Overall P-Value (dose)

Change in Cardiovascular Variables in Response to Inhaler Condition and IV l-Methamphetamine as Measured by Impedance Cardiography.

Data presented as mean (SD).IV-l-meth-IV l-methamphetamine; p-value (time)-compared to baseline vs. 15 minutes and 2 hours post-dose

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tmax (h)

Pharmacokinetic parameters of Tolmetin Sodium estimated after oral and rectal administration of commercial capsule suspension (treatment I) and F8 hydrogel (treatment II) to six rats

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Parameter	Commercial capsule	Rectal hydrogel (F8)

Dose (mg/kg)	50	50

Cmax (µg/ml)	33.877 ± 2.16	45.425 ± 2.745

tmax (h)	1	4

t1/2el (h)	5.137 ± 0.027	6.910 ± 0.003

AUC0−24 (µg h/ml)	129.489 ± 13.55	463.481 ± 48.207

AUC0−∞ (µg.h/ml)	129.489 ± 13.55	514.033 ± 48.207

MRT (h)	3.923 ± 0.24	9.512 ± 0.233

Relative bioavailability	–	357.93%

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Cmax (ng/mL)

Summary of the Pharmacokinetic Parameters for SMT C1100 Following Single Oral Doses and Multiple Doses. Geometric Mean (Coefficient of Variation) Are Presented Unless Otherwise Stated

AUC0‐∞ = area under the plasma concentration‐time curve from time zero to infinity (percentage of AUC that is due to extrapolation from tz to infinity was <10% in all cases); AUC0− τ = area under the plasma concentration‐time curve over a dosing interval; Cmax = maximum observed plasma concentration; tmax = time of maximum observed plasma concentration; t½ = apparent plasma terminal elimination half‐life (for Day 10 of multiple‐dose study this is post drug induction); CL/F = apparent total plasma clearance; VZ/F = apparent volume of distribution during the terminal phase; RAobs = observed accumulation ratio based on AUC0‐ τ.aArithmetic mean (CV%).bMedian (min–max).cn = 5.dn = 3.

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Apparent terminal T½ d , e, hr

Summary statistics of buprenorphine, norbuprenorphine, and naloxone plasma pharmacokinetics following stable maintenance doses of buprenorphine/naloxone 8/2 mg to 24/6 mg once daily with or without coadministration of multiple doses of grazoprevir 200 mg once daily for 10 days in adult participants receiving stable buprenorphine/naloxone substitution therapy

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BUP/NAL alone	BUP/NAL + GZR	BUP/NAL + GZR/ BUP/NAL alone

Pharmacokinetic parameter
<italic>n</italic>
	GM	95% CI
<italic>n</italic>
	GM	95% CI	GMR	90% CI	Pseudo within‐participant %CV<xref ref-type="fn" rid="cts12565-tbl3-note-0004">a</xref>

<italic>BUP</italic>

AUC0‐∞/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng·hr/mL/mg	12	4.65	3.64–5.95	12	4.57	3.35–6.23	0.98	0.81–1.19	26.4

Cmax/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng/mL/mg	12	0.802	0.628–1.02	12	0.722	0.509–1.02	0.90	0.76–1.07	23.4

Tmax
<xref ref-type="fn" rid="cts12565-tbl3-note-0006">c</xref>, hr	12	1.99	1.00, 3.00	12	2.01	1.00, 4.00

Apparent terminal T½
<xref ref-type="fn" rid="cts12565-tbl3-note-0007">d</xref>
,
<xref ref-type="fn" rid="cts12565-tbl3-note-0008">e</xref>, hr	10	10.71	73.09	11	13.43	30.71

<italic>NorBUP</italic>

AUC0‐∞/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng·hr/mL/mg	12	3.53	2.55–4.90	12	3.99	2.76–5.76	1.13	0.97–1.32	20.9

Cmax/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng/mL/mg	12	0.223	0.153–0.324	12	0.246	0.167–0.36	1.10	0.97–1.25	17.2

Tmax
<xref ref-type="fn" rid="cts12565-tbl3-note-0006">c</xref>, hr	12	3.00	1.00, 12.00	12	3.00	1.50, 6.00

Apparent terminal T½
<xref ref-type="fn" rid="cts12565-tbl3-note-0007">d</xref>
,
<xref ref-type="fn" rid="cts12565-tbl3-note-0009">f</xref>, hr	5	16.13	26.12	8	33.87	49.98

<italic>NAL</italic>

AUC0‐∞/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng·hr/mL/mg	12	0.352	0.257–0.482	12	0.387	0.256–0.584	1.10	0.82–1.47	39.6

Cmax/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng/mL/mg	12	0.149	0.113–0.196	12	0.149	0.110–0.204	1.00	0.80–1.27	31.7

Tmax
<xref ref-type="fn" rid="cts12565-tbl3-note-0006">c</xref>, hr	12	0.75	0.50, 3.00	12	1.24	0.50, 2.02

Apparent terminal T½
<xref ref-type="fn" rid="cts12565-tbl3-note-0007">d</xref>
,
<xref ref-type="fn" rid="cts12565-tbl3-note-0010">g</xref>, hr	10	3.33	92.14	12	5.20	107.25

BUP/NAL alone: BUP 8 mg / NAL 2 mg to 24/6 mg on day 1.BUP/NAL + GZR: coadministration of BUP 8 mg / NAL 2 mg to 24/6 mg once daily with GZR 200 mg once daily on days 2–11.AUC0‐∞, area under the concentration–time curve from time 0 extrapolated to infinity; BUP, buprenorphine; CI, confidence interval; Cmax, maximum concentration; D, dose normalized; GM, geometric mean; GMR, geometric mean ratio; GZR, grazoprevir; NAL, naloxone; NorBUP, norbuprenorphine; Tmax, time to Cmax.aPseudo within‐participant %CV = 100 × sqrt[(σA 2 + σB 2 ‐2σAB)/2], where σA 2 and σB 2 are the estimated variance on the log scale for the two treatments, and σAB is the corresponding estimated covariance, each obtained from the linear mixed‐effects model.bBack‐transformed least‐squares mean and CI from the linear mixed‐effects model performed on natural log‐transformed values.cMedian (minimum, maximum) reported for Tmax.dGM and geometric CV reported for apparent terminal T½.eNo apparent terminal T½ could be calculated for two participants following administration of BUP/NAL alone and for one participant following coadministration of BUP/NAL with GZR, due to the lack of data in the terminal phase.fNo apparent terminal T½ could be calculated for seven participants following administration of BUP/NAL alone and for four participants following coadministration of BUP/NAL with GZR, due to the lack of data in the terminal phase.gNo apparent terminal T½ could be calculated for two participants following administration of BUP/NAL alone due to the lack of data in the terminal phase.

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AUC(0-24h) (hr*ng/mL)

Primary PK parameters for CLR457 at cycle 1 day 1 by treatment groups

AUC(0-24h), Area Under The Curve during 24 h; Cmax, maximum plasma concentration; Tmax, time to reach maximum (peak) plasma concentration following drug administration

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Covariate 5: ECOG (0 score) on CL

Parameter estimates of three candidate PK models of durvalumab (a = final model) (with 95% confidence interval derived from nonparametric bootstrapping)

ADA, anti‐drug antibody status; ALB, serum albumin expressed in g/L; CI, confidence interval; CL, clearance; CRCL, creatinine clearance expressed in ml/min; CV%, coefficient of variation in percent; ECOG, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; PK, pharmacokinetic; SD, standard deviation; SEX is 1 for female; sPD‐L1, soluble PD‐L1 level expressed in pg/mL; tumor size is expressed in mm; V1, central volume; V2, peripheral volume; WT, body weight expressed in Kg; ω, standard deviation of omega; σ, standard deviation of sigma.aTumor size and albumin for the semimechanistic time varying CL model were based on samples taken during the trials where the last observation is carried forward for each PK sample. For the other two models tumor size and albumin at baseline were used.η‐shrinkage for the time‐invariant CL model were 16.8%, 21.5%, 33.3% for CL, V1, and V2, respectively. ε‐shrinkage estimate was 13.9%. η‐shrinkage for the empirical time‐varying CL model were 17.6%, 20.9%, 37.3%, and 67.0% for CL, V1, V2, and Tmax, respectively. ɛ‐shrinkage estimate was 14.4%. η‐shrinkage for the semimechanistic time‐varying CL model were 17.5%, 20.6%, and 36.2% for CL, V1, and V2, respectively. ε‐shrinkage estimate was 13.7%.The functional form of the PK‐covariate relationships found in the semimechanistic time‐varying CL model is displayed below. Continuous covariates were centered using the median in the patient population whereas time‐changing covariates were centered based on the median baseline values: CL=0.232*(ADA*(1+0.234))*(1−0.035*(ALB−38))*(1+0.00149*(CRCL−85.65))*(−0.063*ECOG)*(−0.143*SEX)*(1+0.00178*(tumor size−74.8))*(WT/69.8)0.389Vmax=0.824*(1+0.00336*(sPDL1−124.8))V1=3.51*(−0.165*SEX)*(WT/69.8)0.406V2=3.45*(−0.205*SEX)

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Adjusted AUC(after DV) (μmol·h/L)

Area under the curve, basal diurnal variation (DV), serum iron and plasma folate by treatment

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Basal Diurnal Variation (DV)	Powdered Supplement	Tablet Supplement

<bold>Iron</bold>

 AUC (μmol·h/L)	104.5 ± 34.1

 Adjusted AUC(after DV) (μmol·h/L)	10.0 ± 43.3*	41.8 ± 45.9*

 Peak value (μmol/L)	14.6	3.0	8.9

Time to peak value (hrs)	3	4

<bold>Folate</bold>

 Incremental AUC (nmol·h/L)	NA	271.8 ± 110.9	248.7 ± 140.2

 Peak value (nmol/L)	NA	54.4	53.1

Time to peak value (hrs)	NA	4	3

AUC, area under the curve. All values are mean ± SD; n(iron) = 17; n(folate) = 18 (sample size differed according to subject exclusion for iron variables). *p = 0.0003.

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AUC/Dose (ng h/mL/mg)

Summary of pharmacokinetic parameters of sepantronium after continuous intravenous infusion of 1.8, 3.6, 4.8, 6.0, 8.0, or 10.6 mg/m2/day for 168 h

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PK parameters (mean ± SD)	Normal (<italic>n</italic> = 19)	Mild (<italic>n</italic> = 21)	Moderate (<italic>n</italic> = 6)

AUC/Dose (ng h/mL/mg)	29 ± 14	27 ± 7	37 ± 10

CSS/Dose (ng/mL/mg)	0.17 ± 0.08	0.16 ± 0.04	0.22 ± 0.07

CL (L/h)	39 ± 11	39 ± 11	28 ± 9

SD standard deviation, AUC/Dose dose-normalized area under the curve from zero to time t of the last measurable concentration above the limit of quantitation, CSS/Dose dose-normalized steady-state concentration, CL total systemic clearance, CLR renal clearance, GMR geometric mean ratio, CI confidence interval

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AUC(0–72) (ng h/ml)

Mean pharmacokinetic parameters of LCDP following the administration of optimum LCDP polymeric micelles formula and LCDP oral suspension to six albino rabbits.

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PK parameter	LCDP polymeric micelles	LCDP oral suspension	Statistical test

<italic>C</italic>max (ng/ml)	230.68 ± 20.21	3.72 ± 1.55	<italic>p</italic> = .000

<italic>t</italic>max (h)<xref ref-type="table-fn" rid="TF4">
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</xref>	0.5	8	<italic>p</italic> = .000

AUC(0–72) (ng h/ml)	493.22 ± 67.28	69.59 ± 28.38	<italic>p</italic> = .000

AUC(0–∞) (ng h/ml)	498.87 ± 66.38	72.75 ± 26.97	<italic>p</italic> = .000

<italic>λ</italic>z (h−1)	0.05 ± 0.01	0.05 ± 0.01	<italic>p</italic> = .791

<italic>t</italic>1/2 (h)	14.92 ± 3.21	15.02 ± 5.61	<italic>p</italic> = .976

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AUC0−12 (dn), ng·h/mL/mg

Summary of pharmacokinetic parameters following administration of single oral doses of PF‐04447943 5 mg and 25 mg a

AUC0−12, area under the concentration‐time curve from time 0−12 hours postdose; Cmax, maximum concentration; dn, dose normalized to 1 mg; Tmax, time to Cmax. aValues are geometric mean (geometric percent coefficient of variation) unless otherwise noted; bValues are median (range).

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t ½, abs-1 (days)

Final population pharmacokinetic estimates and bootstrap results for benzylpenicillin after administration of monthly injections of BPG in children and adolescents

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Parameter	Mean	Bootstrap, median (95% CI)

Objective function value	−265.078	−300.214 (−458.616 to −161.877)

Structural model parameters

<italic> k</italic>
el (h−1·70 kg−1)	1.32	fixed

<italic> V</italic> (L·70 kg−1)	72.2	72.0 (64.0–84.2)

<italic> t</italic>
½, abs-1 (days)	0.455	0.461 (0.174–0.948)

<italic> t</italic>
½, abs-2 (days)	8.88	8.79 (5.71–12.5)

<italic> </italic>increase in <italic>t</italic>½, abs-2 with BMI ≥25 kg/m2 (%)	86.5	86.8 (33.4–198)

Variable model parameters (shrinkage%)

<italic> </italic>IIV in <italic>V</italic>	26 (9)	24 (10–37)

<italic> </italic>IIV in <italic>t</italic>½, abs-1	78 (12)	75 (40–107)

<italic> </italic>IIV in <italic>t</italic>½, abs-2	63 (12)	62 (32–85)

<italic> </italic>IOV in <italic>t</italic>½, abs-2	30 (46)	31 (20–48)

<italic> r</italic> (<italic>t</italic>½, abs-1, <italic>t</italic>½, abs-2)
<italic>−</italic>1	fixed

<italic> r</italic> (<italic>t</italic>½, abs-2, <italic>V</italic>)
<italic>−</italic>0.746
<italic>−</italic>0.808 (<italic>−</italic>1.00 to <italic>−</italic>0.316)

<italic> </italic>RV (%)	35 (13)	34 (30–38)

k el, elimination rate constant; t½, abs, absorption t½; IIV, interindividual variability; IOV, interoccasion variability; RV, residual variability. IIV, IOV and RV are presented as 100% × √variability estimate.

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T1/2 (h)

Summary of acebilustat blood PK and PD properties in healthy volunteers and CF patients

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<bold>Study Population</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>HV</bold>

<bold>Dosing Day</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>14</bold>

<bold>Dose (mg/day)</bold>

<bold>50</bold>

<bold>50</bold>

<bold>100</bold>

<bold>100</bold>

<bold>150</bold>

<bold>200</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

Cmax (ng/mL)	1,100	280	9	1,100	190	6	2,300	520	8	2,400	1,300	6	4,900	1,700	9	8,100	1,100	9

C3hr (ng/mL)	850	240	9	1,100	180	6	2,000	650	8	2,200	1,200	6	4,100	1,400	9	7,000	1,500	9

Cmin (ng/mL)	190	110	9	160	69	6	580	320	8	340	220	6	1,200	720	9	2,800	1,200	9

AUC0‐24 (ng•h/mL)	11,000	3,700	9	12,000	1,700	6	32,000	9,300	8	26,000	16,000	6	66,000	30,000	9	120,000	30,000	9

Tmax (h)	1.4	0.58	9	2.0	0.90	6	1.7	1.1	8	2.0	0.58	6	2.1	1.8	9	1.6	1.7	9

T1/2 (h)	16<xref ref-type="fn" rid="cts12426-tbl1-note-0002">a</xref>
	4.2	6	9.3	4.2	6	16<xref ref-type="fn" rid="cts12426-tbl1-note-0002">a</xref>
	5.7	6	8.6	2.3	6	18<xref ref-type="fn" rid="cts12426-tbl1-note-0002">a</xref>
	4.4	6	16<xref ref-type="fn" rid="cts12426-tbl1-note-0002">a</xref>
	4.7	4

Ratio of Cmax to blood LTB4 IC50
	34	37	75	79	158	262

Ratio of C3hr to blood LTB4 IC50
	28	34	66	70	132	228

Ratio of Cmin to blood LTB4 IC50
	6	5	19	11	39	91

Peak LTB4 inhibition (%)	ND	73	86	69	86	89

Trough LTB4 inhibition (%)	ND	58	80	67	82	88

HV, healthy volunteers; CF, Cystic fibrosis patients; LTB4, leukotriene B4; AUC0‐24, area under the time–concentration curve; Cmax, maximum observed plasma concentration; C3hr, plasma concentration observed at 3hr (PD) timepoint; Cmi n, minimum observed plasma concentration; IC50, concentration causing 50% inhibition (0.064 μM, 30.8 ng/mL); T1/2, elimination half‐life; ND, not determined.aT1/2 determined after a single dose.

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t1/2, hr

Tedizolid Single-Dose Plasma and Urinary Pharmacokinetics in Subjects Receiving Both IV and Oral Tedizolid Phosphate 200 mg, Administered Using a Crossover Design

AUC = area under the concentration-time curve (over specified time interval); Cmax = maximum observed concentration; CL = systemic clearance; CL/F = oral clearance; IV = intravenous; t = last quantifiable time point up to 72 hrs post dose/end of infusion; t½ = apparent terminal elimination half-life; Tmax = time to maximum concentration; Vdss = apparent volume of distribution at steady state; Vz/F = volume of distribution during the terminal phase.Data are mean (standard deviation) except where noted.aTmax is median (minimum, maximum).

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Cmax/Dose (ng/mL/mg/kg)

Toxicokinetics of S8069 in Male and Female Sprague-Dawley Rats Administered in Diet for 13-Weeks.

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MRT (h)*

Pharmacokinetic parameters obtained after oral administration of optimized DRC (TAP-KyronT-134 complex) and TAP solution at a dose equivalent to 3 mg/Kg TAP.

*p < 0.05 level of significant difference; **p < 0.001 level of significant difference.

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V1 (l kg−1)

Pharmacokinetic parameters

aCited from Mross et al (1998).bCited from Gabizon et al (1994).

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V (L·70 kg−1)

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Apparent clearance

Pharmacokinetic parameter estimates of the final population pharmacokinetic model of CsA.

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Parameter (unit)	Definition of parameter	Bootstrap

Median	95% CI<xref rid="tfn1" ref-type="table-fn">
a
</xref>

<bold>𝜽−<italic>Estimates</italic></bold>

<italic>CL / F</italic> (<italic>l / h</italic>)	Apparent clearance	62.8	(54.4–71.2)

<italic>Vc / F</italic> (<italic>l</italic>)
	Apparent central volume of distribution	254	(226–281)

<italic>Vp / F</italic> (<italic>l</italic>)	Apparent peripheral volume of distribution	388	(344–456)

<italic>Q</italic> (<italic>l / h</italic>)	Intercompartmental clearance between central and peripheral compartment	23.6	(19.3–29.5)

<italic>Ka</italic>(<italic>h</italic>-1)	Absorption rate constant	12.4	(6.57–33.9)

<italic>MTT</italic> (<italic>h</italic>)	Mean transit time	0.812	(0.797–0.831)

<italic>N</italic>	Number of transit compartment	20.2	(16.6–25.6)

<bold>𝝎2−<italic>Estimates</italic></bold>

<italic>IIV CL</italic> (<italic>CV%</italic>)	Interindividual variability on clearance	12.6	(3.69–20.4)

<italic>IIV Ka</italic> (<italic>CV%</italic>)	Interindividual variability on absorption rate	155	(55.9–628)

<italic>IIV Q</italic> (<italic>CV%</italic>)	Interindividual variability on distributional clearance	25.7	(7.74–42.0)

<italic>IIV N</italic> (<italic>CV%</italic>)	Interindividual variability on number of transit compartments	20.2	(7.57–38.2)

<italic>IOV MTT</italic> (<italic>CV%</italic>)	Inter-occasional variability on mean transit time	4.39	(2.31–6.18)

<italic>IOV N</italic> (<italic>CV%</italic>)	Inter-occasional variability on number of transit compartments	17.6	(9.32–25.2)

<bold>𝝈2−<italic>Estimates</italic></bold>

<italic>PRV</italic> (<italic>CV%</italic>)	Proportional residual variability	19.4	(16.0–22.9)

aCI, confidence interval (nonparametric) based on 2.5 and 97.5% percentiles obtained by the bootstrap analysis based on the final model applied to the original dataset; F, bioavailability.CV% for IIV and IOV computed as expω2−1; CV% for PRV computed as expσ2−1.

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A (hot coffee – 20 min)

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      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)

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      Condition
      Cmax (μg/mL) a
      Dose-normalized b  Cmax (μg/mL)
      Tmax (min)
      AUC0–∞ (μg/mL min)
      Dose-normalized b  AUC0–∞ (μg/mL min)
      MRT (min)
      MAT (min)
      CL/F (mL/min/kg)
      Vd,ss/F (mL/kg) a
      t1/2 (min)

      2
      A (hot coffee – 20 min)
      3.74 ± 1.09 (1.96–5.95)
      1.69 ± 0.43 (1.07–2.40)
      59 ± 27 (20–120)
      2312 ± 1338
      1035 ± 541
      601 ± 263
      12 ± 11
      1.2 ± 0.6
      623 ± 129
      408 ± 178 (210–990)

      3
      B (cold coffee – 2 min)
      3.64 ± 1.36 (1.81–8.17)
      1.57 ± 0.59 (0.981–3.13)
      62 ± 32 (40–120)
      2447 ± 1781
      1047 ± 725
      607 ± 267
      14 ± 10
      1.3 ± 0.7
      626 ± 145
      411 ± 183 (187–966)

      4
      C (cold coffee – 20 min)
      3.56 ± 1.06 (1.69–5.77)
      1.60 ± 0.44 (0.917–2.79)
      64 ± 20 (40–90)
      2625 ± 2177
      1172 ± 882
      673 ± 362
      16 ± 6
      1.2 ± 0.6
      642 ± 151
      455 ± 249 (217–1386)

      5
      D (energy drink – 2 min)
      3.36 ± 1.20 (1.40–5.78)
      1.51 ± 0.48 (0.782–2.81)
      70 ± 44 (20–240)
      2473 ± 2302
      1059 ± 834
      665 ± 427
      15 ± 16
      1.4 ± 0.8
      712 ± 194
      450 ± 295 (154–1386)

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      E (energy drink – 20 min)
      3.14 ± 0.95 (1.87–5.25)
      1.41 ± 0.32 (0.940–1.96)
      82 ± 42 (40–240)
      2107 ± 1504
      925.1 ± 565
      593 ± 258
      17 ± 8
      1.5 ± 0.8
      708 ± 144
      399 ± 177 (187–990)

CAPTION: Pharmacokinetic parameters for caffeine in five studied conditions – means and ranges.
FOOTER: A: hot coffee 20 min; B: cold coffee 2 min; C: cold coffee 20 min; D: sugar-free energy drink 2 min; E: sugar-free energy drink 20 min.a -RM ANOVA p ≤ 0.05.b Values normalized by mg/kg dose of caffeine.

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Between‐subject variability V1 ω (CV%)

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Main pharmacokinetic parameters of oral tryptanthrin in KM mice.

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PK parameters	Unit	Value

AIC	–	−49.79

SBC	–	−47.36

V1_F	mL	343.89

<italic>K</italic>01	1/h	1.17

<italic>K</italic>10	1/h	0.59

<italic>K</italic>12	1/h	0.29

<italic>K</italic>21	1/h	0.61

AUC0–<italic>t</italic>	h μg/mL	9.38

AUC0–∞	h μg/mL	9.57

Alpha	1/h	1.19

Beta	1/h	0.30

Alpha_HL	h	0.57

Beta_HL	h	2.27

A	μg/mL	−208.93

B	μg/ml	2.60

CL_F	mL/h	204.58

<italic>T</italic>max	h	1.50

<italic>C</italic>max	μg/mL	3.13

MRT	h	3.06

AIC, Akaike Information Criterion ; Alpha_HL, alpha half life ; AUC0–t, plasma concentration–time curve from time zero to the last time point; Beta_HL, terminal half-life; CL_F, systemic clearance rate; Cmax, maximal plasma concentration; KM, Kunming; MRT, mean retention time ; SBC, Schwarz Bayesian Criterion ; Tmax, highest temperature; V1_F, apparent volume of distribution.

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Elimination rate constant ACT‐333679

Final population PK model parameter estimates

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Population parameters	Interindividual variation (std. dev.)

Parameter	Description	Estimate	Std. error	Rel. std. error (%)
<italic>P</italic>‐value	Estimate	Std. error	Rel. std. error (%)

tlag (h)	Absorption lag time	0.67	‐	‐	1.92	0.20	10

ka (1/h)	Absorption rate constant	0.71	0.04	5	0.39	0.05	12

Vp/F (L)	Apparent volume of distribution, central compartment selexipag	12.90	2.00	16	0.31	0.12	38

Body weight on Vp/F	Covariate effect	1.20	0.30	25	<0.001

CL/F (L/h)	Apparent selexipag clearance	19.10	1.60	8	0.73	0.03	4

Body weight on CL/F	Covariate effect	0.61	0.15	25	<0.001

Total bilirubin on CL/F	Covariate effect	−0.40	0.07	18	<0.001

k12 (1/h)	Transfer rate constant central to peripheral compartment selexipag	0.09	0.02	18	0.25	0.18	73

k21 (1/h)	Transfer rate constant peripheral to central compartment selexipag	0.06	0.01	17	1.06	0.13	12

Vm/F (L)	Apparent volume of distribution, central compartment ACT‐333679	4.65	0.80	17	0.10	0.25	241

Body weight on Vm/F	Covariate effect	0.88	0.18	21	<0.001

kmet (1/h)	Metabolism rate constant selexipag to ACT‐333679	0.67	0.12	18	0.05	0.42	788

k34 (1/h)	Transfer rate constant central to peripheral compartment ACT‐333679	1.04	0.23	22	0.47	0.18	39

k43 (1/h)	Transfer rate constant peripheral to central compartment ACT‐333679	0.18	0.03	14	0.89	0.14	16

km (1/h)	Elimination rate constant ACT‐333679	0.49	0.08	16	0.27	0.06	20

Sex on km
	Covariate effect	0.15	0.05	31	0.001

PAH comedication on km (ERA)	Covariate effect	0.15	0.06	38	0.008

PAH comedication on km (PDE5 inh.)	Covariate effect	0.07	0.05	77	0.190

PAH comedication on km (ERA and PDE5 inh.)	Covariate effect	0.37	0.05	14	<0.001

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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MTC on Vc/Fb

Parameter estimates for the final integrated population pharmacokinetic model of cabozantinib in patients with different cancer types

ALAG, absorption lag time, CI confidence interval, CL/F apparent clearance, CRPC castrate-resistant prostate cancer, F1 fraction of dose split to the first absorption depot in a dual absorption model, GB Glioblastoma multiforme, Ka absorption rate constant, MTC medullary thyroid cancer, Q/F apparent flow parameter between compartments, RCC renal cell carcinoma Vc/F apparent volume of distribution of the central compartment, Vp/F apparent volume of distribution of the peripheral compartmentaAnti-logit transformation was used to obtain F1bFor categorical covariates (e.g., capsule), transformed estimates correspond to fractional change from the reference levelcuntransformed valuesdUntransformed full model variance estimates (90% CI) σ2 = 0.118 (0.114, 0.122); ω2_Ka = 2.063 (1.579, 2.548); ω2_CL/F = 0.202 (0.185, 0.218); ω2_Vc/F = 0.233 (0.193, 0.273); ω2_F1 = 0.466 (0.385, 0.546); ω2_CL/F:Vc/F = 2.475 (1.923, 3.028), where ω2 is the variance–covariance matrix (Ω) of the inter-individual random effects (η) in the pharmacokinetic parameter, and σ the variance–covariance matrix of the intra-individual random effects (ε) in the measurements

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CLb

Pharmacokinetic parameters in plasma after 4 mg/kg i.v. and i.m. administration, respectively.

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Parameters	Units	i.v	i.m

AUC24 h	μg∗h/ml	7.10 ± 0.91	3.94 ± 0.62

AUC	μg∗h/ml	7.94 ± 1.11	6.79 ± 0.45

<italic>T</italic>max	h	–	0.25 ± 0.06

<italic>T</italic>1/2	h	24.02 ± 3.12	44.04 ± 4.56

<italic>C</italic>max	μg/ml	–	0.98 ± 0.11

CLb	L/h	0.46 ± 0.08	0.43 ± 0.07

MRTlast	h	8.06 ± 1.6	22.85 ± 2.96

<italic>F</italic>	%	85.5 ± 7.11

AUC24 h, the area under the curve within 24 h; AUC, the area under the curve; Tmax, the time to peak concentration; T1/2, the eliminate half-life; Cmax, the peak concentration; CLb, relative total systemic clearance; MRT, the mean residence time; F, the bioavailability.

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RAobs

Summary of the Pharmacokinetic Parameters for SMT C1100 Following Single Oral Doses and Multiple Doses. Geometric Mean (Coefficient of Variation) Are Presented Unless Otherwise Stated

AUC0‐∞ = area under the plasma concentration‐time curve from time zero to infinity (percentage of AUC that is due to extrapolation from tz to infinity was <10% in all cases); AUC0− τ = area under the plasma concentration‐time curve over a dosing interval; Cmax = maximum observed plasma concentration; tmax = time of maximum observed plasma concentration; t½ = apparent plasma terminal elimination half‐life (for Day 10 of multiple‐dose study this is post drug induction); CL/F = apparent total plasma clearance; VZ/F = apparent volume of distribution during the terminal phase; RAobs = observed accumulation ratio based on AUC0‐ τ.aArithmetic mean (CV%).bMedian (min–max).cn = 5.dn = 3.

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ΔΔGsol c

Complexation Gibbs free energies and their components for the top 100 scoring virtually designed PCAM analogues. The analogue numbering concatenates the index of each substituent R1 to R5 with the substituent numbers taken from Table 5 except for hydrogen which is directly specified by the letter H.

a MW is molecular mass of the inhibitor; b ΔΔHMM is the relative enthalpic contribution to the Gibbs free energy change related to the InhA-PCAM complex formation ΔΔGcom (for details see footnote of Table 2); c ΔΔGsol is the relative solvation Gibbs free energy contribution to ΔΔGcom; d ΔΔTSvib is the relative entropic (vibrational) contribution to ΔΔGcom; e ΔΔGcom is the relative Gibbs free energy change related to the enzyme-inhibitor InhA-PCAM complex formation ΔΔGcom ≅ ΔΔHMM + ΔΔGsol − ΔΔTSvib; f IC50pre is the predicted half-maximal inhibitory concentration of PCAMx towards InhA of MTb calculated from ΔΔGcom using correlation Equation (B), Table 3; g IC50exp is given for the reference inhibitor PCAM1 instead of IC50pre.

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Cl (L/h)

Mean individual pharmacokinetic parameters and confidence intervals for IFN alpha-2b and IFN gamma (Model V)

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Parameter (units)	Definition	IFN alpha-2b	IFN gamma

Mean	95 % CI	Mean	95 % CI

Tk0 (h)	Duration of zero order absorption	5.71	5.55–5.87	2.66	2.08–3.23

ka (h–1)	First order absorption rate	0.15	0.12–0.19	0.42	0.25–0.58

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

V (L)	Volume of distribution of central compartment	38.4	38.4–38.5	118	21–214

k (h−1)	First order elimination rate order	0.21	0.18–0.23	0.09	0.08–0.09

Cl (L/h)	Total clearance	1.8	1.1–2.4	4.3	0.4–8.1

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MIC (mg/L)

Time (min) above possible MICs ranging from 0.25 to 8 mg/L corresponding to total serum concentration ranging from 0.39 to 12.5 mg/L for the quantiles (Q) 90 and 95% and corresponding value of the T > MIC in % of 24 h.

Q90%: quantile 90%; Q95%: quantile 95%; for a MIC of 2 mg/L corresponding to a total serum concentration of 3.12 mg/L, 90% of the simulated curves were equal or above a free plasma concentration for 821 min, i.e., for 57% of the considered dosing interval.

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CLT (liters/h)

Plazomicin plasma pharmacokinetic parameters by renal function groupa

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PK parameter	Normal renal <break/>function (<italic>n</italic> = 6)	Mild renal <break/>impairment (<italic>n</italic> = 6)	Moderate renal <break/>impairment (<italic>n</italic> = 6)	Severe renal <break/>impairment (<italic>n</italic> = 6)

Cmax (mg/liter)	37.9 ± 5.01	32.8 ± 4.30	39.2 ± 6.43	41.4 ± 7.83

AUC0–∞ (mg · h/liter)	136 ± 17.2	138 ± 23.7	281 ± 96.0	647 ± 259

Vss (liters)	36.0 ± 7.76	28.5 ± 2.17	25.8 ± 6.96	25.1 ± 7.89

CLT (liters/h)	4.64 ± 1.17	3.98 ± 0.481	2.25 ± 0.685	0.96 ± 0.379

aAll values are reported as mean ± SD. PK, pharmacokinetics; Cmax, maximum concentration of drug in plasma; AUC0–∞, area under the concentration-time curve from 0 h to infinity; Vss, volume of distribution at steady state; CLT, total clearance.

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MRT0–inf_obs (h)

PK parameters of TET and RPTNs in the rat after intravenous administration.

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Parameter	<italic>t</italic>1/2 (h)	MRT0–inf_obs (h)	Cmax (ng/mL)	AUC0–<italic>t</italic> (ng/ml h)	AUC0–inf_obs (ng/ml h)

TET	6.56 ± 0.95	2.73 ± 0.50	434.93 ± 70.59	362.71 ± 66.24	370.11 ± 67.92

RPTNs	19.38 ± 1.93	27.18 ± 4.52	202.35 ± 19.21	657.28 ± 56.73	732.18 ± 55.36

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Tmax (hour) − median

Comparison of steady‐state metformin pharmacokinetic parameters and renal elimination parameters with and without co‐administration of rifampicin

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Parameter	With rifampicin (<italic>n</italic> = 24)	Without rifampicin (<italic>n</italic> = 22)
<italic>P</italic> value or GMR estimate (90% CI) (<italic>n</italic> = 22)

AUC0–τ (mg/L × hour)	15.4 (7.8–32.8)	12.1 (8.1–21.6)	1.28 (1.13–1.44)<xref ref-type="fn" rid="cpt1232-note-0003">a</xref>

Cmax (mg/L)	2.3 (1.25–5.22)	2.0 (1.10–3.86)	1.19 (1.03–1.38)<xref ref-type="fn" rid="cpt1232-note-0003">a</xref>

Tmax (hour) − median	1.5 (1–4)	1.5 (0–6)

CL/<italic>F</italic> (L/hour)	36 (21–69)	47 (34–73)	<0.001<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

<italic>V</italic>
d/<italic>F</italic> (L)	332 (201–681)	310 (87–477)	0.586<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

t1/2 (hour)	6.4 (4.2–17.2)	4.6 (1.6–6.6)	0.002<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

AUC0–8 hour (mg/L × hour)	13.4 (7.8–32.8)	10.9 (7.4–11.2)	0.001

AUC0–τ (mg/L × hour) –excluding sessions with ≥ 20% extrapolation	15.1 (7.8–32.8)	12.2 (8.1–21.6)	0.083 (<italic>n</italic> =<italic> </italic>14)

CLcreatinine (mL/min)<xref ref-type="fn" rid="cpt1232-note-0003">c</xref>
	110 (88–155)	106 (74–148)	0.005<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

CL0–8 hour,renal (mL/min)<xref ref-type="fn" rid="cpt1232-note-0003">d</xref>
	309 (90–625)	332 (126–659)	0.836<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

CL0–8 hour,secretion (mL/min)<xref ref-type="fn" rid="cpt1232-note-0003">d</xref>
	205 (–1–494)	219 (52–533)	0.777<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

CL0–τ,secretion (mL/min)<xref ref-type="fn" rid="cpt1232-note-0003">d</xref>
	212 (27–494)	216 (52–533)	0.856<xref ref-type="fn" rid="cpt1232-note-0003">b</xref>

Metformin plasma concentrations were extrapolated from 8–12 or 24‐hours postdose to calculate AUC0–τ for patients on once or twice daily metformin, respectively. Pharmacokinetic parameters are expressed as geometric mean (range), unless stated otherwise. AUC0–τ, area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval; CI, confidence interval; CL, clearance; Cmax, maximum plasma concentration; F, bioavailability; GMR, geometric mean ratio; t1/2, half‐life; Tmax, time to maximum plasma concentration; V d, volume of distribution. aEvaluation of a pharmacokinetic interaction by means of the bioequivalence approach. bPaired‐samples t test on log‐transformed pharmacokinetic parameters. cSession comparison of creatinine clearance based on n = 21 individuals. dDue to miscollection of urine at home between 8 and 24 hours postdose for five individuals, we calculated renal clearance and tubular secretion from observed urine collections up to 8 hours after metformin intake (CL0–8 hour,renal (mL/min) and CL0–8 hour,secretion; n = 21), next to tubular secretion based on confirmed collections during the full time interval (CL0–τ,secretion) (n = 16).

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CL, L/h/m2

Pharmacokinetic parameters after aldoxorubicin infusion on day 1 of cycle 1 (N = 18)

AUC 0-t area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration, AUC 0-∞ area under the concentration-time curve from time 0 to infinity, CL systemic clearance for aldoxorubicin, CL/F apparent clearance for doxorubicin, C max peak plasma concentration of aldoxorubicin after dosing, NA not applicable, NC not calculated, SD standard deviation, t ½ apparent half-life of aldoxorubicin, t max time to reach Cmax, V d /F apparent volume of distribution of doxorubicin, V ss volume of distribution at steady state of aldoxorubicin aCalculated using doxorubicin-equivalent dose; assumes all aldoxorubicin is hydrolyzed to doxorubicin bCalculated using aldoxorubicin dose cThe tmax parameter for doxorubicinol was measured in 4 patients in the 230 mg/m2 cohort

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Chow et al. (2005); 400 mg PE

      0
      1
      2
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      4
      5

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      GT solids and PE pharmacokinetic studies in humans
      Predicted and actual C max in the plasma (μg/mL)
      Predicted and actual C max in the plasma (μg/mL)
      Predicted and actual C max in the plasma (μg/mL)
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

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      GT solids and PE pharmacokinetic studies in humans
      EGCG
      EGC
      EC
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

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      Lee et al. (2002); 20 mg/kg GT solids
      0.06a (0.08)b
      0.07 (0.22)c
      0.04 (0.12)c
      0.200000
      6.060000

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      Chow et al. (2005); 400 mg PE
      0.11 (0.14)
      0.01 (0.02)
      0.01 (0.00)
      0.130000
      8.420000

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      Chow et al. (2001); 600 mg PE
      0.21 (0.17)
      0.02 (0.01)
      0.01 (0.01)
      0.210000
      12.460000

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      Chow et al. (2005); 800 mg PE
      0.21 (0.29)
      0.02 (0.03)
      0.01 (0.00)
      0.250000
      15.710000

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      Chow et al. (2005); 1200 mg PE
      0.35 (0.92)c
      0.04 (0.04)
      0.02 (0.01)
      0.420000
      26.700000

CAPTION: Using C max as a dose surrogate to predict plasma dosimetry of TCM in humans
FOOTER: aValues without brackets are predicted C max of unchanged TCs based on PBPK modeling.bBracketed values are C max from the literature. These C max usually are determined from free tea catechin concentrations except those of Lee et al. (2002) study, which are determined from total tea catechin concentrations (free plus conjugated forms).cCmax is under‐predicted when compare with the observed value.dTotal TCM concentrations are expressed as μg EGCg equivalents/mL plasma; they are calculated using predicted C max and the concentration/dose additivity model (ATSDR, 2004).eAdministered dose metrics are expressed as mg EGCg equivalents/kg BW; they are calculated using the concentrations of individual TCs in PE and the additivity model (ATSDR, 2004).

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Parameter estimates of final dolutegravir population PK model

%RSE: percent relative standard error of the estimate = SE/parameter estimate × 100; 95% CI = 95% confidence interval on the parameter;ALAG, absorption lag-time; CL/F, apparent clearance; CV, coefficient of variation of proportional error (=[σ2prop]0.5*100); IOV, inter-occasion variability; ka, absorption rate constant; PK, pharmacokinetics; σ2prop, proportional component of the residual error model; V/F, volume of central compartment; ω2CL, ω2V, and ω2ka, variance of random effect of CL/F, V/F and ka, respectively.The reference population for PK parameters CL/F and V/F are 40-year-old, 70 kg male, non-current smoker, with total bilirubin of 9 µmol l–1.*From 1000 completed bootstrap runs;†CL/F = 0.901 × 1.16SMOK × 1.35POC × (WT/70)0.438 × (AGE/40)0.193 × (BILI/9)-0.211 (SMOK = 1 for smoking subjects and = 0 for non-smoking subjects; POC = 1 for study ING111521 and = 0 for other studies);‡V/F = 17.4 × (WT/70)0.768;§F = 1.21GEND × 1.24DOSE (GEND = 1 for females and = 0 for males; DOSE = 1 for 10 mg dose and = 0 for other doses) ‖  when ω2P exceeds 0.15

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t1/2 (mean, SD)b h

Human studies reporting pharmacokinetic (PK) parameters for cannabidiol (CBD).

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<bold>References</bold>	<bold>Total n, sex</bold>	<bold>Administration</bold>	<bold>Source</bold>	<bold>CBD dose</bold>	<bold>Plasma</bold><xref ref-type="table-fn" rid="TN1"><bold>a</bold></xref><bold>PK details</bold>	<bold>Other</bold>

<bold>Tmax (median, range),<xref ref-type="table-fn" rid="TN1">b</xref> hrs</bold>	<bold>Cmax (mean, SD)<xref ref-type="table-fn" rid="TN1">b</xref> ng/mL</bold>	<bold>AUC0-t (mean, SD)<xref ref-type="table-fn" rid="TN1">b</xref> h × ng/mL</bold>	<bold>AUC0-inf (mean, SD) h × ng/mL</bold>	<bold>Kel (mean, SD) 1/h</bold>	<bold>t1/2 (mean, SD)<xref ref-type="table-fn" rid="TN1">b</xref> h</bold>	<bold>CL/F (mean, SD) L/h</bold>	<bold>Mean (SD)</bold>

Ohlsson et al., <xref rid="B46" ref-type="bibr">1986</xref>	5, M, infrequent to frequent cannabis smokers	i.v.	In lab	20 mg	686 (239)	ng/ml min × 10−3 = 16.67 (3.23)	24 (6)	74.4 (14.4)	Distribution volume: 32.7 (8.6) l/kg.

<bold>‘'</bold>	Smoking	In lab	19.2 ± 0.3mg	110 (55)	ng/ml min × 10−3 = 4.85 (1.72)	31 (4)	Estimated systemic availability (%) from smoking: 31 (13)

Consroe et al., <xref rid="B8" ref-type="bibr">1991</xref>	15, M/F	Oral capsules	NIDA	10 mg/kg/day daily for 6 weeks	2–5 days

Guy and Robson, <xref rid="B25" ref-type="bibr">2004b</xref>	12, M/F	Oromucosal spray sublingual (CBD and THC)	GW	10 mg	1.63 (SD 0.68)	2.5 (1.83)	6.81 (4.33)	7.12 (4.31)	1.44 (0.79)

Oromucosal spray buccal (CBD and THC)	GW	10 mg	2.79 (SD 1.31)	3.02 (3.15)	6.4 (4.62)	6.8 (4.46)	1.81 (2.05)

Oromucosal spray oro-pharyngeal (CBD and THC)	GW	10 mg	2.04 (SD 1.13)	2.61 (1.91)	7.81 (5.13)	8.28 (5.32)	1.76 (0.8)

CBME oral capsule (CBD and THC)	GW	10 mg	1.27 (SD 0.84)	2.47 (2.23)	5.76 (4.94)	6.03 (4.97)	1.09 (0.46)

Guy and Robson, <xref rid="B24" ref-type="bibr">2004a</xref>	24, M	Oromucosal spray sublingual (CBD and THC)	GW	10 mg	4.22	3.33	11.34	11.97	1.81

Guy and Flint, <xref rid="B23" ref-type="bibr">2004</xref>	6 M/F	Nebuliser (CBD and THC)	GW	20 mg	0.6 (0.08–1)	9.49 (8.01)	9.41 (10.8)	12.11 (10.83)	0.98 (0.58)	1.1 (0.97)

Aerosol (with THC)	GW	20 mg	2.35 (0.75–6)	2.6 (1.38)	5.43 (5.88)	13.53 (3.64)	0.43 (0.26)	2.4 (2.02)

Sublingual drops (CBD)	GW	20 mg	2.17 (1–4)	2.05 (0.92)	2.60 (3.45)

Sublingual drops (CBD and THC)	GW	20 mg	1.67 (1–3)	2.58 (0.68)	3.49 (2.65)	9.65 (4.02)	0.37 (0.114)	1.97 (0.62)

Nadulski et al., <xref rid="B40" ref-type="bibr">2005a</xref>	24, M/F	Oral capsule (CBD and THC)	Scherer GmbH & Co. KG, Eberbach,Germany	5.4mg once a week for 3 weeks	Mean 0.99 (0.5–2)	0.93 (range 0–2.6)	Mean 4.35, range (2.7–5.6)

12, M/F	Oral capsule (CBD and THC) and breakfast consumed 1 hour after	Scherer GmbH & Co. KG, Eberbach,Germany	5.4mg once a week for 3 weeks	Mean 1.07 (0.5–2)	1.13 (range 0.39–1.9)	Mean 4.4 (range 2.5–5.3)

Nadulski et al., <xref rid="B41" ref-type="bibr">2005b</xref>	24, M/F	Cannabis extract	Sigma	5.4 mg	Mean 1.0 (0.5–2.0)	0.95 (range 0.3–2.57)

Karschner et al., <xref rid="B33" ref-type="bibr">2011</xref>	9, M/F cannabis smokers	Oromucosal spray (Sativex: CBD and THC)	GW	5 mg	3.6 (1.0–5.5)	Mean (SE): 1.6 (0.4)	4.5 (SE 0.6)

15 mg	4.6 (1.2–5.6)	Mean (SE): 6.7 (2.0)	18.1 (SE 3.6)

Schwope et al., <xref rid="B47" ref-type="bibr">2011</xref>	10, M/F, usual infrequent cannabis smokers	Cannabis cigarette	NIDA	2 mg	0.25 (0.25–0.50 h) whole blood/plasma	Median (range): plasma 2 (< LOQ−3.4)

Eichler et al., <xref rid="B15" ref-type="bibr">2012</xref>	9, M	Oral capsules (CBD and THC)	Cannapharm AG	Heated CBD (27.8 mg CBD: 0.8 mg CBDA)	0.83 (SD 0.17)	pmol/mL: 0.94 (0.22)	pmol h/moL 3.68 (1.34)

Unheated 14.8 mg CBD:10.8 mg CBDA)	1.17 (SD 0.39)	3.95 (0.92) pmoL/mL	pmol h/mol 7.67 (2.06)

Lee et al., <xref rid="B34" ref-type="bibr">2012</xref>	10, M/F, cannabis smokers	Cannabis cigarette	NIDA	2 mg	Median 0.25 (oral fluid)	0.03 (oral fluid)

Sellers et al., <xref rid="B48" ref-type="bibr">2013</xref>	60, M/F	Oromucosal spray (CBD and THC)	GW	20 mg, 5 days	1.4 (0, 8.45)	1.5 (0.78)	6.1 (5.76)	14.8 (7.87)

51, M/F	90 mg – 60 mg, 5 days	1.5 (0–6.45)	4.8 (3.4)	38.9 (33.75)	60.3 (37.71)

Stott et al., <xref rid="B51" ref-type="bibr">2013b</xref>	12, M	Oromucosal spray (CBD and THC)	GW	10 mg (fed state)	4.00 (3.02–9.02);	3.66 (2.28)	23.13 (9.29)	20.21 (8.43)	0.155 (0.089)	5.49 (2.17)	533 (318)

Stott et al., <xref rid="B50" ref-type="bibr">2013a</xref>	24, M	Oromucosal spray (CBD and THC)	GW	5 mg single dose	Mean 1.00 (0.75–1.50)	0.39 (0.08)	0.82 (0.33)	1.66 (0.51)	0.173 (0.084)	5.28 (3.28)	3,252 (1,002)

10 mg single dose	Mean 1.39 (0.75–2.25)	1.15 (0.74)	4.53 (3.53)	5.64 (4.09)	0.148 (0.079)	6.39 (4.48)	2,546 (1,333)

20 mg single dose	Mean 1.00 (0.75–1.75)	2.17 (1.23)	9.94 (9.02)	13.28 (12.86)	0.123 (0.097)	9.36 (6.81)	3,783 (4,299)

5 mg, 9 days	Mean 1.64 (1.00–4.02)	0.49 (0.21)	2.52 (0.73)

10 mg, 9 days	Mean 1.27 (0.75–2.52)	1.14 (0.86)	6.66 (3.10)

20 mg 9 days	Mean 2.00 (1.02–6.00)	3.22 (1.90)	20.34 (7.29)

Stott et al., <xref rid="B49" ref-type="bibr">2013c</xref>	36, M	Oromucosal spray (CBD and THC)	GW	10 mg (3 groups)	1.00 (0.50–4.00); 1.38 (0.75–6.00); 1.15 (0.50–3.02)	1.03 (0.81); 0.66 (0.37); 0.63 (0.43)	3.23 (2.13); 1.82 (1.03); 1.83 (1.19)	5.10 (3.06); 3.54 (0.80); 3.00 (1.43)	0.148(0.108); 0.122 (0.111); 0.224 (0.158)	10.86(12.71); 7.81 (3.00); 5.22 (4.51)	2817 (1913); 2998 (896); 4,741 (3,835)	Varea/F (L): 28312 (19355); 31994 (12794); 26298 (14532)

15 mg	4.5 (1.2–5.6)	Mean (SE): 6.7 (2.0)

Newmeyer et al., <xref rid="B44" ref-type="bibr">2014</xref>	24, M/F, frequent or occasional cannabis smokers	Cannabis cigarette (frequent smokers)	NIDA	2 ± 0.6 mg	0.5 (0.5–1)	Median (range): 14.8 (1.4–162)	Median (range): 29 (4.7–211)

Cannabis cigarette (occasional smokers)	2 ± 0.6 mg	1 (0.5–2)	Median (range): 7 (1.9–111)	Median (range): 11.6 (4.1–185)

Desrosiers et al., <xref rid="B11" ref-type="bibr">2014</xref>	21, M/F frequent and occasional smokers	Cannabis cigarette (frequent smokers)	NIDA	2 mg	0.5 (0.0–1.1)	1.1 (0.0–1.6)

Cannabis cigarette (occasional smokers)	2 mg	0 (0–500)	0 (0–1300)

Manini et al., <xref rid="B37" ref-type="bibr">2015</xref>	17, M/F	Oral capsules Co-administered with i.v. fentanyl	GW	400 mg	3 and 1.5 (plasma) and 6 and 2 (urine)	Plasma: 181.2 (39.8) and 114.2 (9.5); Urine: 4600 and 2900	704 (283) and 482 (314) mcg*hr/dL

800 mg	3 and 4 (plasma) and 4 and 6 (urine)	Plasma: 221 (35.6) and 157.1 (49.0); Urine: 3700 and 2800	867 (304) and 722 (443) mcg*hr/dL

Haney et al., <xref rid="B28" ref-type="bibr">2016</xref>	8, M/F cannabis smokers	Oral capsules	STI pharmaceuticals	800 mg	Mean 3 (2–6)	77.9 (range 1.6–271.9)

Cherniakov et al., <xref rid="B6" ref-type="bibr">2017a</xref>	9, M	Oral capsules with piperine pro-nanolipospeheres (CBD and THC)	STI pharmaceuticals	10 mg	1 (0.5–1.5)	2.1 (0.4)	6.9 (1.3)

Oromucosal spray (CBD and THC; Sativex®)	10 mg	3 (1–5)	0.5 (0.1)	3.1 (0.4)

Swortwood et al., <xref rid="B53" ref-type="bibr">2017</xref>	20, M/F Cannabis smokers	Cannabis cigarettes – frequent smokers	NIDA	1.5 mg	Mean 0.29 (0.17–1.5) (oral fluid)	93.3 (range 0.65–350) (oral fluid)

Cannabis cigarettes – occasional smokers	NIDA	1.5 mg	Mean 0.17 (oral fluid)	55.9 (range 2.5–291) (oral fluid)

Cannabis containing brownie – frequent smokers	NIDA	1.5 mg	Mean 0.53 (0.17–1.5) (oral fluid)	8.0 (range 0.48–26.3) (oral fluid)

Cannabis containing brownie – occasional smokers	NIDA	1.5 mg	Mean 0.47 (0.17–1.5) (oral fluid)	5.9 (range 2.1–11.4) (oral fluid)

Vaporization – frequent smokers	Volcano® Medic, Storz & Bickel, Tuttlingen, Germany	1.5 mg	Mean 0.29 (0.17–1.5) (oral fluid)	76.3 (range 2.3–339) (oral fluid)

Vaporization – occasional smokers	Volcano® Medic, Storz & Bickel, Tuttlingen, Germany	1.5 mg	Mean 0.17 (oral fluid)	28.2 (range 0.23–167) (oral fluid)

Atsmon et al., <xref rid="B3" ref-type="bibr">2017b</xref>	15, M	CBD extract >93% in a PTL101 formulation (oral gelatin matrix pellet technology)Sublingual/buccal	AiFame-AiLab GmbH (CBD), Gelpell AG (capsules)	10 mg	3.0 (2.0–4.0)	3.22 (1.28)	9.64 (3.99)	10.31 (4.14)	2.95 (2.58)

100 mg	3.5 (1.5–5.0)	47.44 (20.14)	149.54 (34.34)	153.04 (34.7)	3.59 (0.26)

Oromucosal spray (CBD and THC)	GW	10 mg	3.5 (1.0–5.0)	2.05 (1.1)	7.3 (2.86)	7.81 (2.81)	0.33 (0.09)	2.31 (0.72)

Atsmon et al., <xref rid="B2" ref-type="bibr">2017a</xref>	15, M	CBD and THC in a PTL401 capsule (self-emulsifying oral drug delivery system)	STI pharmaceuticals	10 mg	1.25 (0.5–4.0)	2.94 (0.73)	9.85 (4.47)	10.52 (4.53)	0.29 (0.17)	3.21 (1.62)

Devinsky et al., <xref rid="B14" ref-type="bibr">2018b</xref>	34, children	Oral solution	GW	2.5 mg	70.23 (mean from 3 groups)

5 mg/kg/day	241

10 mg/kg/day	722

20 mg/kg/day	963

a, bUnless otherwise stated. PK, pharmacokinetics; CBD, cannabidiol; THC, Tetrahydrocannabinol; M, male; F, female; AUC, area under the curve; Conc., concentration; GW, GW pharmaceuticals; NIDA, US national institute on drug abuse; LOQ, limit of quantification; IV, intravenous; CBME, cannabis based medicine extract; Min(s), min(s).

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k 01 half‐life

Final parameters for the population analysis of levetiracetam concentrations with LEV‐XR administered alone, with phenobarbital, or with zonisamide. Administration of LEV‐XR was repeated every 12 hours to achieve steady‐state conditions before sampling

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LEV‐XR alone	LEV‐XR + phenobarbital	LEV‐XR + Zonisamide	Overall (all groups)

Parameter	Units	Value	Ω2
	CV%	Value	Ω2
	CV%	Value	Ω2
	CV%	Value	Ω2
	CV%

AUC	hours∙μg/mL	352.95	—	—	134.86	—	—	452.76	—	—	388.72	—	—

Clearance	L/kg/hr	0.08	—	—	0.17	—	—	0.07	—	—	0.08	—	—

<italic>C</italic>
MAX
	mg/L	33.01	—	—	13.38	—	—	34.13	—	—	32.99	—	—

<italic>k</italic>
01 half‐life	hr	4.45	—	—	3.72	—	—	5.60	—	—	5.01	—	—

<italic>k</italic>
10 half‐life	hr	1.31	—	—	1.57	—	—	1.57	—	—	1.37	—	—

<italic>T</italic>
MAX
	hr	3.28	—	—	3.38	—	—	4.01	—	—	3.53	—	—

θ<italic>k</italic>
01
	1/hr	0.16	0.030	17.304	0.19	0.020	14.228	0.12	0.0004	2.117	0.138	0.058	24.39

θ<italic>k</italic>
10
	1/hr	0.53	0.0013	3.5870	0.44	0.0009	2.9850	0.44	0.0002	1.322	0.505	0.001	3.32

θ<italic>V</italic>
	L/kg	0.15	0.505	80.946	0.39	0.589	89.405	0.15	0.029	17.264	0.151	0.221	49.66

Abbreviations: LEV‐XR, extended‐release levetiracetam; CV, coefficient of variation; Ω2, variance of the random source error; AUC, area‐under‐the‐curve for the plasma‐concentration versus time profile; C MAX, peak concentration; θk 01, theta (typical value) for absorption rate and associated half‐life; θk 10, theta for elimination rate and associated half‐life; θV, theta for volume of distribution; T MAX, time to peak concentration. Clearance (CL) and V as shown in the table represent V/F and CL/F because they are calculated as per fraction absorbed for an oral dose. Values for Ω2 and CV% are not available for secondary parameters (shown by “—”) because random effects are only measured for primary parameters.

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1st Peripheral volume of distribution of morphinea

Population parameter estimates for the final model

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Description	Parameter	Population estimate (RSE, %)	IIV, %CV (RSE, %)

Nonrenal clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	CLM,NR (L/hr)	44.1 (9)	31.6 (80)

Central volume of distribution of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	VM (L)	9.41 (13)	42.3 (55)

1st Peripheral volume of distribution of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	VP1 (L)	108 (37)	—

1st Intercompartmental clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	QP1 (L/hr)	67.1 (17)	—

2nd Peripheral volume of distribution of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	VP2 (L)	50.7 (21)	—

2nd Intercompartmental clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	QP2 (L/hr)	83.4 (15)	—

Renal clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	CLM,R (L/hr)	6.32 (11)	—

Total clearance of M3G	CLM3G (L/hr)	7.32 (10)	34.5 (38)

Central volume of distribution of M3G	VM3G (L)	9.51 (15)	56.6 (36)

Liver transit rate constant	ktrans (hr−1)	14.4 (14)	—

NASF effect on clearance of M3G<xref ref-type="fn" rid="psp412185-note-0005">b</xref>
	NASF on CLM3G
	−0.628 (26)	—

Correlation between IIV CLM3G and IIV VM3G
	Corr(CLM3G‐VM3G)	—	0.751 (20)

Residual variability (%)

Proportional residual error of morphine in serum<xref ref-type="fn" rid="psp412185-note-0007">c</xref>
	σ2
M
	27.2 (6)	—

Proportional residual error of M3G in serum<xref ref-type="fn" rid="psp412185-note-0007">c</xref>
	σ2
M3G
	38.4 (10)	—

Proportional residual error of morphine in urine<xref ref-type="fn" rid="psp412185-note-0007">c</xref>
	σ2
M‐Urine
	62.1 (25)	—

Proportional residual error of M3G in urine<xref ref-type="fn" rid="psp412185-note-0007">c</xref>
	σ2
M3G‐Urine
	66.5 (22)	—

%CV, percent coefficient of variation; RSE, Relative standard error; IIV, inter‐individual variability; M3G, morphine‐3‐glucuronide; CL, clearance; V, volume of distribution; Corr, correlation.aMorphine volume and clearance parameters were allometrically scaled using total body weight.bFractional change in clearance of M3G for subjects with NASF scores above 4 using a natural logarithmic scale, where  CLM3G,i=CLM3G,pop∗(1−0.6∗Ln(NASFi4))∗e(ηCLM3G,i) for the ith subject.cProportional residual error coded as additive on logarithmic scale.

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ARCmax

Summary of plasma pharmacokinetic parameters of JTE‐052 in AD patients treated with 1% or 3% JTE‐052 ointment twice daily for 7 days in the morning and the evening with a 12‐h interval (part 3)

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Dose	Day 1	Day 7

1%	3%	1%	3%

<italic>n</italic>
	8	7<xref ref-type="fn" rid="jde14322-note-0003">†</xref>
	8	7<xref ref-type="fn" rid="jde14322-note-0003">†</xref>

Tmax (h)	NC	4.0 (2.0, 4.0)<xref ref-type="fn" rid="jde14322-note-0003">‡</xref>
	NC	4.0 (2.0, 4.0)<xref ref-type="fn" rid="jde14322-note-0003">‡</xref>

Cmax (ng/mL)	NC	3.75 ± 1.78<xref ref-type="fn" rid="jde14322-note-0003">‡</xref>
	NC	2.89 ± 1.39<xref ref-type="fn" rid="jde14322-note-0003">‡</xref>

AUCtau (ng•h/mL)	NC	30.4 ± 10.8<xref ref-type="fn" rid="jde14322-note-0003">‡</xref>
	NC	25.2 ± 11.3<xref ref-type="fn" rid="jde14322-note-0003">‡</xref>

ARCmax
	NC	0.797 ± 0.279<xref ref-type="fn" rid="jde14322-note-0003">§</xref>

ARAUCtau
	NC	0.868 ± 0.347<xref ref-type="fn" rid="jde14322-note-0003">§</xref>

ARCtrough
	NC	0.717 ± 0.269<xref ref-type="fn" rid="jde14322-note-0003">¶</xref>

†One subject withdrew due to personal reasons. ‡ n = 6: not detected JTE‐052 concentrations. § n = 5. ¶ n = 4. Parameters are expressed as mean ± standard deviation except for Tmax, median (minimum, maximum). ARAUCtau, accumulation ratio of AUCtau; ARCmax, accumulation ratio of Cmax; ARCtrough, accumulation ratio of trough concentrations; AUCtau, area under the concentration‐time curve during the dosing interval; Cmax, maximum plasma concentration; n, number of patients; Tmax, time to reach Cmax.

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Tmax

Association between genetic polymorphisms and telatinib pharmacokinetic data. Dose normalized Cmax, T1/2 and Tmax

#=*801 number from termination codon TGA (5397). 3UTR

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Tmax (h)

Pharmacokinetic parameters of triptolide in rats after oral administration of triptolide (1 mg/kg, n = 6, mean ± S.D.) with or without puerarin pretreatment (100 mg/kg/day for seven days).

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Parameter	Triptolide	Triptolide + puerarin

<italic>T</italic>max (h)	0.51 ± 0.06	0.27 ± 0.2*

<italic>C</italic>max (ng/mL)	187.25 ± 15.36	219.67 ± 21.52*

<italic>t</italic>1/2 (h)	1.03 ± 0.12	1.18 ± 0.18*

AUC(0–<italic>t</italic>) (ng·h/mL)	201.55 ± 21.08	261.38 ± 31.27*

CL (L/h/kg)	4.92 ± 0.35	3.75 ± 0.19*

*p < 0.05 indicates significant differences from the control.

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Cmax, mg/l

Pharmacokinetic profile across study groups

AUC, area under the concentration-time curve.Data presented as median (IQR) or mean ± SD for the AUC.

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Cmax (ng/ml)

Individual and mean pharmacokinetic parameters of daidzein following a single dose of orally administered soy beverage (B) and soy extract capsules (C).

1Pharmacokinetic parameters adjusted for oral administered dose. ND = statistical analysis was not performed due to differences in oral administered doses between both preparations, *Statistical significance (p < 0.05) compared to corresponding values of soy extract capsules.

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VP1 (L)

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T max, hr

Descriptive statistics for secondary PK parameters

CL/F, apparent systemic clearance after extravascular dosing; CV, coefficient of variation; EU Humira, adalimumab EU Humira; LS, least squares; M923, adalimumab biosimilar M923; PK, pharmacokinetics; t 1/2, terminal half‐life; t max, time to maximum concentration (median and range only); US Humira, adalimumab US Humira; V z/F, apparent volume of distribution.aTwenty‐seven of the 315 subjects in the PK analysis set had individual parameters that were excluded from the PK analysis set due to protocol deviations or failure to meet acceptability criteria. Half‐life and related PK parameters could not be calculated in 6 subjects due to lack of defined terminal elimination phase.

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KREL (min−1)

Parameter estimates of the PK/PD models for quinpirole effect on ACTH, GH, prolactin and TSH with plasma and brainECF as target site

In bold the parameters of the selected models. DPlac, the extent of the placebo effect; ECF, extracellular fluid; EC50, concentration at half maximal drug effect; EMAX, maximal drug effect; kDEC, dose‐independent hormone decay; kDEG, hormone elimination rate; kREL, hormone release reate; RUV, residual unexplained variability; S0, EMAX/EC50.

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CL (L/h)

Summary of pharmacokinetic parameters of sepantronium after continuous intravenous infusion of 1.8, 3.6, 4.8, 6.0, 8.0, or 10.6 mg/m2/day for 168 h

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PK parameters (mean ± SD)	Normal (<italic>n</italic> = 19)	Mild (<italic>n</italic> = 21)	Moderate (<italic>n</italic> = 6)

AUC/Dose (ng h/mL/mg)	29 ± 14	27 ± 7	37 ± 10

CSS/Dose (ng/mL/mg)	0.17 ± 0.08	0.16 ± 0.04	0.22 ± 0.07

CL (L/h)	39 ± 11	39 ± 11	28 ± 9

SD standard deviation, AUC/Dose dose-normalized area under the curve from zero to time t of the last measurable concentration above the limit of quantitation, CSS/Dose dose-normalized steady-state concentration, CL total systemic clearance, CLR renal clearance, GMR geometric mean ratio, CI confidence interval

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Tmax (h)

Pharmacokinetics of S3643 in Male (n = 4) and Female (n = 4) Sprague-Dawley Rats.

Male rat: CL = 5.97 mL/min/kg; Vss = 337 mL/kg Female rat: CL = 8.03 mL/min/kg; Vss = 325 mL/kg.CL = clearance; Vss = steady-state volume of distribution; % F = bioavailability.

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AUC0-t, ng · h/mL

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Apparent t 1/2 (h)

PK parameters of NP046

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PK parameter	Oral	IV

<bold>Nominal Dose (mg/kg)</bold>
	50	10	5

<bold>Apparent t</bold>
<bold>1/2</bold>
<bold>(h)</bold>
	4.4 ± 0.60	3.1 ± 0.46	3.2 ± 0.35

<bold>Blood CL</bold>
<bold>total</bold>
<bold>(mL/min/kg)</bold>
	—	—	62.2 ± 3.0

<bold>Vd (L/Kg)</bold>
	—	—	16.9 ± 1.3

<bold>C</bold>
<bold>max</bold>
<bold>(μM)</bold>
	0.47 ± 0.10	0.13 ± 0.06	—

<bold>T</bold>
<bold>max</bold>
<bold>(min)</bold>
	30	48	—

<bold>AUC</bold>
<bold>0 - ∞</bold>
<bold>(min. μmol/L)</bold>
	80 ± 8.8	30 ± 14.7	248 ± 12.6

<bold>Bioavailability (%)</bold>
	3.2 ± 0.47	6.0 ± 2.9	N/A

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AUC0−∞ (h·ng/mL)

The pharmacokinetic parameters of gefitinib in each study (Geometric Mean (CV%)).

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AUC0–∞ (μg/mL min)

Pharmacokinetic parameters for caffeine in five studied conditions – means and ranges.

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 	Mean values ± SD (range)

Condition	Cmax (μg/mL)<xref rid="TF2" ref-type="table-fn">
a
</xref>	Dose-normalized<xref rid="TF3" ref-type="table-fn">
b
</xref> Cmax (μg/mL)	Tmax (min)	AUC0–∞ (μg/mL min)	Dose-normalized<xref rid="TF3" ref-type="table-fn">
b
</xref> AUC0–∞ (μg/mL min)	MRT (min)	MAT (min)	CL/F (mL/min/kg)	Vd,ss/F (mL/kg)<xref rid="TF2" ref-type="table-fn">
a
</xref>	t1/2 (min)

A (hot coffee – 20 min)	3.74 ± 1.09 (1.96–5.95)	1.69 ± 0.43 (1.07–2.40)	59 ± 27 (20–120)	2312 ± 1338	1035 ± 541	601 ± 263	12 ± 11	1.2 ± 0.6	623 ± 129	408 ± 178 (210–990)

B (cold coffee – 2 min)	3.64 ± 1.36 (1.81–8.17)	1.57 ± 0.59 (0.981–3.13)	62 ± 32 (40–120)	2447 ± 1781	1047 ± 725	607 ± 267	14 ± 10	1.3 ± 0.7	626 ± 145	411 ± 183 (187–966)

C (cold coffee – 20 min)	3.56 ± 1.06 (1.69–5.77)	1.60 ± 0.44 (0.917–2.79)	64 ± 20 (40–90)	2625 ± 2177	1172 ± 882	673 ± 362	16 ± 6	1.2 ± 0.6	642 ± 151	455 ± 249 (217–1386)

D (energy drink – 2 min)	3.36 ± 1.20 (1.40–5.78)	1.51 ± 0.48 (0.782–2.81)	70 ± 44 (20–240)	2473 ± 2302	1059 ± 834	665 ± 427	15 ± 16	1.4 ± 0.8	712 ± 194	450 ± 295 (154–1386)

E (energy drink – 20 min)	3.14 ± 0.95 (1.87–5.25)	1.41 ± 0.32 (0.940–1.96)	82 ± 42 (40–240)	2107 ± 1504	925.1 ± 565	593 ± 258	17 ± 8	1.5 ± 0.8	708 ± 144	399 ± 177 (187–990)

A: hot coffee 20 min; B: cold coffee 2 min; C: cold coffee 20 min; D: sugar-free energy drink 2 min; E: sugar-free energy drink 20 min.a -RM ANOVA p ≤ 0.05.b Values normalized by mg/kg dose of caffeine.

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V/F (liters/kg)

Noncompartmental analysis of quinine in pregnant patients with uncomplicated P. falciparum malaria

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Parameter<italic><xref ref-type="table-fn" rid="TF3-1">a</xref></italic>	Result for quinine (<italic>n</italic> = 21)<italic><xref ref-type="table-fn" rid="TF3-2">b</xref></italic>

Total dose (mg [base]/kg)	7.10 (6.66–7.93)

<italic>C</italic>max (μg/ml)	4.52 (2.58–8.05)

<italic>C</italic>max/dose (μg/ml/[mg/kg])	0.640 (0.370–1.20)

<italic>T</italic>max (h)	2.03 (1.07–4.00)

<italic>CL</italic>/<italic>F</italic> (liters/h)	6.07 (1.88–11.3)

<italic>CL</italic>/<italic>F</italic> (liters/h/kg)	0.110 (0.0300–0.210)

<italic>V</italic>/<italic>F</italic> (liters)	74.2 (51.3–161)

<italic>V</italic>/<italic>F</italic> (liters/kg)	1.45 (0.820–2.59)

<italic>T</italic>1/2 (h)	9.28 (3.24–21.9)

AUC0–LAST (h · μg/ml)	26.5 (15.2–53.3)

AUC0–∞ (h · μg/ml)	61.4 (33.0–231)

AUC0–∞/dose (h · μg/ml/[mg/kg])	9.06 (4.65–34.6)

Day 7 concn (μg/ml)<italic><xref ref-type="table-fn" rid="TF3-3">c</xref></italic>	3.93 (1.02–7.77)

aCmax, maximum observed plasma concentration after the first dose; Tmax, observed time to reach Cmax; CL, elimination clearance; V, apparent volume of distribution; T1/2, terminal elimination half-life; AUC0–LAST, observed area under the plasma concentration-time curve after the first dose from zero time to the last observed concentration; AUC0–∞, predicted area under the plasma concentration time curve after the first dose from zero time to infinity; Day 7 concn, observed day 7 concentration after repeated drug administration; F, oral bioavailability.bValues are given as the median (range) unless otherwise specified.cBased on results for 23 individuals; day 7 concentrations from individual 199 and 251 were also included.

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Mean Cmax (ng/mL) [% CV]

Mean pharmacokinetic parameters of S 47445 (0.3 mg/kg) and donepezil (1.0 mg/kg), given alone or combined in middle-aged mice

Three groups (n = 4 subjects for S 47445 and n = 4 per sampling time for donepezil) were used for the pharmacokinetic (PK) study

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Vc: Allometric exponent for weight (−)d , e

Parameter estimates and standard errors for the fremanezumab final population pharmacokinetic model

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Parameter	Final parameter estimate	Between‐subject variability

Typical value	%RSE	Magnitude	%RSE

CL: Central clearance (L/d)	0.0902	1.50	23.4%CV<xref ref-type="fn" rid="bcp14096-note-0005">a</xref>
,
<xref ref-type="fn" rid="bcp14096-note-0006">b</xref>
	4.60

CL: Allometric exponent for weight (−)<xref ref-type="fn" rid="bcp14096-note-0007">c</xref>
	1.05	4.33

Vc,iv: Central volume of distribution IV (L)<xref ref-type="fn" rid="bcp14096-note-0008">d</xref>
	2.98	FIXED	NE	NA

Vc,SC: Central volume of distribution SC (L)<xref ref-type="fn" rid="bcp14096-note-0009">e</xref>
	1.88	3.38	35.1%CV<xref ref-type="fn" rid="bcp14096-note-0005">a</xref>
,
<xref ref-type="fn" rid="bcp14096-note-0006">b</xref>
,
<xref ref-type="fn" rid="bcp14096-note-0010">f</xref>
	19.9

Vc: Allometric exponent for weight (−)<xref ref-type="fn" rid="bcp14096-note-0008">d</xref>
,
<xref ref-type="fn" rid="bcp14096-note-0009">e</xref>
	1.53	10.3

ka: Absorption rate constant (/d)	0.180	12.2	59.0%CV<xref ref-type="fn" rid="bcp14096-note-0005">a</xref>
,
<xref ref-type="fn" rid="bcp14096-note-0006">b</xref>
,
<xref ref-type="fn" rid="bcp14096-note-0010">f</xref>
	15.8

Q: Intercompartmental clearance (L/d)	0.262	FIXED	NE	NA

Vp: Peripheral volume of distribution (L)	1.72	FIXED	NE	NA

F1: Bioavailability	0.658	FIXED	NE	NA

ALAG1: Lag time (d)	0.0803	FIXED	NE	NA

Residual variability iv	0.0467	32.6	NA	NA

Residual variability SC proportional component<xref ref-type="fn" rid="bcp14096-note-0011">g</xref>
	0.0531	4.03

Residual variability SC additive component<xref ref-type="fn" rid="bcp14096-note-0011">g</xref>
	0.204	25.6

Minimum value of the objective function = 73303.561

%CV, coefficient of variation expressed as a percent; IV, intravenous; NA, not applicable; NE, not estimated; %RSE, relative standard error expressed as a percent; SC, subcutaneous.a %CVx=ωx2×100.bBayesian shrinkage of η estimates was 10.6% for clearance, 37.1% for Vc, and 42.7% for ka.c Typical Value for CL = 0.0902 × (Weight/71)1.05 d Typical Value for Vc,iv = 2.98 × (Weight/71)1.53 e Typical Value for Vc,sc = 1.88 × (Weight/71)1.53 fPhase 1 data (subcutaneous [SC]) and the patients with additional pharmacokinetic samples in Study TV48125‐CNS‐30051 were considered to have appropriate and informative data to contribute to the estimation of between‐subject variability (BSV) in the central volume of distribution (Vc) and absorption rate constant (ka). Thus, data from other patients were excluded from the estimation of BSV and calculation of shrinkage in the BSV of Vc and ka.gEpsilon shrinkage ranged from 3.1 to 9.0%.

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Cmax (SDS)

PD Response Summary of IGF-I to a Single Dose Administration of VRS-317 in the PK/PD Population (n = 48)

Stability refers to the time during which daily rhGH treatment was given. Baseline refers to day 1, before the dose of VRS-317 or placebo. The IGF-I AUC was calculated using the linear trapezoid rule. Average IGF-I was calculated by dividing AUC by the observation interval of 29 days. The dose proportionality correlation coefficients (log:log) were 0.76 for baseline corrected Cmax and 0.76 for baseline corrected AUC0–t.Abbreviations: AUC0–t, area under the curve from time zero to the last measurable time point; Cmax, maximum concentration; ND, not determined; Tmax, time to maximum concentration.

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Race (Asian) on CL/Fb

Parameter estimates for the final integrated population pharmacokinetic model of cabozantinib in patients with different cancer types

ALAG, absorption lag time, CI confidence interval, CL/F apparent clearance, CRPC castrate-resistant prostate cancer, F1 fraction of dose split to the first absorption depot in a dual absorption model, GB Glioblastoma multiforme, Ka absorption rate constant, MTC medullary thyroid cancer, Q/F apparent flow parameter between compartments, RCC renal cell carcinoma Vc/F apparent volume of distribution of the central compartment, Vp/F apparent volume of distribution of the peripheral compartmentaAnti-logit transformation was used to obtain F1bFor categorical covariates (e.g., capsule), transformed estimates correspond to fractional change from the reference levelcuntransformed valuesdUntransformed full model variance estimates (90% CI) σ2 = 0.118 (0.114, 0.122); ω2_Ka = 2.063 (1.579, 2.548); ω2_CL/F = 0.202 (0.185, 0.218); ω2_Vc/F = 0.233 (0.193, 0.273); ω2_F1 = 0.466 (0.385, 0.546); ω2_CL/F:Vc/F = 2.475 (1.923, 3.028), where ω2 is the variance–covariance matrix (Ω) of the inter-individual random effects (η) in the pharmacokinetic parameter, and σ the variance–covariance matrix of the intra-individual random effects (ε) in the measurements

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AUC0–∞ (nmol∙hours/L)

Non-compartmental PK parameters (geometric means ± geometric coefficients of variation, unless otherwise stated) for the first and second infusions of BI 831266

aMedian (minimum, maximum)–Insufficient data to calculate descriptive statistics AUC 0–24 area under the plasma concentration–time curve over the time interval from 0 to 24 h after the start of infusion; AUC 0–∞ area under the plasma concentration–time curve over the time interval from 0 extrapolated to infinity; CL total clearance of analyte in plasma after intravenous administration; C max maximum measured concentration; norm dose normalized; PK pharmacokinetic; t 1/2 terminal half-life; t max time from dosing to maximum measured concentration

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AUCinf

Bioequivalence metrics

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Parameter	Ratio of LS means	90% confidence interval

AUCT
	99.5%	93.8–105.6%

AUCinf
	98.1%	92.2–104.3%

Recovery (IU/dL per IU/kg)	100.6%	97.6–103.6%

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Vp/F (L)

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AUC0‐t, ng ⋅ h/mL

Summary of Steady‐State Pharmacokinetic Parameters of Rucaparib in Food Effect Cohorts

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Dose	Visit	Statistics	Cmax, ng/mL	tmax, h	AUC0‐t, ng ⋅ h/mL	AUC0‐12h, ng ⋅ h/mL<xref ref-type="fn" rid="cpdd575-tbl3-note-0002">a</xref>
	t1/2, h

40 mg QD (Part 1)	Cycle 1, day 15	n	3	3	1	2

Arithmetic mean	129	1050	9.23

Arithmetic mean CV%	62	86

Median	103	4	1050	9.23

Min, max	65.3, 220	1, 4.03	1050, 1050	3.63, 14.8

300 mg QD (Part 1)	Cycle 1, day 15	n	5	5	3	3

Arithmetic mean	727	13 300	20

Arithmetic mean CV%	79	106	68

Median	444	2.47	5220	27.5

Min, max	341, 1720	1.08, 6	5070, 29 600	4.24, 28.2

600 mg BID (Part 3)	Cycle 1, day 15	n	18	18	18	12	12

Arithmetic mean	1940	15 800	16 900	12.6

Arithmetic mean CV%	54	58	54	54

Median	1480	1.92	12 900	14 700	10.9

Min, max	626, 4050	0, 5.98	5400, 34 200	7580, 39 300	5.31, 26.6

AUC0‐t, area under the plasma concentration‐time curve from 0 to time t (t = 24 hours for QD; t = 10 hours for BID); AUC0‐12h, area under the plasma concentration‐time curve from 0 to 12 hours; BID, twice daily; Cmax, maximum plasma concentration; CV, coefficient of variation; QD, once daily; t1/2, half‐life; tmax, time of occurrence of maximum plasma concentration.aFor the BID dosing schedule, concentration at 12 hours was calculated by extrapolation from last observed concentration in the same dosing interval.

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CL (ml h−1 kg−1)

Biophysical and in vivo murine PK data of PASylated proteins

PMC3715784 | Table I. | DOI: 10.1093/protein/gzt023

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θV

Final parameters for the population analysis of levetiracetam concentrations with LEV‐XR administered alone, with phenobarbital, or with zonisamide. Administration of LEV‐XR was repeated every 12 hours to achieve steady‐state conditions before sampling

Abbreviations: LEV‐XR, extended‐release levetiracetam; CV, coefficient of variation; Ω2, variance of the random source error; AUC, area‐under‐the‐curve for the plasma‐concentration versus time profile; C MAX, peak concentration; θk 01, theta (typical value) for absorption rate and associated half‐life; θk 10, theta for elimination rate and associated half‐life; θV, theta for volume of distribution; T MAX, time to peak concentration. Clearance (CL) and V as shown in the table represent V/F and CL/F because they are calculated as per fraction absorbed for an oral dose. Values for Ω2 and CV% are not available for secondary parameters (shown by “—”) because random effects are only measured for primary parameters.

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F

The PK parameters of FF after I.M and I.V administrations (30 mg/kg) in pigs (n = 8).

Ke, presented elimination rate constant; t1/2ke, presented elimination half-life; Clb, presented body clearance; AUC, presented area under the curve; AUC0-24h, presented area under the curve from 0 to 24 h; Cmax, peak concentration; Tmax, the time of maximum serum concentration; the MRT, presented mean residence time; F, the bioavailability.

F


AUC (μ × h/mL)

Pharmacokinetics of extended release levetiracetam in serum after PO (mean ± SD: 32.67 ± 2.35 mg/kg) administration of a single dose to dogs (n = 12)

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Parameter	Mean ± SD Fasted	95% Confidence Interval	Mean ± SD Fed	95% Confidence Intervals
<italic>P</italic> Values Fed Versus Fasted

<italic>C</italic>
max (μ/mL)	26.6 ± 5.8	21–31	30.7 ± 7.1	25–36	.30

<italic>T</italic>
max (hours)*	3.4 ± 0.8	2.7–4	6.6 ± 1.5	5.4–7.8	.0010*

<italic>t</italic>
½ (hours)	4.4 ± 2.1	3.8–6	4.2 ± 1.1	3.5–5.4	.53

<italic>k</italic>
d (hours)	0.16 ± 0.04	0.13–0.18	0.17 ± 0.03	0.15–0.19	.72

MRT (hours)	9.8 ± 2.0	8.4–11	10.8 ± 1.8	9.5–12	.31

MAT (hours)	4.7 ± 0.9	4–5.4	5.6 ± 1.7	4.3–6.9	.31

AUC (μ × h/mL)	335.4 ± 74.3	276–393	393.4 ± 138.3	282–503	.39

<italic>F</italic> (%)*	1.0 ± 0.1	0.96–1.1	1.3 ± 0.2	1.12–1.39	.02*

Data from 4 pilot animals were included for t 1/2, k d; disappearance rate constant; MRT, F (n = 16). Variables marked with an (*) represent statistically significant differences between fasted and fed groups. C max, maximum plasma drug concentration at time = t max; t 1/2, disappearance half‐life; k d, disappearance rate constant; MRT, mean residence time; MAT, mean absorption time; AUC, area under the curve; F, % bioavailability.

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Baseline (pg·mL−1)

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Peripheral T-cell lymphoma

      0
      1
      2
      3

      0
      Unnamed: 0_level_0
      MLN8237 PIC
      MLN8237 ECT
      Total

      1
      Unnamed: 0_level_1
      n = 28
      n = 30
      N = 58

      2
      Median age, years (range)
      62 (41–74)
      57 (27–82)
      61 (27–82)

      3
      Male, n (%)
      14 (50)
      13 (43)
      27 (47)

      4
      Race
      Race
      Race
      Race

      5
      White
      24 (86)
      28 (93)
      52 (90)

      6
      Black or African American
      3 (11)
      1 (3)
      4 (7)

      7
      Asian
      0
      1 (3)
      1 (2)

      8
      Not reported
      0
      1 (3)
      1 (2)

      9
      Tumor type, n (%)
      Tumor type, n (%)
      Tumor type, n (%)
      Tumor type, n (%)

      10
      Non-Hodgkin lymphomaa
      18 (64)
      18 (60)
      36 (62)

      11
      Diffuse large B-cell lymphoma
      9 (32)
      7 (23)
      16 (28)

      12
      Follicular lymphoma
      5 (18)
      5 (17)
      10 (17)

      13
      Mantle-cell lymphoma
      2 (7)
      0
      2 (3)

      14
      Peripheral T-cell lymphoma
      0
      2 (7)b
      2 (3)

      15
      Multiple myeloma
      8 (29)
      11 (37)
      19 (33)

      16
      Chronic lymphocytic leukemia/small lymphocytic leukemia
      2 (7)
      1 (3)
      3 (5)

      17
      ECOG performance status 0/1/2, n (%)
      5 (18)/17 (61)/6 (21)
      8 (27)/16 (53)/6 (20)
      13 (22)/33 (57)/12 (21)

      18
      Prior therapy, n (%)
      Prior therapy, n (%)
      Prior therapy, n (%)
      Prior therapy, n (%)

      19
      Radiation therapy
      11 (39)
      14 (47)
      25 (43)

      20
      ASCT
      12 (43)
      11 (37)
      23 (40)

      21
      ≥3 prior systemic therapies, n (%)
      22 (79)
      22 (73)
      44 (76)

      22
      Primary refractory disease
      8 (36)
      12 (43)
      22 (39)

CAPTION: Patient demographics and baseline characteristics
FOOTER: ASCT autologous stem-cell transplant; EBV Epstein–Barr virus; ECOG Eastern Cooperative Oncology Group; ECT enteric-coated tablet; NHL non-Hodgkin lymphoma; PIC powder-in-capsule aOther types of NHL (each n = 1) were: angio-immunoblastic T-cell lymphoma; nodal marginal zone B-cell lymphoma; EBV-positive T-cell lymphoma; marginal zone B-cell lymphoma transforming to diffuse large B-cell lymphoma; natural killer/T-cell lymphoma, nasal type; and small cell lymphoma/follicular lymphoma bBoth patients had noncutaneous peripheral T-cell lymphoma—not otherwise specified

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T max (min)

PK parameters of NP046

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V T1 (L)

The comparison of typical estimates obtained in this study (surgery cancer patients) and results obtained by Schnider et al. (volunteers) and Eleveld et al. (patients and volunteers)

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Parameter (unit)	This study, patients	Schnider, volunteers	Eleveld, volunteers	Eleveld, patients

Typical (median)	Typical (median)	Bias (%)	Typical (median)	Bias (%)	Typical (median)	Bias (%)

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<italic>P</italic> (L)	5.11	4.27	16	5.18	−1.4	8.16	−60

<italic>CL</italic> (L/min)	2.38	1.94	28	1.96	18	1.64	31

<italic>V</italic>
<italic>T1</italic> (L)	14.2	16.2	−14	10.5	26	31.4	−121

<italic>Q</italic>
<italic>1</italic> (L/min)	1.17	1.12	4.3	1.20	−4.6	1.27	−8.5

<italic>V</italic>
<italic>T2</italic> (L)	189	238	−26	231	−22	105	44

<italic>Q</italic>
<italic>2</italic> (L/min)	0.608	0.836	−38	1.38	−127	0.41	32

<italic>MDPE</italic>
	−0.50	−8.4	−1.0 %	−29.4

<italic>MDAPE</italic>
	12.1	13.6	9.3 %	29.4

All parameters were scaled to the typical patient of this study. The bias indicates the relative difference in parameters between studies. The median prediction error (MDPE) and median absolute prediction error (MDAPE) are provided to compare models performance

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Association between genetic polymorphisms and telatinib pharmacokinetic data. Dose normalized Cmax, T1/2 and Tmax

#=*801 number from termination codon TGA (5397). 3UTR

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t1/2 (min)

Pharmacokinetic parameters of commercial tablets, NI loaded NLR, NI loaded NSR, NI loaded NS after intragastric administration in rats, mean ± S.D., n = 6.

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t1/2 (h)

Pharmacokinetic parameters of TAS‐205 in the single‐ and repeated‐dose periods

SD, standard deviation; CV, coefficient of variation; C max, maximum plasma concentration; AUC0‐48, area under the plasma concentration–time curve from 0 to 48 h post‐dose; AUC0‐inf, AUC to infinite time; t1/2, half‐life of elimination; Ae, urinary excretion rate; t max, time to maximum plasma concentration; Cpre, trough plasma concentration.

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T1/2 (hr)

A comparison of the artemether pharmacokinetic properties to literature values

aMedian and ranges were derived from the empirical Bayes estimates.bPopulation estimate (%RSE).cAfter a single dose of 300 mg artemether and four consecutive 100 mg artemether doses daily.dAfter a single dose of artemether-lumefantrine (Co-Artem).eAfter five doses artemether mono-therapy.AUC: area under the concentration-time curve, CMAX: maximum concentration, TMAX: time to maximum concentration and T1/2: elimination half-life. AUC and CMAX were normalized by artemether dose.

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AUCinf (ng h/mL)a

Summary of (S)-warfarin and (R)-warfarin pharmacokinetic parameters after administration of a single 25-mg dose of warfarin alone and with amenamevir at a dosage of 200 or 400 mg once daily in study 15L-CL-018

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Parameter	(<italic>S</italic>)-Warfarin	(<italic>R</italic>)-Warfarin

Warfarin alone (<italic>n</italic> = 18)	Warfarin + amenamevir 200 mg (<italic>n</italic> = 18)	Warfarin alone (<italic>n</italic> = 17)	Warfarin + amenamevir 400 mg (<italic>n</italic> = 15)	Warfarin alone (<italic>n</italic> = 18)	Warfarin + amenamevir 200 mg (<italic>n</italic> = 18)	Warfarin alone (n = 17)	Warfarin + amenamevir 400 mg (<italic>n</italic> = 15)

AUCinf (ng h/mL)a
	48,072 ± 19,712	46,725 ± 18,437	50,329 ± 24,609	45,032 ± 23,503	69,581 ± 18,385	67,092 ± 18,315	75,652 ± 18,160	68,723 ± 12,736

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max (ng/mL)a
	1194 ± 132	1217 ± 134	1168 ± 162	1251 ± 237	1197 ± 133	1240 ± 134	1187 ± 149	1262 ± 232

<italic>t</italic>
max (h)b
	4.0 (2.0–4.0)	4.0 (1.0–4.0)	4.0 (1.0–4.0)	2.0 (1.0–4.0)	4.0 (2.0–4.0)	4.0 (1.0–12.0)	4.0 (2.0–12.0)	4.0 (2.0–12.0)

<italic>t</italic>
½ (h)	34.6 ± 8.6	35.0 ± 7.1	36.4 ± 12.2	36.4 ± 9.7	42.0 ± 7.0	39.7 ± 6.3	45.7 ± 8.5	40.8 ± 6.0

CL/F (L/h)	0.25 ± 0.07	0.26 ± 0.07	0.25 ± 0.08	0.27 ± 0.08	0.17 ± 0.04	0.18 ± 0.04	0.16 ± 0.04	0.17 ± 0.03

LS GMRc
	(<italic>S</italic>)-Warfarin + amenamevir 200 mg vs (<italic>S</italic>)-warfarin alone	(<italic>S</italic>)-Warfarin + amenamevir 400 mg vs (<italic>S</italic>)-warfarin alone	(<italic>R</italic>)-Warfarin + amenamevir 200 mg vs (<italic>R</italic>)-warfarin alone	(<italic>R</italic>)-Warfarin + amenamevir 400 mg vs (<italic>R</italic>)-warfarin alone

 AUCinf
	0.97 (0.94–1.01)	0.92 (0.89–0.96)	0.96 (0.94–0.99)	0.91 (0.88–0.95)

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max
	1.02 (0.98–1.06)	1.08 (1.02–1.15)	1.04 (1.01–1.07)	1.07 (1.01–1.13)

All values are presented as the arithmetic mean ± standard deviation unless stated otherwise AUC inf area under the plasma concentration versus time curve from time zero to infinity, CL/F clearance, C max maximum plasma concentration, LS GMR least squares geometric mean ratio, t ½, half-life, t max time to maximum plasma concentration aValues are presented as the geometric mean ± standard deviation bValues are presented as the median, with the range in parentheses cThe 90% confidence interval is given in parentheses

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AUC ratio (remogliflozin/remogliflozin etabonate)

Summary of plasma remogliflozin and GSK279782 PK parameters in healthy subjectsa

a. n = 8 unless otherwise specified.b. R = remogliflozin.c. The median percentage of AUC(0-∞) extrapolated for R was low ranging from 0.07% to 2.1% across all doses and for 279782 ranging from 0.29% to 4.51%.d. n = 5.

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Ka (h− 1)

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AUC0‐8 (ng·h /mL)

Difference in pharmacokinetic parameters of sildenafil between the two combination therapies

Data are expressed as the median (interquartile range). S+B, coadministration of sildenafil with bosentan; S+A, coadministration of sildenafil with ambrisentan; tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; AUC0‐8, area under the plasma concentration‐time curve from 0 to 8 hours; CL/F, oral clearance.

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Urinary bladder wall

ODs and ED for (+)-[18F]flubatine based on mice data

ODs calculated for the adult male model (73.7 kg, implemented in OLINDA) based on mouse biodistribution and organ geometry data that were scaled to human circumstances OD organ dose, ED effective dose (ICRP 103), SD standard deviation mean over three animals

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λz, 1/h

Baseline‐Corrected Pharmacokinetic Parameters for sFetot in Healthy Volunteers After Intravenous Administration of Ferric Pyrophosphate Citrate Iron

AUC0‐t, area under the serum concentration‐time curve from 0 to the time of the last quantifiable concentration; CL, total drug clearance; Cmax, maximum serum concentration; FPC, ferric pyrophosphate citrate; λz, terminal rate constant; sFetot, serum total iron; t½app, apparent terminal‐phase half‐life; tmax, time to maximum serum concentration.aValues are expressed as mean (SD) unless otherwise indicated.bMedian value.

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volume of distribution Vd (L/kg)

Volume of Distribution, Percentage of Unbound Plasma Proteins, log D, and log BBB Coefficient Partition of VLB and Its Metabolites

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Cmax (ng/ml)

MEDI4893 nasal pharmacokinetic parameters for each dose determined by noncompartmental analysisa

aData are expressed as the mean ± standard deviation.

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CLR, mL/h

Isavuconazole pharmacokinetic parameters for day 1 for healthy participants compared with individuals with renal impairment

All data are expressed as mean ± standard deviation, except t max which is expressed as median (range) Ae last cumulative amount of unchanged isavuconazole excreted in the urine, AUC area under the concentration–time curve, AUC 72 AUC from time of dosing until 72 h, AUC ∞ AUC extrapolated to infinity, AUC last AUC to last measurable plasma concentration, CL total clearance of isavuconazole, CL R renal clearance of isavuconazole from plasma, RI renal impairment, t max time to reach maximum concentration, t ½ half-life of isavuconazole, V z volume of distribution

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Cmax, ng/mL

Bioequivalence Evaluation of OLZ for Comparison of ALKS 3831 Versus B‐OLZ and OLZ Versus B‐OLZ

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ALKS 3831	OLZ	B‐OLZ

Parameter Statistics	(n = 46)	(n = 45)	(n = 48)

AUC0‐∞, ng·h/mL

Geometric mean	627.9	607.0	610.4

Geometric mean ratio	1.0	0.994	—

90%CI	(0.995–1.063)	(0.962–1.028)	—

AUC0‐t, ng·h/mL

Geometric mean	594.4	578.9	578.9

Geometric mean ratio	1.0	1.0	—

90%CI	(0.993–1.062)	(0.967–1.034)	—

Cmax, ng/mL

Geometric mean	16.3	16.3	16.4

Geometric mean ratio	0.994	0.995	—

90%CI	(0.954–1.036)	(0.955–1.037)	—

AUC0‐∞, area under the plasma concentration‐time curve from zero to infinity; AUC0‐t, area under the plasma concentration‐time curve from zero to the time of the last quantifiable concentration; B‐OLZ, brand olanzapine; Cmax, maximal plasma concentration; OLZ, olanzapine; PK, pharmacokinetics.

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Kel (1/h)

PHARMACOKINETIC PARAMETERS OF COMPOUNDS LM 13765 AND LM 13765-C

aCmax, tmax and AUC observed in compound LM 13765 were measured as compound LM 13765-C as compound LM 13765 was found to get metabolized to its aminal LM 13765-C.

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Cmax (μg/mL)

Summary of Key IV and SC PK Parameters for PF-06645849 in Rats and Monkeys.

Cmax, maximum observed concentration; Tmax, time to Cmax; AUCinf, area under the concentration-time curve from time zero extrapolated to infinity; Cl, systemic clearance; Vss, volume of distribution at steady state; t1/2, terminal half-life; F (%), SC bioavailability. All values are expressed as (Means ± SD) with n = 3 for rats and n = 2 for monkeys.

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MTC on CL/Fb

Parameter estimates for the final integrated population pharmacokinetic model of cabozantinib in patients with different cancer types

ALAG, absorption lag time, CI confidence interval, CL/F apparent clearance, CRPC castrate-resistant prostate cancer, F1 fraction of dose split to the first absorption depot in a dual absorption model, GB Glioblastoma multiforme, Ka absorption rate constant, MTC medullary thyroid cancer, Q/F apparent flow parameter between compartments, RCC renal cell carcinoma Vc/F apparent volume of distribution of the central compartment, Vp/F apparent volume of distribution of the peripheral compartmentaAnti-logit transformation was used to obtain F1bFor categorical covariates (e.g., capsule), transformed estimates correspond to fractional change from the reference levelcuntransformed valuesdUntransformed full model variance estimates (90% CI) σ2 = 0.118 (0.114, 0.122); ω2_Ka = 2.063 (1.579, 2.548); ω2_CL/F = 0.202 (0.185, 0.218); ω2_Vc/F = 0.233 (0.193, 0.273); ω2_F1 = 0.466 (0.385, 0.546); ω2_CL/F:Vc/F = 2.475 (1.923, 3.028), where ω2 is the variance–covariance matrix (Ω) of the inter-individual random effects (η) in the pharmacokinetic parameter, and σ the variance–covariance matrix of the intra-individual random effects (ε) in the measurements

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MRT (h)

Pharmacokinetic parameters of Tolmetin Sodium estimated after oral and rectal administration of commercial capsule suspension (treatment I) and F8 hydrogel (treatment II) to six rats

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Parameter	Commercial capsule	Rectal hydrogel (F8)

Dose (mg/kg)	50	50

Cmax (µg/ml)	33.877 ± 2.16	45.425 ± 2.745

tmax (h)	1	4

t1/2el (h)	5.137 ± 0.027	6.910 ± 0.003

AUC0−24 (µg h/ml)	129.489 ± 13.55	463.481 ± 48.207

AUC0−∞ (µg.h/ml)	129.489 ± 13.55	514.033 ± 48.207

MRT (h)	3.923 ± 0.24	9.512 ± 0.233

Relative bioavailability	–	357.93%

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Cmax, μg mL−1

RBC and plasma voxelotor PK parameters in healthy volunteers and SCD patients

Data are presented as mean ± standard deviation for C max, AUC, T 1/2, RBC/plasma ratio, RAUC(0–24h) or median (range) for T max. For multiple dose, PK parameters on day 15 are presented.aAUCinf value for single dose and AUC(0–24h) value on Day 15 for multiple doses are shown.

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Pharmacokinetic data

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Plasma water flow rate (ml/min)	118 ± 11

Citrate plasma water clearance  (ml/min)	98 ± 10

Net citrate dose per 4 h of HD  (mmol)	17 ± 7

Citrate mass removal (%)	83 ± 5

Citrate half-life (min)	60 ± 29

Citrate distribution volume, litres  (% of body weight)	41 ± 22 (54 ± 18)

Calcium removal rate, mmol/min  (mg/min)	0.18 ± 0.02 (7.2 ± 0.8)

Calcium loss per 4 h of HD, mmol  (mg)	43 ± 4 (1720 ± 160)

Calcium substitution per 4 h of  HD, mmol (mg)	48 ± 1 (1920 ± 40)

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AUC0–∞ (h · μg/ml)

Noncompartmental analysis of quinine in pregnant patients with uncomplicated P. falciparum malaria

aCmax, maximum observed plasma concentration after the first dose; Tmax, observed time to reach Cmax; CL, elimination clearance; V, apparent volume of distribution; T1/2, terminal elimination half-life; AUC0–LAST, observed area under the plasma concentration-time curve after the first dose from zero time to the last observed concentration; AUC0–∞, predicted area under the plasma concentration time curve after the first dose from zero time to infinity; Day 7 concn, observed day 7 concentration after repeated drug administration; F, oral bioavailability.bValues are given as the median (range) unless otherwise specified.cBased on results for 23 individuals; day 7 concentrations from individual 199 and 251 were also included.

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Clearance (mL/day/kg)

Non-compartmental PK parameters of TAC TAb and ac-dmDNA31 following a single IV administration of TAC in mice infected with S. aureus.

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 	TAC Total Antibody
	Antibody-conjugated dmDNA31

PK Parameters	25 mg/kg	50 mg/kg	25 mg/kg	50 mg/kg

Cmax (nM)	3850	7640	5060	13100

AUC0-inf (day • nM)	29560	53720	12630	24390

Clearance (mL/day/kg)	5.78	6.37	26.6	27.5

Vss (mL/kg)	115	123	114	110

t1/2λz (day)	14.0	13.8	3.81	3.73

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t1/2λz (day)

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