, Rint), we aimed to determine whether a dose-response to salbutamol could be detected in wheezy preschool children and if so, which dose of salbutamol should be administered to routinely evaluate bronchial reversibility. MethodWheezy children (3 to <7 years) were enrolled in a prospective multicenter study. Rint was measured at baseline, and after random assignment to a first dose (100 or 200g) and a second dose (cumulative dose: 400, 600, or 800g) of salbutamol. Data were analyzed using mixed modeling approach with an inhibitory maximal effect (I-max) model, to account for a sparse sampling design. Simulations were performed to predict the percentage of children with significant Rint reversibility at several doses. ResultsFinal results were available in 99 children out of 106 children included. The model adequately fitted the data, showing satisfactory goodness-of-fit plots and a low residual error of 8%. Children with uncontrolled symptoms had lower I-max (ie, showed less reversibility) compared to children with totally/partly controlled symptoms (0.23 vs. 0.31, P<0.001). Dose to reach 50% of I-max (D-50) was 51g. According to simulations, 88.1% of children with significant reversibility at dose 800g would already show significant reversibility at 400g. ConclusionInterrupter resistance was able to measure a dose-response curve to salbutamol in wheezy preschool children, which was similar to that of older patients. Young children require a high dose of salbutamol to correctly assess airway bronchodilator response, especially these with poor symptom control."	"[Beydon, Nicole] Hop Enfants Armand Trousseau, APHP, Unite Fonct Physiol Explorat Fonct Resp, Paris, France; [Beydon, Nicole] Ctr Rech St Antoine, INSERM, U938, Paris, France; [Thu Thuy Nguyen; Mentre, France] Univ Paris Diderot, IAME, INSERM, Sorbonne Paris Cite,UMR 1137, Paris, France; [Amsallem, Francis] CHRU Montpellier, Unite Pneumol Pediat, Montpellier, France; [Denjean, Andre] Hop Robert Debre, APHP, Serv Physiol Explorat Fonct Resp, Paris, France; [Fenu, Grazia; Lombardi, Enrico] Meyer Paediat Univ Hosp, Paediat Pulm Unit, Florence, Italy; [Seddon, Paul] Royal Alexandra Childrens Hosp, Resp Care, Brighton, E Sussex, England; [Alberti, Corinne] Hop Enfants Robert Debre, AP HP, Unite Epidemiol Clin, Paris, France; [Alberti, Corinne] Univ Paris Diderot, INSERM, Sorbonne Paris Cite, CIE5, Paris, France"	"Beydon, N (corresponding author), Hop Armand Trousseau, Unite Fonct Physiol Explorat Fonct Resp EFR, 26 Ave Docteur Arnold Netter, F-75571 Paris 12, France."	"nicole.beydon@trs.aphp.fr"	"Lombardi, Enrico/K-3356-2016"	"Lombardi, Enrico/0000-0003-4749-9091"	"Programme Hospitalier de Recherche Clinique [P100504]"	"Programme Hospitalier de Recherche Clinique, Grant number: P100504"	40	2	2	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"8755-6863"	"1099-0496"	"NA"	"PEDIATR PULM"	"Pediatr. Pulmonol."	"SEP"	2018	53	9	1252	1259	"NA"	"10.1002/ppul.24116"	8	"Pediatrics; Respiratory System"	"Pediatrics; Respiratory System"	"GR4OT"	"WOS:000442593900013"	29972634	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Olafsdottir, HK; Leander, J; Almquist, J; Jirstrand, M"	"Olafsdottir, Helga Kristin; Leander, Jacob; Almquist, Joachim; Jirstrand, Mats"	"NA"	"M"	"Exact Gradients Improve Parameter Estimation in Nonlinear Mixed Effects Models with Stochastic Dynamics"	"AAPS JOURNAL"	"English"	"Article"	"extended Kalman filter; first-order conditional estimation (FOCE); nonlinear mixed effects modeling; sensitivity equations; stochastic differential equations"	"DIFFERENTIAL-EQUATIONS; NICOTINIC-ACID; KALMAN FILTER; IMPLEMENTATION; INSULIN; TIME"	"Nonlinear mixed effects (NLME) modeling based on stochastic differential equations (SDEs) have evolved into a promising approach for analysis of PK/PD data. SDE-NLME models go beyond the realm of standard population modeling as they consider stochastic dynamics, thereby introducing a probabilistic perspective on the state variables. This article presents a summary of the main contributions to SDE-NLME models found in the literature. The aims of this work were to develop an exact gradient version of the first-order conditional estimation (FOCE) method for SDE-NLME models and to investigate whether it enabled faster estimation and better gradient precision/accuracy compared to the use of gradients approximated by finite differences. A simulation-estimation study was set up whereby finite difference approximations of the gradients of each level were interchanged with the exact gradients. Following previous work, the uncertainty of the state variables was accounted for using the extended Kalman filter (EKF). The exact gradient FOCE method was implemented in Mathematica 11 and evaluated on SDE versions of three common PK/PD models. When finite difference gradients were replaced by exact gradients at both FOCE levels, relative runtimes improved between 6- and 32-fold, depending on model complexity. Additionally, gradient precision/accuracy was significantly better in the exact gradient case. We conclude that parameter estimation using FOCE with exact gradients can successfully be applied to SDE-NLME models."	"[Olafsdottir, Helga Kristin; Leander, Jacob; Almquist, Joachim; Jirstrand, Mats] Fraunhofer Chalmers Ctr, Chalmers Sci Pk, Gothenburg, Sweden; [Olafsdottir, Helga Kristin; Leander, Jacob] Chalmers Univ Technol, Dept Math Sci, Gothenburg, Sweden; [Olafsdottir, Helga Kristin; Leander, Jacob] Univ Gothenburg, Gothenburg, Sweden; [Leander, Jacob; Almquist, Joachim] AstraZeneca, IMED Biotech Unit, Quantitat Clin Pharmacol, Early Clin Dev, Gothenburg, Sweden; [Almquist, Joachim] Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden"	"Olafsdottir, HK (corresponding author), Fraunhofer Chalmers Ctr, Chalmers Sci Pk, Gothenburg, Sweden.; Olafsdottir, HK (corresponding author), Chalmers Univ Technol, Dept Math Sci, Gothenburg, Sweden.; Olafsdottir, HK (corresponding author), Univ Gothenburg, Gothenburg, Sweden."	"khelga@chalmers.se"	"NA"	"Jirstrand, Mats/0000-0002-6612-8037; Leander, Jacob/0000-0002-7411-2967"	"Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research"	"This project has been supported by the Swedish Foundation for Strategic Research, which is gratefully acknowledged."	40	0	0	0	1	"SPRINGER"	"NEW YORK"	"ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES"	"1550-7416"	"NA"	"NA"	"AAPS J"	"AAPS J."	"SEP"	2018	20	5	"NA"	"NA"	88	"10.1208/s12248-018-0232-7"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GP2IF"	"WOS:000440652300001"	30069613	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"Vucenovic, VT; Rajkovaca, Z; Jelic, D; Stanimirovic, D; Vuleta, G; Miljkovic, B; Vucicevic, K"	"Vucenovic, Valentina Topic; Rajkovaca, Zvezdana; Jelic, Dijana; Stanimirovic, Dragi; Vuleta, Goran; Miljkovic, Branislava; Vucicevic, Katarina"	"NA"	"A"	"Investigation of factors influencing radioiodine (I-131) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Radioiodine uptake; Variability; Population model; Benign thyroid disorders"	"GRAVES-DISEASE; RADIOACTIVE IODINE; NODULAR GOITER; DOSIMETRY PRIOR; HALF-LIFE; THERAPY; HYPERTHYROIDISM; METHIMAZOLE; PRETREATMENT; MEDICATION"	"Radioiodine (I-131) therapy is the common treatment option for benign thyroid diseases. The objective of this study was to characterize I-131 biokinetics in patients with benign thyroid disease and to investigate and quantify the influence of patients' demographic and clinical characteristics on intra-thyroidal I-131 kinetics by developing a population model. Population pharmacokinetic analysis was performed using a nonlinear mixed effects approach. Data sets of 345 adult patients with benign thyroid disease, retrospectively collected from patients' medical records, were evaluated in the analysis. The two-compartment model of I-131 biokinetics representing the blood compartment and thyroid gland was used as the structural model. Results of the study indicate that the rate constant of the uptake of I-131 into the thyroid (k (tu)) is significantly influenced by clinical diagnosis, age, functional thyroid volume, free thyroxine in plasma (fT(4)), use of anti-thyroid drugs, and time of discontinuation of therapy before administration of the radioiodine (THDT), while the effective half-life of I-131 is affected by the age of the patients. Inclusion of the covariates in the base model resulted in a decrease of the between subject variability for k (tu) from 91 (3.9) to 53.9 (4.5)%. This is the first population model that accounts for the influence of fT(4) and THDT on radioiodine kinetics. The model could be used for further investigations into the correlation between thyroidal exposure to I-131 and the outcome of radioiodine therapy of benign thyroid disease as well as the development of dosing recommendations."	"[Vucenovic, Valentina Topic; Jelic, Dijana] Univ Banja Luka, Dept Pharm, Fac Med, Save Mrkalja 14, Banja Luka 78000, Bosnia & Herceg; [Rajkovaca, Zvezdana; Stanimirovic, Dragi; Vuleta, Goran] Univ Clin Ctr Republ Srpska, Inst Nucl Med & Thyroid Gland Dis, 12 Beba Bb, Banja Luka 78000, Bosnia & Herceg; [Miljkovic, Branislava; Vucicevic, Katarina] Univ Belgrade, Dept Pharmacokinet & Clin Pharm, Fac Pharm, Vojvode Stepe 450, Belgrade 11000, Serbia"	"Vucenovic, VT (corresponding author), Univ Banja Luka, Dept Pharm, Fac Med, Save Mrkalja 14, Banja Luka 78000, Bosnia & Herceg."	"valentina.topic.vucenovic@med.unibl.org"	"Vucicevic, Katarina/W-1032-2019; Vucicevic, Katarina/AAZ-7835-2020"	"Vucicevic, Katarina/0000-0001-9676-5785;"	"NA"	"NA"	45	0	0	0	4	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"AUG"	2018	74	8	1037	1045	"NA"	"10.1007/s00228-018-2459-8"	9	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GM6GZ"	"WOS:000438263100007"	29754217	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Yin, AY; Yamada, A; Stam, WB; van Hasselt, JGC; van der Graaf, PH"	"Yin, Anyue; Yamada, Akihiro; Stam, Wiro B.; van Hasselt, Johan G. C.; van der Graaf, Piet H."	"NA"	"A"	"Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin in vasoconstriction"	"BRITISH JOURNAL OF PHARMACOLOGY"	"English"	"Article"	"NA"	"SMALL MESENTERIC-ARTERY; SMOOTH-MUSCLE-CELLS; HYPERTENSIVE-RATS; CONTRACTILE RESPONSES; RESISTANCE VESSELS; RECEPTOR AGONISTS; IN-VIVO; AORTA; AFFINITY; PHENOXYBENZAMINE"	"BACKGROUND AND PURPOSE Development of combination therapies has received significant interest in recent years. Previously, a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction and performed inter-species scaling to humans using this mechanism-based model. EXPERIMENTAL APPROACH Contractile data were obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine-vasopressin with or without pretreatment with the irreversible -adrenoceptor antagonist, phenoxybenzamine. Data were analysed using the 2R-1T model to characterize the observed exposure-response relationships and drug-drug interaction. The model was then scaled to humans by accounting for differences in receptor density. KEY RESULTS With receptor affinities set to published values, the 2R-1T model satisfactorily characterized the interaction between noradrenaline and arginine-vasopressin in rat small mesenteric arteries (relative standard error <= 20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries. CONCLUSIONS AND IMPLICATIONS The 2R-1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments."	"[Yin, Anyue; Yamada, Akihiro; van Hasselt, Johan G. C.; van der Graaf, Piet H.] Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands; [Yin, Anyue] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands; [Yamada, Akihiro] Astellas Pharma Inc, Clin Pharmacol, PKMS Grp, Tokyo, Japan; [Stam, Wiro B.] Dutch Minist Hlth & Sports, The Hague, Netherlands; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England"	"van der Graaf, PH (corresponding author), Canterbury Innovat Ctr, Certara QSP, Unit 43, Univ Rd, Canterbury CT2 7FG, Kent, England."	"piet@certara.com"	"van Hasselt, Coen/H-5593-2019"	"Yin, Anyue/0000-0001-9924-6040; van Hasselt, J.G.C./0000-0002-1664-7314"	"IMI TransQST consortium"	"This work was supported by the IMI TransQST consortium. We also would like to thank Dr Viji Chelliah (Certara QSP) for help with receptor expression data mining."	54	4	4	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0007-1188"	"1476-5381"	"NA"	"BRIT J PHARMACOL"	"Br. J. Pharmacol."	"AUG"	2018	175	16	3394	3406	"NA"	"10.1111/bph.14385"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GO1WK"	"WOS:000439750500018"	29859008	"Green Published, Bronze"	"NA"	"NA"	"2020-10-02"
"J"	"Oniki, K; Watanabe, T; Kudo, M; Izuka, T; Ono, T; Matsuda, K; Sakamoto, Y; Nagaoka, K; Imafuku, T; Ishima, Y; Watanabe, H; Maruyama, T; Otake, K; Ogata, Y; Saruwatari, J"	"Oniki, Kentaro; Watanabe, Takehisa; Kudo, Miku; Izuka, Tomoko; Ono, Tatsumasa; Matsuda, Kazuki; Sakamoto, Yuki; Nagaoka, Katsuya; Imafuku, Tadashi; Ishima, Yu; Watanabe, Hiroshi; Maruyama, Toru; Otake, Koji; Ogata, Yasuhiro; Saruwatari, Junji"	"NA"	"A"	"Modeling of the Weight Status and Risk of Nonalcoholic Fatty Liver Disease in Elderly Individuals: The Potential Impact of the Disulfide Bond-Forming Oxidoreductase A-Like Protein (DsbA-L) Polymorphism on the Weight Status"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"CGAMP-STING PATHWAY; ADIPONECTIN MULTIMERIZATION; INSULIN-RESISTANCE; SERUM-ALBUMIN; PREVALENCE; MANAGEMENT; OBESITY"	"Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. Disulfide bond-forming oxidoreductase A-like protein (DsbA-L) is known to be a key molecule in protection against obesity and obesity-induced inflammation. In the present study, we used a modeling and simulation approach in an attempt to develop body mass index (BMI) and BMI-based NAFLD prediction models incorporating the DsbA-L polymorphism to predict the BMI and NAFLD in 341 elderly subjects. A nonlinear mixed-effect model best represented the sigmoidal relationship between the BMI and the logit function of the probability of NAFLD prevalence. The final models for BMI and NAFLD showed that DsbA-L rs1917760 polymorphism, age, and gender were associated with the BMI, whereas gender, patatin-like phospholipase 3 rs738409 polymorphism, HbA1c, and high-density and low-density lipoprotein cholesterol levels were associated with the risk of NAFLD. This information may aid in the genetic-based prevention of obesity and NAFLD in the general elderly population."	"[Oniki, Kentaro; Kudo, Miku; Izuka, Tomoko; Ono, Tatsumasa; Matsuda, Kazuki; Sakamoto, Yuki; Saruwatari, Junji] Kumamoto Univ, Grad Sch Pharmaceut Sci, Div Pharmacol & Therapeut, Kumamoto, Japan; [Watanabe, Takehisa; Nagaoka, Katsuya; Ogata, Yasuhiro] Kumamoto Univ, Fac Life Sci, Dept Gastroenterol & Hepatol, Kumamoto, Japan; [Imafuku, Tadashi; Watanabe, Hiroshi; Maruyama, Toru] Kumamoto Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, Kumamoto, Japan; [Sakamoto, Yuki] Tokushima Univ, Inst Biomed Sci, Dept Pharmacokinet & Biopharmaceut, Tokushima, Japan; [Otake, Koji] Japanese Red Cross Kumamoto Hlth Care Ctr, Kumamoto, Japan; [Saruwatari, Junji] Kumamoto Univ, Ctr Clin Pharmaceut Sci, Kumamoto, Japan"	"Saruwatari, J (corresponding author), Kumamoto Univ, Grad Sch Pharmaceut Sci, Div Pharmacol & Therapeut, Kumamoto, Japan.; Saruwatari, J (corresponding author), Kumamoto Univ, Ctr Clin Pharmaceut Sci, Kumamoto, Japan."	"junsaru@gpo.kumamoto-u.ac.jp"	"Saruwatari, Junji/Q-7748-2019"	"Saruwatari, Junji/0000-0001-6266-1347"	"Ministry of Education, Culture, Sports, Science and Technology, JapanMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [25860117, 15K18925, 16K08406]; Japan Research Foundation for Clinical Pharmacology"	"The work was supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant numbers: 25860117, 15K18925, and 16K08406), and the Japan Research Foundation for Clinical Pharmacology."	37	4	4	1	5	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"JUN"	2018	7	6	384	393	"NA"	"10.1002/psp4.12292"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GL2FU"	"WOS:000436934400004"	29569850	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Schultink, AHMD; Boekhout, AH; Gietema, JA; Burylo, AM; Dorlo, TPC; van Hasselt, JGC; Schellens, JHM; Huitema, ADR"	"Schultink, Aurelia H. M. de Vries; Boekhout, Annelies H.; Gietema, Jourik A.; Burylo, Artur M.; Dorlo, Thomas P. C.; van Hasselt, J. G. Coen; Schellens, Jan H. M.; Huitema, Alwin D. R."	"NA"	"A"	"Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Trastuzumab; Anthracyclines; Cardiac biomarkers; Breast cancer; Pharmacodynamics; Pharmacometrics"	"INDUCED CARDIOTOXICITY; HERCEPTIN ADJUVANT; MYOCARDIAL INJURY; HEART-FAILURE; TROPONIN-I; CHEMOTHERAPY; DOXORUBICIN; TRIAL; DYSFUNCTION; INHIBITION"	"Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies."	"[Schultink, Aurelia H. M. de Vries; Dorlo, Thomas P. C.; Huitema, Alwin D. R.] Antoni van Leeuwenhoek Netherlands Canc Inst, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands; [Boekhout, Annelies H.; Burylo, Artur M.; Schellens, Jan H. M.] Antoni van Leeuwenhoek Netherlands Canc Inst, Div Pharmacol, POB 90203, NL-1006 BE Amsterdam, Netherlands; [Gietema, Jourik A.] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands; [van Hasselt, J. G. Coen] Leiden Univ, Leiden Acad Ctr Drug Res, Div Syst Biomed & Pharmacol, Einsteinweg 55, NL-2333 CC Leiden, Netherlands; [Schellens, Jan H. M.] Univ Utrecht, UIPS, Fac Sci, Div Pharmacoepidemiol & Clin Pharmacol, POB 80082, NL-3508 TB Utrecht, Netherlands; [Huitema, Alwin D. R.] Univ Utrecht, Dept Clin Pharm, Univ Med Ctr Utrecht, POB 85500, NL-3508 GA Utrecht, Netherlands"	"Schultink, AHMD (corresponding author), Antoni van Leeuwenhoek Netherlands Canc Inst, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands."	"ah.d.vriesschultink@nki.nl"	"van Hasselt, Coen/H-5593-2019; Dorlo, Thomas/F-1339-2011"	"Dorlo, Thomas/0000-0003-3076-8435; van Hasselt, J.G.C./0000-0002-1664-7314; Gietema, Jourik/0000-0003-0629-7354"	"NA"	"NA"	30	6	6	0	2	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"JUN"	2018	45	3	431	442	"NA"	"10.1007/s10928-018-9579-8"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"GF9VV"	"WOS:000432328100008"	29429038	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Mo, G; Baldwin, JR; Luffer-Atlas, D; Ilaria, RL; Conti, I; Heathman, M; Cronier, DM"	"Mo, Gary; Baldwin, John R.; Luffer-Atlas, Debra; Ilaria, Robert L., Jr.; Conti, Ilaria; Heathman, Michael; Cronier, Damien M."	"NA"	"A"	"Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFR alpha Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer"	"CLINICAL PHARMACOKINETICS"	"English"	"Article"	"NA"	"MEDIATED DRUG DISPOSITION; BODY-SIZE; GROWTH; MEDICINE"	"Background and Objectives Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-alpha (PDGFR alpha). In a randomized phase II study, olaratumab plus doxorubicin met its pre-defined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. Methods Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM (R). Results The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V-1), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. Conclusion The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents."	"[Mo, Gary; Baldwin, John R.; Luffer-Atlas, Debra; Ilaria, Robert L., Jr.; Conti, Ilaria; Heathman, Michael; Cronier, Damien M.] Eli Lilly & Co, Indianapolis, IN 46285 USA"	"Mo, G (corresponding author), Eli Lilly & Co, Indianapolis, IN 46285 USA."	"gary.mo@lilly.com"	"NA"	"Luffer-Atlas, Debra/0000-0001-5841-5063"	"Eli Lilly and Company, USAEli Lilly"	"This study was funded by Eli Lilly and Company, USA, and/or one of its subsidiaries."	26	7	7	0	5	"ADIS INT LTD"	"NORTHCOTE"	"5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND"	"0312-5963"	"1179-1926"	"NA"	"CLIN PHARMACOKINET"	"Clin. Pharmacokinet."	"MAR"	2018	57	3	355	365	"NA"	"10.1007/s40262-017-0562-0"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FW5DI"	"WOS:000425336000007"	28620891	"Green Published, Other Gold"	"NA"	"NA"	"2020-10-02"
"J"	"McLay, JS; Engelhardt, T; Mohammed, BS; Cameron, G; Cohen, MN; Galinkin, JL; Christians, U; Avram, MJ; Henthorn, TK; Dsida, RM; Anderson, BJ"	"McLay, James S.; Engelhardt, Thomas; Mohammed, Baba S.; Cameron, Gary; Cohen, Mindy N.; Galinkin, Jeffrey L.; Christians, Uwe; Avram, Michael J.; Henthorn, Thomas K.; Dsida, Richard M.; Anderson, Brian J."	"NA"	"A"	"The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis"	"PEDIATRIC ANESTHESIA"	"English"	"Article"	"analgesia; child; ketorolac; nonlinear mixed-effects modelling; pharmacokinetics"	"POSTOPERATIVE PAIN; PEDIATRIC ANESTHESIA; BODY-SIZE; MORPHINE; TROMETHAMINE; MODEL; HUMANS; ACETAMINOPHEN; ANALGESIA; STANDARD"	"Background: Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg(.)L(-1) is described in adults. Aims: The aim of this study was to review age- and weight-related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules. Methods: Pooled intravenous ketorolac (0.5 mg(.)kg(-1)) concentration-time data in children aged 2months to 16years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person. Results: There were 64 children aged 2months to 16years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L(.)h(-1.) 70 kg(-1) and intercompartment clearance was 4.43 (CV 95.6%) L(.)h(-1.) 70 kg(-1). Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L(.)70 kg(-1) and V2 5.53 (CV 47.6%) L(.)70 kg(-1). Conclusion: Clearance, expressed as L(.)h(-1.)kg(-1), decreased with age from infancy. A dosing regimen of 0.5 mg(.)kg(-1) every 6hours maintains a trough concentration larger than 0.37 mg(.)L(-1) in children 9months to 16years of age. This dosing regimen is consistent with current recommendations."	"[McLay, James S.; Cameron, Gary] Univ Aberdeen, Dept Child Hlth, Div Appl Hlth Sci, Aberdeen, Scotland; [Engelhardt, Thomas] Royal Aberdeen Childrens Hosp, Dept Paediat Anaesthesia, Aberdeen, Scotland; [Mohammed, Baba S.] Univ Dev Studies, Pharmacol Unit, Tamale, Ghana; [Cohen, Mindy N.; Galinkin, Jeffrey L.; Christians, Uwe; Henthorn, Thomas K.] Univ Colorado, Dept Anesthesiol, Anschutz Med Campus, Aurora, CO USA; [Avram, Michael J.] Northwestern Univ, Dept Anesthesiol, Feinberg Sch Med, Chicago, IL 60611 USA; [Dsida, Richard M.] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Anesthesiol, Chicago, IL 60611 USA; [Anderson, Brian J.] Univ Auckland, Dept Anaesthesiol, Fac Med & Hlth Sci, Auckland, New Zealand"	"Engelhardt, T (corresponding author), Royal Aberdeen Childrens Hosp, Dept Paediat Anaesthesia, Aberdeen, Scotland."	"t.engelhardt@nhs.net"	"Avram, Michael/M-7681-2019"	"Hawwa, Ahmed/0000-0003-0547-7361"	"Scottish Children Research Network (ScotCRN), a center for mounting clinical trials and addressing the knowledge gaps in support of the effective and safe use of medicines in children"	"This work was carried out under the auspices of the Scottish Children Research Network (ScotCRN), a center for mounting clinical trials and addressing the knowledge gaps in support of the effective and safe use of medicines in children."	41	4	4	0	8	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"1155-5645"	"1460-9592"	"NA"	"PEDIATR ANESTH"	"Pediatr. Anesth."	"FEB"	2018	28	2	80	86	"NA"	"10.1111/pan.13302"	7	"Anesthesiology; Pediatrics"	"Anesthesiology; Pediatrics"	"FS9ZP"	"WOS:000422779700001"	29266539	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Ramamoorthy, A; Sadler, BM; van Hasselt, JGC; Elassaiss-Schaap, J; Kasichayanula, S; Edwards, AY; van der Graaf, PH; Zhang, L; Wagner, JA"	"Ramamoorthy, Anuradha; Sadler, Brian M.; van Hasselt, J. G. Coen; Elassaiss-Schaap, Jeroen; Kasichayanula, Sreeneeranj; Edwards, Alena Y.; van der Graaf, Piet H.; Zhang, Lei; Wagner, John A."	"NA"	"A"	"Crowdsourced Asparagus Urinary Odor Population Kinetics"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"PHARMACOLOGY; INGESTION"	"The consumption of asparagus is associated with the production of malodorous urine with considerable interindividual variability (IIV). To characterize the urinary odor kinetics after consumption of asparagus spears, we conducted a study with consenting attendees from two American Society for Clinical Pharmacology and Therapeutics (ASCPT) meetings. Subjects were randomized to eat a specific number of asparagus spears, and then asked to report their urinary odor perception. Eighty-seven subjects were included in the final analysis. A mixed effect proportional odds model was developed that adequately characterized the dose-response relationship. We estimated the half-life of the asparagus effect on malodorous urine to be 4.7 hours (relative standard error (RSE)=13.2%), and identified a dose-response slope term with good precision (24.3%). Age was found as the predictor of IIV in slope estimates. This study design and tools can be used as a demonstration crowdsourcing project for studying population kinetics in organizational and educational settings."	"[Ramamoorthy, Anuradha; Zhang, Lei] US FDA, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA; [Sadler, Brian M.] ICON Plc, Pharmacokinet Pharmacodynam Modeling & Simulat, Cary, NC USA; [van Hasselt, J. G. Coen; Elassaiss-Schaap, Jeroen; van der Graaf, Piet H.] Leiden Univ, Leiden Acad Ctr Drug Res, Cluster Syst Biomed & Pharmacol, Leiden, Netherlands; [Elassaiss-Schaap, Jeroen] PD Value BV, Houten, Netherlands; [Kasichayanula, Sreeneeranj] Amgen Inc, Clin Pharmacol Modeling & Simulat, Thousand Oaks, CA USA; [Edwards, Alena Y.] ICON Plc, Pharmacokinet Pharmacodynam Modeling & Simulat, Marlow, Bucks, England; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England; [Wagner, John A.] Takeda Pharmaceut Int Co, Cambridge, MA 02139 USA"	"Wagner, JA (corresponding author), Takeda Pharmaceut Int Co, Cambridge, MA 02139 USA."	"john.wagner.md.phd@gmail.com"	"Elassaiss-Schaap, Jeroen/Q-5451-2016; van Hasselt, Coen/H-5593-2019"	"van Hasselt, J.G.C./0000-0002-1664-7314"	"ASCPT"	"We thank all the subjects who participated and all the ASCPT volunteers who were engaged in the design and conduct of the study. ASCPT sponsored this study. We thank ICON, who provided extensive logistic and scientific support, and sponsored the IRB submission. In particular, we acknowledge the ASCPT staff, the ICON staff, including Mario Rocci, Siobhan Hayes, Patricia Puente, and Lawrene Nodier, and the volunteers who helped with study logistics, including Alex Oh, Ann Moyer, Anne Zajicek, Cecilia Fosser, Gloria Chou, Guy-Armel Bounda, Henk-Jan Guchelaar, Jesse Swen, Joan Korth-Bradley, Joel Cavallo, Mike Fedock, Miriam Mooij, Naomi Gronich, Sabrina Marsilio, Susan Vear, Terry Podoll, Vivek Purohit, and Wenndy Hernandez. The views expressed in this article are those of the authors and should not be construed to represent the views or policies of the US Food and Drug Administration."	23	1	1	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"JAN"	2018	7	1	34	41	"NA"	"10.1002/psp4.12264"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FT8KV"	"WOS:000423402600004"	29239147	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Danielak, D; Twardosz, J; Kasprzyk, A; Wachowiak, J; Kalwak, K; Glowka, F"	"Danielak, Dorota; Twardosz, Jadwiga; Kasprzyk, Anna; Wachowiak, Jacek; Kalwak, Krzysztof; Glowka, Franciszek"	"NA"	"A"	"Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation"	"EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"Hematopoietic stem cell transplantation; Area under curve; Infusions, intravenous; Population pharmacokinetics"	"HIGH-DOSE TREOSULFAN; PREPARATIVE REGIMEN; PEDIATRIC-PATIENTS; WEIGHT; HSCT"	"There is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug. The study included 15 pediatric patients with malignant and non-malignant diseases, undergoing conditioning regimens prior to HSCT including TREO administered as a 1 h or 2 h infusion at daily doses of 10, 12, or 14 g/m(2). A population pharmacokinetic model was developed by means of non-linear mixed-effect modeling approach in MonolixA (R) software. Multivariate regression analysis and Bayesian method were used to develop 2- and 3-point strategies for estimation of exposure to TREO. Pharmacokinetics of TREO was best described with a two-compartmental linear model with proportional residual error. Following sampling schedules allowed accurate estimation of exposure to TREO: 1 h and 6 h or 1 h, 2 h, and 6 h for a TREO dose 12 g/m(2) in a 1 h infusion, or at 2 h and 6 h or 2 h, 4 h, and 8 h for a TREO dose of 12 g/m(2) and 14 g/m(2) in a 2 h infusion. A two-compartmental population pharmacokinetic model of TREO was developed and successfully used to establish 2- and 3-point LSSs for accurate and precise estimation of TREO AUC(0 -> a)."	"[Danielak, Dorota; Twardosz, Jadwiga; Kasprzyk, Anna; Glowka, Franciszek] Poznan Univ Med Sci, Dept Phys Pharm & Pharmacokinet, Swiecickiego 6 St, PL-60781 Poznan, Poland; [Wachowiak, Jacek] Poznan Univ Med Sci, Dept Pediat Hematol Oncol & Transplantol, Poznan, Poland; [Kalwak, Krzysztof] Wroclaw Med Univ, Dept Pediat Hematol Oncol & Bone Marrow Transplan, Wroclaw, Poland"	"Danielak, D (corresponding author), Poznan Univ Med Sci, Dept Phys Pharm & Pharmacokinet, Swiecickiego 6 St, PL-60781 Poznan, Poland."	"danielak@ump.edu.pl"	"Kalwak, Krzysztof/U-1724-2019"	"Kalwak, Krzysztof/0000-0003-1174-5799; Glowka, Franciszek/0000-0002-6611-5789; Wachowiak, Jacek/0000-0002-4680-603X; Danielak, Dorota/0000-0001-5807-1109"	"Poznan University of Medical Sciences [502-14-03306413-09628]"	"The study was funded by Poznan University of Medical Sciences grant number 502-14-03306413-09628."	28	9	10	0	0	"SPRINGER HEIDELBERG"	"HEIDELBERG"	"TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY"	"0031-6970"	"1432-1041"	"NA"	"EUR J CLIN PHARMACOL"	"Eur. J. Clin. Pharmacol."	"JAN"	2018	74	1	79	89	"NA"	"10.1007/s00228-017-2344-x"	11	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FR5RK"	"WOS:000419123700009"	28975382	"Other Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Aoyama, T; Ishida, Y; Kaneko, M; Miyamoto, A; Saito, Y; Tohkin, M; Kawai, S; Matsumoto, Y"	"Aoyama, Takahiko; Ishida, Yoshimasa; Kaneko, Masato; Miyamoto, Aoi; Saito, Yoshiro; Tohkin, Masahiro; Kawai, Shinichi; Matsumoto, Yoshiaki"	"NA"	"A"	"Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"HEALTHY-VOLUNTEERS; PHARMACOKINETIC/PHARMACODYNAMIC MODEL; CLINICAL PHARMACOKINETICS; CIRCADIAN-RHYTHM; COX-2 INHIBITOR; POLYMORPHISMS; ROSUVASTATIN; CYP2C9; ABSORPTION; EXTENSION"	"We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population PK analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 white) under strictly controlled trial conditions with regulated meals and a single lot of the drug. We found that CYP2C9 genotype and lean body mass were statistically significant predictors of clearance and volume of distribution, respectively. A statistical significant difference in the PK parameters between ethnic groups could not be identified. Simulations using PK/PD models showed that CYP2C9 genotype is the factor that affects the PDs of meloxicam. The genetic polymorphisms highlighted in this study would be beneficial for conducting clinical trials in East Asians with similar genetic backgrounds."	"[Aoyama, Takahiko; Ishida, Yoshimasa; Kaneko, Masato; Miyamoto, Aoi; Matsumoto, Yoshiaki] Nihon Univ, Sch Pharm, Lab Clin Pharmacokinet, Chiba, Japan; [Ishida, Yoshimasa] Bristol Myers Squibb, Japan Med & Dev, Clin Pharmacol Strategy, Tokyo, Japan; [Kaneko, Masato] Bayer Yakuhin Ltd, Clin Sci Japan, Osaka, Japan; [Saito, Yoshiro] Natl Inst Hlth Sci, Biochem & Immunochem, Tokyo, Japan; [Tohkin, Masahiro] Natl Inst Hlth Sci, Div Med Safety Sci, Tokyo, Japan; [Tohkin, Masahiro] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Regulatory Sci, Nagoya, Aichi, Japan; [Kawai, Shinichi] Toho Univ, Dept Inflammat & Pain Control Res, Sch Med, Tokyo, Japan"	"Matsumoto, Y (corresponding author), Nihon Univ, Sch Pharm, Lab Clin Pharmacokinet, Chiba, Japan."	"matsumoto.yoshiaki@nihon-u.ac.jp"	"NA"	"NA"	"Research on Regulatory Science of Pharmaceuticals and Medical Devices from the Japan Agency for Medical Research and Development (AMED)Japan Agency for Medical Research and Development (AMED)"	"This study was supported by the Research on Regulatory Science of Pharmaceuticals and Medical Devices from the Japan Agency for Medical Research and Development (AMED). The authors thank Daisuke Suzuki and Tomomi Ogino for their assistance."	45	3	4	2	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"DEC"	2017	6	12	823	832	"NA"	"10.1002/psp4.12259"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FR1JY"	"WOS:000418824000004"	29024493	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Antunes, ND; van Dijkman, SC; Lanchote, VL; Wichert-Ana, L; Coelho, EB; Alexandre, V; Takayanagui, OM; Tozatto, E; van Hasselt, JGC; Della Pasqua, O"	"Antunes, Natalicia de Jesus; van Dijkman, Sven C.; Lanchote, Vera Lucia; Wichert-Ana, Lauro; Coelho, Eduardo Barbosa; Alexandre Junior, Veriano; Takayanagui, Osvaldo Massaiti; Tozatto, Eduardo; van Hasselt, J. G. Coen; Della Pasqua, Oscar"	"NA"	"A"	"Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects"	"EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES"	"English"	"Article"	"Oxcarbazepine; 10-Hydroxycarbazepine; Verapamil; P-glycoprotein; Population pharmacokinetics"	"P-GLYCOPROTEIN; 10-HYDROXY METABOLITE; ACTIVE METABOLITE; EPILEPSY; BRAIN; ENANTIOMERS; PLASMA; CARBAMAZEPINE; TRANSPORTERS; PERFORMANCE"	"Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-()-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n = 12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300 mg b.i.d. and 80 mg t.i.d., respectively. Blood samples (n = 185) were collected over a period of 12 h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9 L/h (69.5-100.3) for oxcarbazepine and 2.0 L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131 L (97-165)) as compared to R-(-)- and S-()-MHD (23.6 L (14.4-32.8) vs. 31.7 L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition."	"[Antunes, Natalicia de Jesus; Lanchote, Vera Lucia; Tozatto, Eduardo] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Clin Chem & Toxicol, Sao Paulo, Brazil; [van Dijkman, Sven C.; van Hasselt, J. G. Coen; Della Pasqua, Oscar] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands; [Wichert-Ana, Lauro; Coelho, Eduardo Barbosa] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Internal Med, Sao Paulo, Brazil; [Alexandre Junior, Veriano; Takayanagui, Osvaldo Massaiti] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Neurobehav Sci, Sao Paulo, Brazil; [Della Pasqua, Oscar] UCL, Sch Life & Med Sci, Clin Pharmacol & Therapeut Grp, London, England"	"Della Pasqua, O (corresponding author), UCL, Clin Pharmacol & Therapeut Grp, BMA House,Tavistock Sq, London WC1H 9JP, England."	"o.dellapasqua@ucl.ac.uk"	"Coelho, Eduardo B/G-3463-2012; van Hasselt, Coen/H-5593-2019; Lanchote, Vera Lucia/P-5925-2016; Coelho, Eduardo Barbosa/M-8532-2019; Wichert-Ana, Lauro/C-8373-2012"	"Coelho, Eduardo B/0000-0003-3491-3396; Lanchote, Vera Lucia/0000-0002-0074-4953; Coelho, Eduardo Barbosa/0000-0003-3491-3396; Wichert-Ana, Lauro/0000-0003-2059-5120; van Dijkman, Sven/0000-0002-2799-7643; van Hasselt, J.G.C./0000-0002-1664-7314"	"Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2011/06887-1, 2012/18175-9]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)National Council for Scientific and Technological Development (CNPq); Fundacao de Apoio ao Ensino, Pesquisa e Assistcncia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA)"	"The authors are grateful to Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (Grant numbers: 2011/06887-1 and 2012/18175-9), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Apoio ao Ensino, Pesquisa e Assistcncia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA) for their financial support."	33	3	3	0	7	"ELSEVIER SCIENCE BV"	"AMSTERDAM"	"PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS"	"0928-0987"	"1879-0720"	"NA"	"EUR J PHARM SCI"	"Eur. J. Pharm. Sci."	"NOV 15"	2017	109	"NA"	"S116"	"S123"	"NA"	"10.1016/j.ejps.2017.05.034"	8	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FM7TI"	"WOS:000415283100019"	28528287	"NA"	"NA"	"NA"	"2020-10-02"
"J"	"Yamamoto, Y; Valitalo, PAV; Huntjens, DR; Proost, JH; Vermeulen, A; Krauwinkel, W; Beukers, MW; van den Berg, DJ; Hartman, R; Wong, YC; Danhof, M; van Hasselt, JGC; de Lange, ECM"	"Yamamoto, Yumi; Valitalo, Pyry A.; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; van den Berg, Dirk-Jan; Hartman, Robin; Wong, Yin Cheong; Danhof, Meindert; van Hasselt, John G. C.; de lange, Elizabeth C. M."	"NA"	"A"	"Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model"	"CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY"	"English"	"Article"	"NA"	"BLOOD-BRAIN-BARRIER; TARGET SITE CONCENTRATIONS; ELECTRICAL-RESISTANCE; RAT-BRAIN; IN-VIVO; MICRODIALYSIS; DIFFUSION; SYSTEM; ENDOTHELIUM; NEUTRALITY"	"Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration-time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development."	"[Yamamoto, Yumi; Valitalo, Pyry A.; van den Berg, Dirk-Jan; Hartman, Robin; Wong, Yin Cheong; Danhof, Meindert; van Hasselt, John G. C.; de lange, Elizabeth C. M.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands; [Huntjens, Dymphy R.; Vermeulen, An] Janssen Res & Dev, Quantitat Sci, Beerse, Belgium; [Proost, Johannes H.] Univ Groningen, Div Pharmacokinet Toxicol & Targeting, Groningen, Netherlands; [Krauwinkel, Walter] Astellas Pharma BV, Dept Clin Pharmacol & Exploratory Dev, Leiden, Netherlands; [Beukers, Margot W.] Sci Business Support, Leiden, Netherlands"	"de Lange, ECM (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands."	"ecmdelange@lacdr.leidenuniv.nl"	"van Hasselt, Coen/H-5593-2019; Wong, Yin Cheong/E-5273-2013"	"Wong, Yin Cheong/0000-0002-8577-3277; van den Berg, Dirk-Jan/0000-0002-2253-579X; van Hasselt, J.G.C./0000-0002-1664-7314; de lange, elizabeth/0000-0001-8303-1117"	"Lygature (Leiden, The Netherlands) [D2-501]; European Union Marie Curie programmeEuropean Union (EU) [661588]"	"This research article was prepared within the framework of project number D2-501 of the former Dutch Top Institute Pharma, currently Lygature (Leiden, The Netherlands; www.lygature.org). J.G.C.H. received funding from the European Union Marie Curie programme (Project ID 661588)."	47	19	19	0	3	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"2163-8306"	"NA"	"NA"	"CPT-PHARMACOMET SYST"	"CPT-PHARMACOMET. SYST. PHARMACOL."	"NOV"	2017	6	11	765	777	"NA"	"10.1002/psp4.12250"	13	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FR1JT"	"WOS:000418823400008"	28891201	"DOAJ Gold, Green Published"	"NA"	"NA"	"2020-10-02"
"J"	"Valitalo, PA; Kemppainen, H; Kulo, A; Smits, A; van Calsteren, K; Olkkola, KT; de Hoon, J; Knibbe, CAJ; Allegaert, K"	"Valitalo, Pyry A.; Kemppainen, Heidi; Kulo, Aida; Smits, Anne; van Calsteren, Kristel; Olkkola, Klaus T.; de Hoon, Jan; Knibbe, Catherijne A. J.; Allegaert, Karel"	"NA"	"A"	"Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics"	"BRITISH JOURNAL OF CLINICAL PHARMACOLOGY"	"English"	"Article"	"ketorolac; nonlinear mixed-effects modelling; pain; population pharmacokinetics; pregnancy"	"PLASMA-PROTEIN BINDING; INTRAVENOUS KETOROLAC; CESAREAN DELIVERY; TROMETHAMINE; METABOLISM; CHILDREN; PHARMACOLOGY; DISPOSITION; ANALGESIA; ANIMALS"	"AIMS Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and inmale (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS For both the R-and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36%[95% confidence interval (CI) 15%, 58%] higher inmale than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS Besides the anticipated impact of body weight on clearance, R-and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight."	"[Valitalo, Pyry A.; Kemppainen, Heidi; Knibbe, Catherijne A. J.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands; [Kemppainen, Heidi] Univ Eastern Finland, Sch Pharm, Kuopio, Finland; [Kulo, Aida] Univ Sarajevo, Inst Pharmacol Clin Pharmacol & Toxicol, Fac Med, Sarajevo, Bosnia & Herceg; [Smits, Anne] Univ Hosp Leuven, Neonatal Intens Care Unit, Leuven, Belgium; [van Calsteren, Kristel] Univ Hosp Leuven, Dept Obstet & Gynecol, Leuven, Belgium; [van Calsteren, Kristel] Univ Hosp Leuven, Dept Dev & Regenerat, Leuven, Belgium; [Olkkola, Klaus T.] Univ Helsinki, Dept Anaesthesiol Intens Care & Pain Med, Helsinki, Finland; [Olkkola, Klaus T.] Helsinki Univ Hosp, Helsinki, Finland; [de Hoon, Jan] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium; [de Hoon, Jan] Univ Hosp Leuven, Ctr Clin Pharmacol, Leuven, Belgium; [Knibbe, Catherijne A. J.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands; [Allegaert, Karel] Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg & Intens Care, Rotterdam, Netherlands"	"Allegaert, K (corresponding author), Katholieke Univ Leuven, Dept Dev & Regenerat, Herestr 49, B-3000 Leuven, Belgium."	"karel.allegaert@uzleuven.be"	"allegaert, karel/C-3611-2016; Kulo, Aida/AAC-3341-2020; Smits, Anne/AAG-4433-2019; de Hoon, Jan/E-3256-2018"	"allegaert, karel/0000-0001-9921-5105; Smits, Anne/0000-0002-0710-6698; de Hoon, Jan/0000-0002-5215-9836; Olkkola, Klaus/0000-0001-7872-8665; kulo cesic, Aida/0000-0002-5891-3780"	"NA"	"NA"	34	6	8	0	0	"WILEY"	"HOBOKEN"	"111 RIVER ST, HOBOKEN 07030-5774, NJ USA"	"0306-5251"	"1365-2125"	"NA"	"BRIT J CLIN PHARMACO"	"Br. J. Clin. Pharmacol."	"SEP"	2017	83	9	1966	1975	"NA"	"10.1111/bcp.13311"	10	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FP2YI"	"WOS:000417485500010"	28429492	"Green Published, Bronze"	"NA"	"NA"	"2020-10-02"
"J"	"van Esdonk, MJ; Burggraaf, J; van der Graaf, PH; Stevens, J"	"van Esdonk, Michiel J.; Burggraaf, Jacobus; van der Graaf, Piet H.; Stevens, Jasper"	"NA"	"A"	"A two-step deconvolution-analysis-informed population pharmacodynamic modeling approach for drugs targeting pulsatile endogenous compounds"	"JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS"	"English"	"Article"	"Population PK/PD modeling; Growth hormone; Deconvolution analysis; Pulsatile secretion"	"GROWTH-HORMONE-SECRETION; ANTAGONIST INTERACTION-MODEL; RECEPTOR ANTAGONIST; PREMENOPAUSAL WOMEN; CLEARANCE RATE; GH SECRETION; HALF-LIFE; OCTREOTIDE; PROLACTIN; SOMATOSTATIN"	"Pharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, C-max). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach. Pulse frequency and pulse times were obtained by deconvolution analysis of 24 h GH profiles. The estimated pulse times then informed a non-linear mixed effects population pharmacodynamic model in NONMEM V7.3. The population parameter estimates were used to perform simulations that show agonistic and antagonistic drug effects on the secretion of GH. Additionally, a clinical trial simulation shows the application of this method in the quantification of a hypothetical drug effect that inhibits GH secretion. The GH profiles were modeled using a turnover compartment in which the baseline secretion, k(out), pulse secretion width, amount at time point 0 and pulse amplitude were estimated as population parameters. Population parameters were estimated with low relative standard errors (ranging from 2 to 5%). Total body water (%) was identified as a covariate for pulse amplitude, baseline secretion and the pulse secretion width following a power relationship. Simulations visualized multiple gradients of a hypothetical drug that influenced the endogenous secretion of GH. The established model was able to fit and quantify the highly variable individual 24 h GH profiles over time. This pharmacodynamic model can be used to quantify drug effects that target other endogenous pulsatile compounds."	"[van Esdonk, Michiel J.; Burggraaf, Jacobus; van der Graaf, Piet H.] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands; [van Esdonk, Michiel J.; Burggraaf, Jacobus; Stevens, Jasper] Ctr Human Drug Res, Leiden, Netherlands; [van der Graaf, Piet H.] Certara QSP, Canterbury, Kent, England; [Stevens, Jasper] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands"	"van Esdonk, MJ (corresponding author), Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands.; van Esdonk, MJ (corresponding author), Ctr Human Drug Res, Leiden, Netherlands."	"m.j.van.esdonk@lacdr.leidenuniv.nl"	"Stevens, Jasper/G-6118-2017; van Esdonk, Michiel Joost/Y-7595-2019"	"Stevens, Jasper/0000-0003-1601-9008; van Esdonk, Michiel Joost/0000-0001-8159-0273"	"NA"	"NA"	33	2	2	0	1	"SPRINGER/PLENUM PUBLISHERS"	"NEW YORK"	"233 SPRING ST, NEW YORK, NY 10013 USA"	"1567-567X"	"1573-8744"	"NA"	"J PHARMACOKINET PHAR"	"J. Pharmacokinet. Pharmacodyn."	"AUG"	2017	44	4	389	400	"NA"	"10.1007/s10928-017-9526-0"	12	"Pharmacology & Pharmacy"	"Pharmacology & Pharmacy"	"FB0KW"	"WOS:000405835000008"	28497294	"Green Published"	"NA"	"NA"	"2020-10-02"