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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If CRE affect CL ?

Hypothesis test results of covariates affecting on vancomycin clearance (CL)

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<bold>Hypothesis test</bold>

<bold>OBJ</bold>

<bold>ΔOBJ</bold>

<bold>P-value</bold>

<bold>Comments</bold>

Basic model	2206.3

If Gender affect CL ?	2205.0	-1.3	>0.05	NO

If Age affect CL ?	2097.6	-108.7	<0.01	YES

If Weight affect CL ?	2094.0	-112.3	<0.01	YES

If Body surface area affect CL ?	2095.4	-110.9	<0.01	YES

If ALT affect CL ?	2204.8	-1.5	>0.05	NO

If AST affect CL ?	2204.8	-1.5	>0.05	NO

If CRE affect CL ?	2197.5	-8.8	<0.01	YES

If BUN affect CL ?	2205.6	-0.7	>0.05	NO

If GFR affect CL ?	2140.6	-65.7	<0.01	YES

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Race (Other) 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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Tmax (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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AUC0−24 (µg h/ml)

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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ALAG (h)

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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AER Fed vs Fasting

Point Estimates of Anagrelide

Point estimates (90% confidence intervals) of PK parameter are presented. Except for the MRT of the metabolite RL603, no PK parameter lies within the predefined margins (0.8–1.25). Thus, PK parameters are significantly different between AER and the commercially available reference product (CARP), and food intake has a significant impact on the PK of AER (P < .001 for all tests); n = 28.

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FOIH (DISKUS) on C 0

Parameter estimates from final model for fluticasone furoate AUC and serum cortisol

AUC 50 the FF area under the concentration–time curve over 24 h (AUC24) producing 50 % of maximum effect, C 0 the weighted mean 24 at zero FF AUC24, CI confidence interval, DPI dry powder inhaler, FF fluticasone furoate, FOIH formulation/inhaled, GAM slope for single dose and repeat dose, k coefficient on the number of days of dosing, RD repeat dose, RSE relative standard error, SD single dose

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Pharmacokinetic parameters of arctigenin (2.687 μmol/kg) after intravenous (i.v) and hypodermic injection (i.h) AG administrations in Wistar rats (n = 6 per treatment group, results were presented as Mean ± SD).

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t ssa,b (h)

PK parameters (CV %) for vismodegib following single-dose (day 1 or 5) and multiple-dose (day 7 or 11, steady state) administration of oral vismodegib (150 mg QD)

Geometric mean (CV %) data are presented unless indicated CV % coefficient of variation, NC not calculated, PK pharmacokinetic, QD once daily aMedian (min, max) presented for t max and t ss  b t ss estimated after continuous QD dosing (AUC0–24h, C max, and t max estimated after the first dose)

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MRTlast

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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AUC0–LAST (h · μg/ml)

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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Cl/F (L/h)

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Q/F (liters/day)

Summary of the results obtained from the final model and the bootstrap analysis

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Parameter<xref ref-type="table-fn" rid="T2F1"><italic>a</italic></xref>	Median value for<xref ref-type="table-fn" rid="T2F2"><italic>b</italic></xref>:

Estimate	%RSE	%CV	Bootstrap estimate (95% CI)

CL/<italic>F</italic> (liters/day)	377	6.58	371.7	(302–435)

<italic>V</italic>2/<italic>F</italic> (liters)	2,230	6.59	2,212	(1,930–2,580)

<italic>V</italic>3/<italic>F</italic> (liters)	3,230	15.0	3,298	(2,360–4,710)

<italic>Q</italic>/<italic>F</italic> (liters/day)	804	11.2	831	(651–1,130)

<italic>Ka</italic> (day−1)	17.9	11.7	17.7	(14.1–22.5)

θ6 age on <italic>V</italic>3/<italic>F</italic>	0.624	38.6	0.629	(0.224–1.05)

θ7 formulation on <italic>Ka</italic>	1.63	37.8	1.86	(0.517–4.11)

IIV

    CL/<italic>F</italic>	0.166	26.7	40.7	0.160	(0.055–0.318)

    <italic>V</italic>2/<italic>F</italic>	0.993	8.76	99.6	0.994	(0.805–1.170)

    <italic>V</italic>3/<italic>F</italic>	0.256	48.4	50.6	0.265	(0.033–0.593)

    <italic>Q</italic>/<italic>F</italic>

    <italic>Ka</italic>	0.433	26.6	65.8	0.413	(0.194–0.669)

RV (additive error)	0.195	12.1	0.195	(0.15–0.244)

aFor both of the derived parameters distribution half-life (T1/2α) and elimination half-life (T1/2β) for pediatric malaria patients, the mean value ± standard deviation was 0.9 ± 0.6. F, oral bioavailability; CL, clearance; V2, central volume of distribution; V3, peripheral volume of distribution; Q, intercompartmental clearance; Ka, first-order absorption rate constant; IIV, interindividual variability; RV, residual variability.b%RSE, relative standard error [(SE/mean) × 100%]; %CV, percent coefficient of variation [(SD/estimate) × 100%].

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Systemic Vascular Resistance (dynes*sec*cm5)

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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C max (μg/L)

Pharmacokinetic parameters of regorafenib and its metabolites M‐2 and M‐5 in NMRI Foxn1 nu/nu mice after oral administration at a dose of 10 mg/kg/day for 5 consecutive days

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Administered compound	Regorafenib	M‐2	M‐5

Analyte	Regorafenib	M‐2	M‐5	Regorafenib	M‐2	M‐5	M‐5<xref ref-type="fn" rid="cam4883-note-0008">a</xref>

AUC (<italic>μ</italic>g × h/L)	38,649	7490	772	11,601	52,101	3391	52,796

AUC (<italic>μ</italic>Mol × h/L)	80.0	15.0	1.6	24.0	104.4	7.0	108.9

AUC (% of total)<xref ref-type="fn" rid="cam4883-note-0009">b</xref>
	83	16	2	18	78	5	100

<italic>C</italic>
max (<italic>μ</italic>g/L)	4146	753	63	967	6150	342	5284

<italic>C</italic>
max (<italic>μ</italic>M/L)	8.6	1.5	0.1	2.0	12.3	0.7	10.9

aOnly M‐5 concentration was determined, because M‐2 and regorafenib formation does not occur.bTotal refers to the sum of the molar concentrations of regorafenib, M‐2, and M‐5 regardless of unbound fraction.

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Clb

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.

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T½β (h)

Pharmacokinetic variables for doxycycline hyclate (Dox-h) in horses after the oral administration of three experimental formulations

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	<bold>Dox-a</bold>
	<bold>Dox-pol|</bold>
	<bold>Dox-β</bold>

 	<bold>Mean ± SD</bold>	<bold>Mean ± SD</bold>	<bold>Mean ± SD</bold>

AUC (μg · h/mL)
	3.1 <bold>±</bold> 0.2 a
	17.0 ± 2.2b
	1.5 ± 0.1 c

AUMC (μg · h2/mL)
	35.2 <bold>±</bold> 1.2 a
	208.3 ± 31.1b
	12.3 ± 0.1 c

AUC0<bold>-</bold>∞ (μg · h/mL)
	3.0 ± 0.2 a
	16.1 ± 4.8 b
	1.5 ± 0.9 c

AUMC0 <bold>-</bold>∞ (μg · h2/mL)
	31.2 ± 2.3 a
	171.3 ± 5.8 b
	12.3 ± 0.5 c

MRT (h)
	11.3 ± 4.4 a
	12.2 ± 4.2a
	8.1 ± 2.1 a

MRT0 <bold>-</bold>∞ (h)
	10.2 ± 2.6 a
	10.7 ± 2.1 a
	8.1 ± 1.2 a

T½β (h)
	2.8 ± 0.9a
	4.9 ± 1.0b
	4.2 ± 0.9b

T½ab(h)
	1.2 ± 0.2 a
	3.5 ±1.2 b
	1.4 ± 0.1 a

Kel (h-1)
	0.2 ± 0.0 a
	0.1 ± 0.1 a
	0.2 ± 0.1 a

Kab (h-1)
	1.6 ± 0.2 a
	0.2 ± 0.2 b
	0.5 ± 0.3 c

α (h-1)
	1.2 ± 0.0
	-
	-

β (h-1)
	9.2 ± 0.0
	-
	-

Cmax (μg/mL)
	0.3 ± 0.1 a
	1.3 ± 0.7 b
	0.2 ± 0.0 c

Tmax (h)
	2.2 ± 0.4 a
	5.9 ± 1.7 b
	3.4 ± 0.6 c

Frel (%)*	-	548% a	48% b

a,b,c, The values within a row with no common superscript differ significantly (P < 0.05).* Mean of means.AUC, Area under the concentration-time curve; AUC0-∞, Area under the concentration –time to infinity; AUMC, Area under the first moment of the concentration-time curve; AUMC0-∞, Area under the first moment of the concentration-time curve to infinity; MRT, Mean residence time; MRT0-∞, Mean residence time to infinity; α, distribution hybrid rate constant; β, elimination hybrid rate constant; A, B,, zero time intercepts of the distribution and post-distribution phases; Kel, Elimination rate constant from the central compartment; Kab, Absorption rate constant; T½ab, Absorption half-life; T½β, Elimination half-life; Cmax, Calculated maximum plasma concentration; Tmax, Time of maximum plasma concentration; Frel, Relative bioavailability.

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Covariate 4: CRCL on CL (linear)

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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Comparison of pharmacokinetic and pharmacodynamic parameters of epinephrine for inhalative administration (B: 4 mg, C: 8 mg) relative to i.m. administration (A: 0.3 mg) or to placebo inhalation (D) (point estimates and 90 % confidence intervals)

AUC area under the concentration vs. time profile (indices apply for the postdose time interval); AUEC area under the effect curve; Cmax maximal concentration; Emax maximal effect; MRTlast mean residence time calculated from concentrations up to the last point of observation; BP blood pressure; *blood pressure did not show consistent differences between treatments, fractional AUECs are presented in the Supplementary Material

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Renal glucose clearance0‐24h, mL/min

Demographic and baseline characteristics (PDAS)

Values are presented as n (%) or mean ± standard deviation.aSafety analysis set data (placebo n = 11, ipragliflozin 25 mg n = 10, 50 mg n = 12, and 100 mg n = 10).Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; PDAS, pharmacodynamic analysis set.

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Cmax

Bioequivalence evaluations of CUR-C-HLN and CUR after oral administration at the CUR dose of 15 mg/kg or intravenous injection at the CUR dose of 2.5 mg/kg

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Administration route	Parameter	90% confidence interval calculated	<italic>P</italic> value calculated	Bioequivalence standard	Bioequivalence

Oral administration	<italic>AUC</italic>	464.88%–633.13%	-	80%–125%	No

<italic>C</italic>max	189.19%–319.46%	-	70%–143%	No

<italic>T</italic>max	-	< 0.05	> 0.05	No

In all	-	-	-	No

Intravenous injection	<italic>AUC</italic>	565.32%–671.09%	-	80%–125%	No

<italic>C</italic>max	546.04%–636.78%	-	70%–143%	Yes

<italic>T</italic>max	-	< 0.05	> 0.05	No

In all	-	-	-	No

Note: Data presented as the mean ± standard deviation (n = 6).

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K a (/h)

Base model PK estimates with associated bootstrap (1000 replicates)

CL, clearance; K a, absorption rate constant; SE, standard error; V d, volume of distribution; ωCL, between subject variability on rivaroxaban clearance; ωVd, between subject variability on rivaroxaban volume of distribution.

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tmax, h

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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First order absorption rate

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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Vd (L/Kg)

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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AUClast, mg*h/L

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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θCL/F, weight

Parameter estimates in the final population pharmacokinetic model

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Parameter	Unit	Estimate	Relative SE (%)<xref ref-type="fn" rid="psp412288-note-0009">a</xref>
	Lower confidence interval (2.5%)<xref ref-type="fn" rid="psp412288-note-0010">b</xref>
	Upper confidence interval (97.5%)<xref ref-type="fn" rid="psp412288-note-0010">b</xref>

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

Fmax
	Proportion	1.25	– (fixed)<xref ref-type="fn" rid="psp412288-note-0011">c</xref>
	–	–

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

θCL/F, weight
	Power	−0.278	15.4	−0.359	−0.187

θV/F, weight
	Power	0.216	17.4	0.143	0.278

θV/F, Age
	Power	−0.189	16.3	−0.246	−0.127

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

θCL/F, Strong CYP3A4 inhibitor
	Proportion	0.978	5.40	0.902	1.97

θCL/F, Medium CYP3A4 inhibitor
	Proportion	0.863	3.79	0.793	0.920

θCL/F, Weak CYP3A4 inhibitor
	Proportion	0.939	2.17	0.900	0.975

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

θCL/F, VTE ≤72 h
	Proportion	1.04	1.96	0.992	1.08

θCL/F, VTE >72 h
	Proportion	1.29	1.76	1.24	1.34

ω<xref rid="psp412288-bib-0002" ref-type="ref">2</xref>
ka
	Variance	0.628 (32.8)<xref ref-type="fn" rid="psp412288-note-0012">d</xref>
	5.39	0.544	0.703

ω<xref rid="psp412288-bib-0002" ref-type="ref">2</xref>
CL/F
	Variance	0.167 (10.3)<xref ref-type="fn" rid="psp412288-note-0012">d</xref>
	2.96	0.157	0.176

ω<xref rid="psp412288-bib-0002" ref-type="ref">2</xref>
CL/F, V/F
	Covariance	0.0674	6.84	0.0586	0.0782

ω2
V/F
	Variance	0.0391 (25.7)<xref ref-type="fn" rid="psp412288-note-0012">d</xref>
	10.6	0.0318	0.048

σ<xref rid="psp412288-bib-0002" ref-type="ref">2</xref>
prop
	Variance	0.203 (10.3)<xref ref-type="fn" rid="psp412288-note-0012">d</xref>
	1.54	0.197	0.21

ACS, acute coronary syndrome; AF, atrial fibrillation; CL/F, apparent clearance; CrCL, creatinine clearance; CYP3A4, cytochrome P450 3A4; D, dose; F, relative bioavailability as a function of dose; ka, first‐order absorption rate constant; V/F, apparent volume of distribution; PGP, P‐glycoprotein; VTE, venous thromboembolism.aRelative standard errors (SE) were obtained from the estimated covariance matrix.bThe 95% confidence intervals of the estimates were obtained from a nonparametric bootstrap evaluation with 200 runs.cRelative bioavailability was fixed at 1.0 for a 10 mg dose.dFor interindividual variability terms (ω2) and residual variability (σ2), the respective shrinkage estimates are displayed in parentheses.

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Vz (l)

Pharmacokinetic parameters in 2‐h IV Infusion and 5‐day IV Infusion of subjects

Cmax, AUC0‐t, AUCinf, t1/2, CL and Vz are described as geometric mean (CV%); Tmax is described as median (range).AUC0–t, area under the concentration–time curve for the sampling period; AUCinf, area under the concentration–time curve extrapolated to infinity; CL, clearance; Cmax, maximum plasma concentration; CV%, percentage coefficient of variation; IV, intravenous; t1/2, terminal half‐life; Tmax, time to Cmax; Vz, volume of distribution during the terminal phase

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CL/F (L/h)

Summary of glycopyrronium pharmacokinetic parameters (mITT population)

aMedian (Min, Max); bn = 11; cn = 10; dn = 12; en = 19; fn = 16.AUCx-y = area under the concentration-time curve from time x to time y; CL/F = apparent oral clearance; Cmax = maximum plasma concentration; CV% = coefficient of variation; GP MDI = glycopyrronium metered-dose inhaler; t1/2 = apparent terminal elimination half-life; tmax = time to maximum concentration; Vz/F = apparent volume of distribution; mITT=modified intention to treat.

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AUC0–∞, norm (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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ηtlag

Final population model estimates of pantoprazole

aCalculated as 100%xSE/estimatebCalculated as 100%xSE(omega)/(2*estimate(omega)

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Pharmacokinetic parameters of arctigenin (2.687 μmol/kg) after intravenous (i.v) and hypodermic injection (i.h) AG administrations in Wistar rats (n = 6 per treatment group, results were presented as Mean ± SD).

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Cavg c (μM)

Plasma and media unbound fractions for the studied retinoids, in vitro EC50,u values, and predicted magnitude of in vivo change in CYP2D6 based on clinical 13cisRA, atRA, and 4‐oxo‐13cisRA exposures

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End point	Precipitant

13<italic>cis</italic>RA
<italic>at</italic>RA	4‐oxo‐13<italic>cis</italic>RA	Combined parent and metabolites<xref ref-type="fn" rid="cts12616-note-0003">a</xref>

<italic>f</italic>
u,plasma
<xref ref-type="fn" rid="cts12616-note-0003">b</xref>
	0.0004 (0.0001)	0.0002 (5 × 10−5)	0.012 (0.004)

<italic>f</italic>
u,media
<xref ref-type="fn" rid="cts12616-note-0003">b</xref>
	0.011 (0)	0.027 (0.008)	0.121 (0.013)

Cavg
<xref ref-type="fn" rid="cts12616-note-0003">c</xref> (μM)	0.69	0.01	5.4

<bold>Donor 1</bold>
<xref ref-type="fn" rid="cts12616-note-0003">d</xref>

Emin
	0.63 (0.57–0.68)	0.64 (0.58–0.70)	0.63 (0.58–0.69)

EC50,u (nM)	0.18 (0.09–0.44)	0.37 (0.16–0.81)	3.8 (1.2–8.5)

Predicted % CYP2D6 remaining	0.78	1.0	0.65	0.65

<bold>Donor 3</bold>
<xref ref-type="fn" rid="cts12616-note-0003">e</xref>

Emin
	0.05	0.07	0.05

EC50,u (nM)	0.91	1.3	17

Predicted % CYP2D6 remaining	0.78	1.0	0.24	0.23

Donor 2 was excluded from quantitative predictions due to the wide confidence intervals of the determined EC50 values of retinoids on CYP2D6 mRNA in this donor (Figure  1 ). atRA, all‐trans‐RA; Cavg, average concentration; CYP, cytochrome P450; EC50,u, unbound half‐maximal effective concentration; Emin, minimum concentration; fu,plasma, fraction unbound in plasma; fu,media, fraction unbound in media; NA, not applicable; RA, retinoic acid. aThe combined effect of 13cisRA and its metabolites on CYP2D6 expression in vivo was predicted using Eq. (2). bBinding experiments were conducted in triplicate and data are presented as mean (SD). cCavg following administration of 20 mg b.i.d. 13cisRA reported in Amory et al.17 dThe concentration‐dependent effects of retinoids in donor 1 hepatocytes are presented as mean (90% confidence interval). eThe concentration‐dependent effects of retinoids in donor 3 hepatocytes were assessed in three replicate experiments, and the median value from the three experiments is reported.

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t1/2 (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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h


k12 (1/h)

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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CL (mL/h)

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

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AUC0-∞ (ng•h/mL)

Mean (SD) pharmacokinetic parameters for hydrocodone by treatment

λz = apparent plasma terminal elimination rate constant; AUC0–∞=area under the plasma drug concentration by time curve (AUC) from 0 to infinity; AUC0-0.75 = AUC from 0 to 0.75 hours after study drug administration; Cmax = maximum observed plasma drug concentration; AUC0–4 = AUC from 0 to 4 hours after study drug administration; AUC0–7 = AUC from 0 to 7 hours after study drug administration; AUC0–t = AUC from time 0 to the time of the last measurable drug concentration; ER = extended-release; IR = immediate release; tmax = time to maximum observed plasma drug concentration.*Values for tmax are median (range).†Percent extrapolation: 100 x (AUC0–∞ – AUC0–t)/AUC0–∞.‡Abuse quotient: Cmax/tmax.

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Differences in mean individual predicted PK parameters for toxicity endpoints, assessed by calculation of geometric mean ratios (GMR) and 90% CI (n = 606).

aDid not have the event/had the event.CI, confidence interval; AUC0‐24, area under the concentration‐time curve over 24‐hour interval; Cmax, maximum concentration; C24, trough concentration, 24 hours postdose; C12, concentration 12 hours postdose representing the mid‐dose interval.

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V_obs (L/kg)

Pharmacokinetic parameter values estimated from non-compartmental analysis after an intravenous bolus of stable-labeled TPM.

LOW = 10 mg/kg dose; HIGH = 20 mg/kg dose; t1/2, elimination half-life; C1, first measured concentration; AUCINF_obs, observed area under the curve from time 0 to infinity; V_obs, observed volume of distribution; Cl_obs, observed clearance.

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t1/2 (h)

Mean PK parameters (SD) of ST zolpidem

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CL/F (L/h)

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CL/Fa, 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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AUC (% of total)b

Pharmacokinetic parameters of regorafenib and its metabolites M‐2 and M‐5 in NMRI Foxn1 nu/nu mice after oral administration at a dose of 10 mg/kg/day for 5 consecutive days

aOnly M‐5 concentration was determined, because M‐2 and regorafenib formation does not occur.bTotal refers to the sum of the molar concentrations of regorafenib, M‐2, and M‐5 regardless of unbound fraction.

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p for Tmax#

The ratio and the P-values of pharmacokinetic parameters of the fed vs. fasting study with the test drug from the same sponsor.

*Another fasting (study 3) vs. fasting (study 5) with drug from sponsor 2; # the Wilicoxon test was used to compare the Tmax between the fasting study and the fed study; e.g., the AUC0−t of R under fed conditions vs. AUC0−t of R under fasting conditions with drug from sponsor 1 from Table 3 is equal to 5483/3475 = 1.58.

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Fab

Biophysical and in vivo murine PK data of PASylated proteins

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

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CrCL (ml/minute)

Observed meropenem concentrations in serum and cerebrospinal fluid

Abbreviations: C min Median observed serum trough concentration, C max Median observed serum peak concentration, C trough Median observed cerebrospinal fluid concentration at serum trough concentration, C after 4h Median observed cerebrospinal fluid concentration 4 h after serum trough concentration, N/A Not available (patient with only meropenem 1000 mg or only 2000 mg intravenously every 8 h), CrCL Estimated creatinine clearance (calculated using the Cockcroft-Gault equation [16])Observed meropenem concentrations after 1000 mg or 2000 mg intravenously every 8 h (4-h infusion)

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Vmp (L)

Model Parameters for the Final Integrated Model

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Parameters	Population mean (%CV)	Inter-individual variability (%CV)

ADC

 Emax (1/h)	0.0407 (5.5)	0.0945 (25.4)

 Km (nmol/L)	0.959 (1.68)	––

 Vc (L)	0.0996 (2.6)	0.0118 (36.9)

 CLd (L/h)	0.00197 (1.9)	–

 Vp (L)	0.183 (8.7)	0.230 (25.4)

 λ [Weibull scale parameter]	1.51 (0.9)	–

 κ [Weibull shape parameter]	1.10 (0.6)	–

 Fmp	0.783 (2.2)	–

 Fmd	0.0242 (30.9)	1.78 (34.2)

MMAE

 CLm (L/h)	2.27 (8.3)	0.333 (20.2)

 Vm (L)	1.00 (0.3)	–

 CLmd (L/h)	23.0 (0.7)	–

 Vmp (L)	88.4 (4.8)	0.0670 (31.9)

 σacMMAE [Residual error for acMMAE]	0.257 (4.6)	–

 σAb [Residual error for Tab]	0.194 (4.1)	–

 σMMAE [Residual error for unconjugated MMAE]	0.327 (8.9)	–

ADC: antibody-drug conjugate; CLd: distributional clearance of ADC; CLm: systemic clearance of unconjugated MMAE from the central compartment; CLmd: distributional clearance of unconjugated MMAE; CV: coefficient of variation; Emax: maximal target-mediated proteolytic degradation rate of ADC; Fmd: fraction of formation of unconjugated MMAE in the central compartment from the deconjugation pathway of ADC; Fmp: fraction of formation to unconjugated MMAE in the central compartment from the proteolytic degradation pathway of ADC; Km: concentration of ADC to reach half of the maximal Emax; MMAE: monomethyl auristatin E; Vc: central volume of distribution for ADC; Vp: peripheral volume of distribution for ADC; Vm: central volume of distribution for unconjugated MMAE; Vmp: peripheral volume of distribution for unconjugated MMAE

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Emax (% of E0)

IMPDH1 expression

Data are given as median (range). The belatacept group includes 3 patients at week 13 and for the maximum, minimum and AUC calculations at week 2. E0, predose expression; Emax, maximum expression; Emin, minimum expression; AUC, area under the variable versus time curve.

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CAV

Pharmacokinetic parameters calculated from the PEG-IFN concentration in serum.

Data are reported as mean ± standard deviation, except for Tmax expressed as median ± quartile range.CI: confidence intervals of the mean Test/Reference ratioOne volunteer (#13) was excluded from the pharmacokinetic comparison (see text)* Parameters corrected by corporal surfacep: Paired t test between groups, except for Tmax (Wilcoxon's test)

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HVD (h)

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C. SN-38 parameters

      0
      1
      2
      3
      4
      5
      6
      7

      0
      0
      1
      2
      3
      4
      5
      6
      7

      1
      A. Common parameters
      A. Common parameters
      A. Common parameters
      A. Common parameters
      A. Common parameters
      A. Common parameters
      A. Common parameters
      A. Common parameters

      2
      Parameter
      Unit
      Irinotecan
      SN-38
      SN-38G
      NPC
      APC
      Theoretical lower limit

      3
      Vcentral
      L/kg
      0.075 ~ 0.75
      0.075 ~ 0.75
      0.075 ~ 0.75
      0.075 ~ 0.75
      0.075 ~ 0.75
      0.074a

      4
      ka
      /h
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0

      5
      kfeces
      /h
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0

      6
      Rdif,h
      -
      -b,c
      0.01 ~ 1.0
      0.01 ~ 1.0
      -c
      -c
      0

      7
      1/β
      -
      -b
      1.1 ~ 10
      1.1 ~ 10
      1.1 ~ 10
      1.1 ~ 10
      1

      8
      CLint,all
      L/h/kg
      -b
      0.1 ~ 100
      0.1 ~ 100
      0.1 ~ 100
      0.1 ~ 100
      0

      9
      1/fbile
      -
      -b
      -e
      -d
      1.1 ~ 10
      -d
      1

      10
      kbile
      /h
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0.06 ~ 6.0
      0

      11
      Rdif,ent
      -
      0.1 ~ 10
      0.1 ~ 10
      0.1 ~ 10
      -c
      -c
      0

      12
      B. Irinotecan parameters
      B. Irinotecan parameters
      B. Irinotecan parameters
      B. Irinotecan parameters
      B. Irinotecan parameters
      B. Irinotecan parameters
      B. Irinotecan parameters
      B. Irinotecan parameters

      13
      Parameter
      Unit
      Value
      Theoretical lower limit
      nan
      nan
      nan
      nan

      14
      PSdif,inf,h
      L/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      15
      CLSN-38,h(irinotecan)
      L/h/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      16
      CLNPC,h(irinotecan)
      L/h/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      17
      CLAPC,h(irinotecan)
      L/h/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      18
      CLothers,h(irinotecan)
      L/h/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      19
      CLbile
      L/h/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      20
      PSdif,eff,ent
      L/h/kg
      0.1 ~ 100
      0
      nan
      nan
      nan
      nan

      21
      CLSN-38,h(irinotecan) /CLSN-38,ent(irinotecan)
      -
      1.1 ~ 10
      1
      nan
      nan
      nan
      nan

      22
      CLNPC,h(irinotecan) / CLNPC,ent(irinotecan)
      -
      1.1 ~ 10
      1
      nan
      nan
      nan
      nan

      23
      C. SN-38 parameters
      C. SN-38 parameters
      C. SN-38 parameters
      C. SN-38 parameters
      C. SN-38 parameters
      C. SN-38 parameters
      C. SN-38 parameters
      C. SN-38 parameters

      24
      Parameter
      Unit
      Value
      Theoretical lower limit
      nan
      nan
      nan
      nan

      25
      1/fglu e
      -
      1.1 ~ 10
      1
      nan
      nan
      nan
      nan

      26
      CLSN-38G,h(SN-38) /CLSN-38G,ent(SN-38)
      -
      1.1 ~ 10
      1
      nan
      nan
      nan
      nan

      27
      D. SN-38G parameters
      D. SN-38G parameters
      D. SN-38G parameters
      D. SN-38G parameters
      D. SN-38G parameters
      D. SN-38G parameters
      D. SN-38G parameters
      D. SN-38G parameters

      28
      Parameter
      Unit
      Value
      Theoretical lower limit
      nan
      nan
      nan
      nan

      29
      kdec
      /h
      0.06 ~ 6
      0
      nan
      nan
      nan
      nan

Initial Range and Theoretical Lower Limit of Parameters for CNM

aVcentral is larger than blood volume bHybrid parameters were not used. Instead of it, as shown in Table 1B. parameters for representing elementary steps were used cNo involvement of active uptake or efflux transporters for these compounds dfbile value was fixed as 1 eThe ratio (fglu) of metabolic clearance for glucuronidation of SN-38 to hepatic intrinsic clearance was estimated using the following equation, fglu = 1 - fblie

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Recovery (IU/dL per IU/kg)

Bioequivalence metrics

      0
      1
      2

      0
      Parameter
      Ratio of LS means
      90% confidence interval

      1
      AUCT
      99.5%
      93.8–105.6%

      2
      AUCinf
      98.1%
      92.2–104.3%

      3
      Recovery (IU/dL per IU/kg)
      100.6%
      97.6–103.6%

CAPTION: Bioequivalence metrics
FOOTER: []

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MRT (min)

Pharmacokinetic parameters of the four components in rat plasma after oral administration of LDXGT (10 g/kg, p.o.).

Data expressed as mean ± S.E.M. (n = 6); Cmax: the maximum plasma concentration, Tmax: time to reach the maximum concentrations, t1/2: half-life, AUC: area under the concentration-time curve, CL: clearance, MRT: mean resident time; a Significantly different (p < 0.05) from the other active components in Cmax; b Significantly different (p < 0.05) from the other active components in AUC.

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AUC0–inf_obs (ng/ml h)

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

<!DOCTYPE html>
<colgroup><col width="1*"/><col width="1*"/><col width="1*"/><col width="1*"/><col width="1*"/><col width="1*"/></colgroup>

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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Vss (mL/kg)

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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tmax (min)c

Non-compartmental pharmacokinetic parameters obtained for metformin (30 mg/kg) after its oral administration with Plantago ovata husk (300 mg/kg) to diabetic rabbits (n = 6)

<!DOCTYPE html>

Parameters	Standard chow	Supplemented chow
<italic>p</italic> valuesa

<inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
				\usepackage{wasysym}
				\usepackage{amsfonts}
				\usepackage{amssymb}
				\usepackage{amsbsy}
				\usepackage{mathrsfs}
				\usepackage{upgreek}
				\setlength{\oddsidemargin}{-69pt}
				\begin{document}$$ \overline{x} $$\end{document}</tex-math><mml:math id="M10" display="inline"><mml:mover accent="false"><mml:mi>x</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="12906_2017_1809_Article_IEq5.gif"/></alternatives></inline-formula> ± SD	CV (%)
<inline-formula id="IEq6"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
				\usepackage{wasysym}
				\usepackage{amsfonts}
				\usepackage{amssymb}
				\usepackage{amsbsy}
				\usepackage{mathrsfs}
				\usepackage{upgreek}
				\setlength{\oddsidemargin}{-69pt}
				\begin{document}$$ \overline{x} $$\end{document}</tex-math><mml:math id="M12" display="inline"><mml:mover accent="false"><mml:mi>x</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="12906_2017_1809_Article_IEq6.gif"/></alternatives></inline-formula> ± SD	CV (%)

λ (min−1)	0.0039 ± 0.0010	25.17	0.0025 ± 0.0014	53.87	0.053a

AUC (μg·min/mL)	1164.9 ± 262.1	22.50	1496.9 ± 438.9	29.32	0.160a

Cmax (μg/mL)	3.39 ± 0.290	8.53	3.12 ± 0.197	6.32	0.087a

tmax (min)c
	110.0 ± 15.49	14.08	120.0 ± 0.00	-	0.138b

Cl/F (mL/min/kg)	26.83 ± 5.81	21.67	21.65 ± 6.88	31.76	0.160a

Va/F (mL/kg)	7070.8 ± 884.9	12.52	9317.5 ± 1803.8	19.36	0.022a

Vss/F (mL/kg)	3891.2 ± 731.8	18.81	3080.4 ± 908.7	29.50	0.101a

t1/2λ (min)	189.6 ± 44.7	17.48	336.2 ± 152.6	45.40	0.052a

AUMC (μg·min2/mL)	380,326.9 ± 158,923.7	41.79	827,234.6 ± 560,290.1	67.73	0.093a

MRT (min)	145.9 ± 6.37	4.36	143.1 ± 4.07	2.84	0.409a

MAT (min)	64.21	56.07

F (%)	36.73	41.52

at Test bMann-Whitney Test csignificant differences with the value obtained when metformin was administered alone (Mann-Whitney Test)

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CRP, mg/dL

Clinical activity assessments in the multi dose phase at eight weeks

Data are expressed as group mean, with ranges depicted between parentheses. ACR, American College of Rheumatology; CRP, C-reactive protein; DAS, disease activity score; ESR, erythrocyte sedimentation rate; IV, intravenous; SC, subcutaneous; SJC, swollen joint count; TJC, tender joint count; VAS, visual analog scale.

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Rd

      0
      1
      2
      3
      4
      5
      6
      7
      8
      9
      10
      11

      0
      Unnamed: 0_level_0
      Unnamed: 1_level_0
      Unnamed: 2_level_0
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper

      1
      Protein or gene
      Uniprot ID
      Closely relative diseases to myocardial ischemia
      Rg1
      Rb1
      Rd
      R1
      CTS
      DHI
      TS I
      TS IIA
      Total (all ingredients against one target)

      2
      F2
      P00734
      Myocardial infarction, coronary ischemic syndrome, coronary heart disease
      12/2.899
      12/2.915
      12/3.169
      –
      –
      12/2.746
      –
      12/2.858
      60/14.587

      3
      MAPK10
      P53779
      Angina
      –
      10/2.984
      10/2.964
      8/2.963
      8/2.752
      8/2.71
      9/2.752
      9/2.735
      62/19.86

      4
      ESR1
      P03372
      Myocardial infarction, coronary heart disease
      6/2.904
      6/3.008
      –
      6/3.149
      6/2.866
      6/2.852
      8/2.866
      8/2.581
      46/20.226

      5
      HSD11B1
      P28845
      ∗
      7/3.155
      –
      –
      –
      7/3.142
      7/3.805
      8/3.142
      –
      29/13.244

      6
      CASP3
      P42574
      Ischemia
      7/2.92
      7/2.948
      7/2.928
      7/2.978
      –
      –
      –
      –
      28/11.774

      7
      CMA1
      P23946
      Heart failure
      –
      –
      8/2.693
      8/2.681
      –
      –
      –
      –
      16/5.374

      8
      SEC14L2
      O76054
      ∗
      –
      –
      –
      3/3.972
      3/3.61
      3/3.636
      3/3.61
      3/3.502
      15/18.33

      9
      MAOB
      P27338
      Ischemia
      6/4.359
      –
      –
      –
      –
      –
      –
      –
      6/4.359

      10
      SOD2
      P04179
      Oxidative injury
      5/3.447
      –
      –
      –
      –
      –
      –
      –
      5/3.447

      11
      PLAU
      P00749
      ∗
      –
      –
      3/3.52
      –
      –
      –
      –
      –
      3/3.52

      12
      PDE5A
      O76074
      ∗
      –
      –
      2/2.954
      –
      –
      –
      –
      –
      2/2.954

      13
      CTSS
      P25774
      ∗
      –
      –
      –
      2/2.845
      –
      –
      –
      –
      2/2.845

      14
      RTN4R
      Q9BZR6
      ∗
      –
      –
      –
      2/2.511
      –
      –
      –
      –
      2/2.511

      15
      HMGCR
      P04035
      ∗
      –
      2/3.744
      –
      –
      –
      –
      –
      –
      2/3.744

      16
      Total (closely relative to myocardial ischemia issues)
      Total (closely relative to myocardial ischemia issues)
      Total (closely relative to myocardial ischemia issues)
      36/16.529
      35/11.855
      37/11.754
      29/11.771
      14/5.618
      26/8.308
      17/5.618
      29/8.174
      nan

      17
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan

CAPTION: The results of systems pharmacology investigation for the eight ingredients in GDPP.
FOOTER: ∗Means the others related-cardiovascular affairs excluded.–Represents the protein failed to be selected in the target fishing due to negative z′-score by PharmMapper.

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AUC∞ [ng·h/mL; mean ± SD]

Pharmacokinetic parameters of clopidogrel, the carboxylic acid metabolite of clopidogrel (CLPM) and the H3 and H4 isomers of the clopidogrel thiol metabolite

<!DOCTYPE html>

Parameter	Clopidogrel	H3	H4 (active)	CLPM

Dose: clopidogrel 75 mg	(<italic>n</italic> = 41)	(<italic>n</italic> = 30)	(<italic>n</italic> = 30)	(<italic>n</italic> = 45)

 <italic>C</italic>
max [ng/mL; mean ± SD]	2.04 ± 2.0	5.29 ± 5.54	7.13 ± 6.32	2,516 ± 1,754

 <italic>t</italic>
max [h; mean ± SD]	1.40 ± 1.07	1.08 ± 0.62	1.04 ± 0.53	1.37 ± 0.74

 <italic>t</italic>
½ [h; mean ± SD]	1.71 ± 1.28	0.78 ± 0.78	0.90 ± 0.86	7.14 ± 3.32

 AUC<italic>t</italic> [ng·h/mL; mean ± SD]	5.07 ± 3.80	7.37 ± 6.71	11.30 ± 9.58	11,077 ± 7,768

 AUC∞ [ng·h/mL; mean ± SD]	6.29 ± 4.11	7.96 ± 6.85	11.97 ± 9.75	12,383 ± 8,552

 CL/<italic>F</italic> [×103 L/h; mean ± SD]	18.96 ± 15.89	–	–	–

 <italic>V</italic>
d/<italic>F</italic> [×103 L; mean ± SD]	39.24 ± 33.52	–	–	–

Dose: clopidogrel 300 mg	(<italic>n</italic> = 3)	(<italic>n</italic> = 3)	(<italic>n</italic> = 3)	(<italic>n</italic> = 17)

 <italic>C</italic>
max [ng/mL; mean ± SD]	4.51 ± 3.42	8.47 ± 1.69	17.92 ± 20.38	8,464 ± 3,772

 <italic>t</italic>
max [h; mean ± SD]	1.17 ± 0.76	0.83 ± 0.29	0.83 ± 0.29	1.61 ± 1.21

 <italic>t</italic>
½ [h; mean ± SD]	1.99 ± 0.44	0.72 ± 0.18	0.84 ± 0.20	7.11 ± 3.50

 AUC<italic>t</italic> [ng·h/mL; mean ± SD]	20.82 ± 13.35	11.24 ± 8.31	25.04 ± 27.41	32,979 ± 12,321

 AUC∞ [ng·h/mL; mean ± SD]	21.76 ± 13.34	11.70 ± 8.33	25.69 ± 27.54	37,249 ± 13,861

 CL/<italic>F</italic> [×103 L/h; mean ± SD]	16.98 ± 10.41	–	–	–

 <italic>V</italic>
d/<italic>F</italic> [×103 L; mean ± SD]	45.50 ± 19.22	–	–	–

AUC area under the plasma concentration–time curve, AUC t AUC from time zero to time t, AUC ∞ AUC from time zero to infinity, CL/F plasma drug clearance, C max maximum plasma concentration, t ½ elimination half-life, t max time to reach the C max, V d /F volume of distribution

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t ½, h*

Pharmacokinetic endpoints

The aPTT reagents used for the one‐stage clotting assay were SynthAFax and Actin FSL for N9‐GP and rFIXFc, respectively. The ROX factor IX kit was used for the chromogenic assay with both treatments. All assays were calibrated using NHP.aPTT, activated partial thromboplastin time; AUC0‐inf,norm, area under the FIX activity–time curve from 0 to infinity, dose‐normalized to 50 IU/kg; C168h, FIX activity at 168 h; C240h, FIX activity at 240 h; CL, clearance; Cmax,norm, maximum FIX activity dose‐normalized to 50 IU/kg; IR30min, incremental recovery at 30 min; CV, geometric coefficient of variation; NHP, normal human plasma; PK, pharmacokinetic; rFIXFc, recombinant factor IX‐Fc fusion protein; t ½, terminal half‐life; V ss, apparent volume of distribution at steady state.*N = 12; two patients missed the last two PK time‐points and were excluded from the analysis for these parameters.

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kon (M−1 s−1)

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AUClast (ng·h/ml)

Pharmacokinetic parameters (summary statistics) in single-dose study

<!DOCTYPE html>

Cohort (dosage level)	n	AUClast (ng·h/ml)
	Cmax (ng/ml)

Mean ± SD

S1 (5 mg)	4	1110 ± 360	236 ± 89

S2 (10 mg)	4	2550 ± 110	589 ± 88

S3 (20 mg)	4	5460 ± 680	999 ± 135

AUC last, area under the curve from time 0 to last time point with quantifiable concentration before the next hemodialysis; S, single-dose.

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Race (Black) 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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t1/2 (min)

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

<!DOCTYPE html>
<colgroup><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/><col width="80pt" align="left"/></colgroup>

 	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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      0
      1
      2
      3
      4

      0
      Parameter
      Clopidogrel
      H3
      H4 (active)
      CLPM

      1
      Dose: clopidogrel 75 mg
      (n = 41)
      (n = 30)
      (n = 30)
      (n = 45)

      2
      C max [ng/mL; mean ± SD]
      2.04 ± 2.0
      5.29 ± 5.54
      7.13 ± 6.32
      2,516 ± 1,754

      3
      t max [h; mean ± SD]
      1.40 ± 1.07
      1.08 ± 0.62
      1.04 ± 0.53
      1.37 ± 0.74

      4
      t ½ [h; mean ± SD]
      1.71 ± 1.28
      0.78 ± 0.78
      0.90 ± 0.86
      7.14 ± 3.32

      5
      AUCt [ng·h/mL; mean ± SD]
      5.07 ± 3.80
      7.37 ± 6.71
      11.30 ± 9.58
      11,077 ± 7,768

      6
      AUC∞ [ng·h/mL; mean ± SD]
      6.29 ± 4.11
      7.96 ± 6.85
      11.97 ± 9.75
      12,383 ± 8,552

      7
      CL/F [×103 L/h; mean ± SD]
      18.96 ± 15.89
      –
      –
      –

      8
      V d/F [×103 L; mean ± SD]
      39.24 ± 33.52
      –
      –
      –

      9
      Dose: clopidogrel 300 mg
      (n = 3)
      (n = 3)
      (n = 3)
      (n = 17)

      10
      C max [ng/mL; mean ± SD]
      4.51 ± 3.42
      8.47 ± 1.69
      17.92 ± 20.38
      8,464 ± 3,772

      11
      t max [h; mean ± SD]
      1.17 ± 0.76
      0.83 ± 0.29
      0.83 ± 0.29
      1.61 ± 1.21

      12
      t ½ [h; mean ± SD]
      1.99 ± 0.44
      0.72 ± 0.18
      0.84 ± 0.20
      7.11 ± 3.50

      13
      AUCt [ng·h/mL; mean ± SD]
      20.82 ± 13.35
      11.24 ± 8.31
      25.04 ± 27.41
      32,979 ± 12,321

      14
      AUC∞ [ng·h/mL; mean ± SD]
      21.76 ± 13.34
      11.70 ± 8.33
      25.69 ± 27.54
      37,249 ± 13,861

      15
      CL/F [×103 L/h; mean ± SD]
      16.98 ± 10.41
      –
      –
      –

      16
      V d/F [×103 L; mean ± SD]
      45.50 ± 19.22
      –
      –
      –

Pharmacokinetic parameters of clopidogrel, the carboxylic acid metabolite of clopidogrel (CLPM) and the H3 and H4 isomers of the clopidogrel thiol metabolite

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t1/2λ (min)

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λ

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Cmax (µg/mL)

Pharmacokinetic parameters of enantiomers in rats (mean±SD).

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t1/2 (h)

Pharmacokinetic parameters of NG after intravenous (2 mg/kg) and intragastric (10 mg/kg) administrations in rats (mean±SD, n=6).

t1/2: elimination half-time; C2min: the observed plasma concentration at 2 min; Tmax: time to peak value; Cmax: peak concentration; AUC0–t: area under the plasma concentration-time curve from time zero to t; AUC0–∞: area under the curve from time zero to infinity; Vz:apparent volume of distribution.; MRT: mean residence time; F: bioavailability.

t

h


Vz/F (L)

Summary of glycopyrronium pharmacokinetic parameters (mITT population)

aMedian (Min, Max); bn = 11; cn = 10; dn = 12; en = 19; fn = 16.AUCx-y = area under the concentration-time curve from time x to time y; CL/F = apparent oral clearance; Cmax = maximum plasma concentration; CV% = coefficient of variation; GP MDI = glycopyrronium metered-dose inhaler; t1/2 = apparent terminal elimination half-life; tmax = time to maximum concentration; Vz/F = apparent volume of distribution; mITT=modified intention to treat.

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t1/2α (min)

Pharmacokinetic parameters

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

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F%

Pharmacodynamics of insulin in rats with alloxan-induced diabetes.

<!DOCTYPE html>
<colgroup><col width="1*"/><col width="1*"/><col width="1*"/><col width="1*"/></colgroup>

Formulation	Dose (IU/kg)	AAC0–240 min (% glucose/min)	F%

Insulin alone	2	721.0 ± 478.2	3.2 ± 2.1

+0.25 mM <sc>l</sc>-TCTP-PTD 13	2	4860.1 ± 424.5	22.4 ± 1.7

+0.25 mM <sc>l</sc>-TCTP-PTD 13M2	2	9604.5 ± 1204.6	42.3 ± 5.3

Insulin (s.c.)	1	11354.3 ± 507.8	100

Values are expressed as means ± SEM (n = 6–8).AAC: area above the blood glucose curve; F%: relative pharmacological bioavailability compared to s.c.; s.c.: subcutaneous.

F


IIV−Vc/F

Parameter estimates of the model and parameter results from a non-parametric bootstrap

<!DOCTYPE html>

Description	Estimate	RSE*	Bootstrap

Mean	95% CI

Ka (h–1)	2.85	8.7%	2.24	1.21 to 3.87

CL/F (L h–1)	25.4	3.6%	25.4	23.7 to 27.4

Vc/F (L)	2390.	12.6%	2377.8	1479 to 3690

Q/F (L h-1)	8.41	13.3%	9.80	6.54 to 16.20

Vp/F (L)	168.	11.7%	175.9	135 to 239

ALAG1	0.877	4.7%	0.800	0.672 to 0.928

DRUG0 ON Ka	1.89	22.0%	2.00	1.23 to 2.88

DRUG0 ON Vc/F	0.216	13.1%	0.220	0.138 to 0.359

DRUG1 ON Vc/F	0.207	12.8%	0.210	0.128 to 0.328

DRUG0 ON CL/F	0.610	6.6%	0.610	0.537 to 0.696

DRUG1 ON CL/F	0.610	5.9%	0.610	0.545 to 0.695

WT ON Vc	0.579	25.7%	0.590	0.191 to 1.06

<inline-formula><mml:math id="inf1"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Ka	88.2%	24.0%	73.1%	37.7% to 115%

<inline-formula><mml:math id="inf2"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>CL/F	49.1%	7.4%	46.7%	39.8% to 53.4%

<inline-formula><mml:math id="inf3"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi>ω</mml:mi></mml:mrow></mml:mrow></mml:mstyle></mml:math></inline-formula>covCL/F-Vc/F	0.174	–	0.174	0.0832 to 0.259

<inline-formula><mml:math id="inf4"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Vc/F	40.8%	16.1%	39.7%	22.9% to 51.4%

<inline-formula><mml:math id="inf5"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Q/F	0 FIXED	–	–	–

<inline-formula><mml:math id="inf6"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Vp/F	52.4%	29.3%	50.1%	11.5% to 90.1%

Prop-Error	0.216	5.0%	0.200	0.189 to 0.232

Add-Error	0.303	14.5%	0.300	0.215 to 0.382

*Relative SE.ALAG1, the time lag for absorption; CL/F, apparent clearance of the central compartment; Ka, absorption rate constant; Q, transport rate between the central and peripheral compartments; Vc/F, apparent volume of the central compartment; Vp/F, apparent volume of the peripheral compartment.

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F


AUC0–t, ng·h/mL

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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Diastolic blood pressure (mmHg)

      0
      1
      2
      3

      0
      Vital signs
      Treatment Arm A
      Treatment Arm B
      Combination

      1
      Unnamed: 0_level_1
      LDX alone
      VXR alone
      LDX + VXRb

      2
      Pulse rate (beats/min)
      −0.78c to 12.76
      −3.73 to 8.73
      4.66–20.85

      3
      Systolic blood pressure (mmHg)
      −0.77c to 6.56
      −0.52 to 4.32
      4.44c to 13.78

      4
      Diastolic blood pressure (mmHg)
      0.57c to 5.74
      1.18–5.39
      7.05–12.46

CAPTION: Range (1–2 h post-dose) of mean change from time-matched baselinea in vital signs over 1–12 h post-dose
FOOTER: LDX lisdexamfetamine dimesylate, VXR venlafaxine extended-releaseaBaseline was defined as the time-matched measurement at day −1 for each treatment periodbIncludes subjects who received LDX + VXR in Treatment Arm A as well as those who received VXR + LDX in Treatment Arm BcValue occurred at first post-dose measurement (1 h post-dose)

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T ½ (h)

Pharmacokinetic parameters for total testosterone, free testosterone, and dihydrotestosterone after F1 and F2 administration

<!DOCTYPE html>

Dosing
<italic>C</italic>
max (ng/mL)
<italic>T</italic>
max (h)	AUC(0–1,590) (ng*h/mL)
<italic>T</italic>
½ (h)

F1 total testosterone (ng/mL)	5.65 ± 2.35	0.256 ± 0.063	6.41 ± 2.23	0.726 ± 0.165

F2 total testosterone (ng/mL)	7.84 ± 3.69*	0.201 ± 0.043	8.10 ± 2.49	0.598 ± 0.080

F1 free testosterone (pg/mL)	36.2 ± 14.9	0.250 ± 0.083	35.1 ± 18.8	0.674 ± 0.187

F2 free testosterone (pg/mL)	52.4 ± 20.8*	0.194 ± 0.054	55.5 ± 31.1*	0.798 ± 0.247

F1 dihydrotestosterone (ng/mL)	0.519 ± 0.222	0.410 ± 0.105	1.39 ± 0.87	1.14 ± 0.49

F2 dihydrotestosterone (ng/mL)	0.578 ± 0.245	0.451 ± 0.066	1.17 ± 0.47	0.850 ± 0.336

For all calculations, the predose concentration is subtracted from the determined concentration after dosing. The values are mean ± SD. The means of F1 are calculated with the data of 13 women and the means of F2 are based on the data of 12 womenTo convert total testosterone to nanomoles per liter, multiply by 3.467 AUC area under the curve, C max maximum concentration, T max time to maximum concentration, T ½ half-life* p < 0.05, value at F2 is significantly different from F1

T

½

h


Pharmacokinetics properties of ticagrelor and AR-C124910XX after administration of single 180 mg oral dose for the different CYP3A5∗3 genotypes; values are mean (SD).

A

R

C

X

X


Cmax (μg/ml)

ASN-1 and ASN-2 serum pharmacokinetic parameters for each dose by noncompartmental analysisa

aData are expressed as means (percent coefficients of variation [%CV]). IP, investigational product; NA, not applicable.

C

m

a

x

μ

g

m

l


AUC(0‐72) (ng h/mL)

Noncompartmental pharmacokinetic parameters of prexasertib

Data are geometric mean (CV%) unless otherwise indicated.aGeographic mean (range).b R A = intercycle accumulation (Cycle 2, Day 1 AUC[0‐24]/Cycle 1, Day 1 AUC[0‐24]).AUC, area under the plasma concentration vs time curve; AUC(0‐24), AUC from time zero to 24 h; AUC(0‐72), AUC from time zero to 72 h; C av,72, average plasma concentration over 72 h after prexasertib infusion; CL, systemic clearance; C max, maximum plasma concentration; CV, coefficient of variation; N, number of pharmacokinetic observations; NC, not calculated; R A, accumulation ratio; t 1/2, terminal elimination half‐life; V ss, volume of distribution at steady state.

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Ke

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.

K

e


Ceoinf (μg/mL) geomean (CV%)

      0
      1
      2
      3
      4
      5
      6

      0
      Dose (mg)
      Dose regimen
      n
      Cmin (μg/mL) geomean (CV%)
      Ceoinf (μg/mL) geomean (CV%)
      AI Cmin (μg/mL) geomean (CV%)
      AI Ceoinf (μg/mL) geomean (CV%)

      1
      60
      1st infusion in C1
      12
      0.75 (83.83)a
      20.01 (22.67)
      2.54 (49.60)b
      1.08 (7.54)

      2
      60
      1st infusion in C5
      7
      1.48 (124.88)
      19.22 (13.34)
      nan
      nan

      3
      200
      1st infusion in C1
      12
      9.94 (28.32)c
      70.02 (23.31)
      2.56 (12.84)
      1.23 (21.46)

      4
      200
      1st infusion in C5
      5
      29.78 (31.64)
      92.66 (31.64)
      nan
      nan

      5
      400
      1st infusion in C1
      11
      25.84 (26.78)d
      121.43 (16.66)
      3.07 (6.68)
      1.53 (13.60)

      6
      400
      1st infusion in C5
      5
      70.50 (32.23)e
      184.03 (11.64)
      nan
      nan

CAPTION: The trough (Cmin) and end of infusion (Ceoinf) concentrations of SHR-1210 after the first dose (C1D1) and the dose at steady state (C5D1) and the corresponding accumulation index (AI)
FOOTER: Only 1 infusion was administered in C1 (4 weeks); Q2W dosing starts from C2.AI accumulation index, calculated as concentration (Cmin or Ceoinf) at C5 divided by the corresponding concentration at C1 of each dose, C Cycle, Cminday 14 concentration at C1 and C5, CV% coefficient of variation %, n number of subjects contributing to the mean, Q2W every 2 weeks.an = 11bn = 6cn = 11dn = 10en = 4

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Cmin (μg/mL) geomean (CV%)

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V


AUCt

Levodopa bioequivalence results LCIG‐HV vs LCIG‐LV Commercial (Test vs Reference)

<!DOCTYPE html>
<col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/>

PK parameter	Geometric mean ratio

Point estimate	90% CI

<italic>C</italic>
max
	1.036	0.894‐1.201

AUCt
	0.999	0.892‐1.117

AUCinf
	0.995	0.891‐1.111

A

U

C

t


Tmax,a h

Plasma and urinary pharmacokinetics of lesinurad following single doses of lesinurad in healthy fed male subjects – tablet versus capsule (bioavailability study)

Notes: Data are geometric mean (95% confidence interval) unless otherwise noted.aTmax values are presented as median (minimum, maximum).bThe t1/2 summary statistics values were considered unreliable as more than half of the subjects had t1/2 calculated from a period of less than twofold of the calculated t1/2 value.Abbreviations: Ae, amount of drug excreted in urine over a time interval; AUC(0–24h), area under the plasma concentration–time curve from time zero to 24 hours post-dose; AUC(0–inf), AUC from time zero to infinity; CLR, renal clearance; Cmax, maximum observed plasma concentration; fe, fraction of the dose (% dose) excreted in urine following dosing; t½, half-life; Tmax, time to Cmax.

T

m

a

x

a

h


MRT (0-t) (h)

Pharmacokinetic parameters of the seven components of Shengjiang decoction

aP < 0.05 vs CG + SJD. ALEM: Aloe-emodin; CHRY: Chrysophanol; DEME: Demethoxycurcumin; BISD: Bisdemethoxycurcumin; Cmax: Maximum concentration; Tmax: Time of maximum concentration; MRT: Mean residence time.

M

R

T

t

h


AUCss dosing 210 mg Q2W+1 (µg d/mL)

Model‐derived secondary pharmacokinetic parameters for a reference patient (body‐weight of 90 kg) receiving 210 mg Q2W+1

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<col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/>

Pharmacokinetic parameter	Mean	Median	CV%

<italic>C</italic>
max at week 1 dosing 210 mg Q2W+1 (µg/mL)	9.95	9.57	50.7

<italic>C</italic>
max at steady‐state dosing 210 mg Q2W+1 (µg/mL)	20.2	16.1	76.8

tmax at steady‐state dosing 210 mg Q2W+1 (d)	NR	4	1‐6

AUCss dosing 210 mg Q2W+1 (µg d/mL)	225	160	92.8

AUCss, area under the concentration‐time curve in a dosing interval at steady‐state; C max, maximum concentration; CV%, coefficient of variation (range is provided for t max); NR, not reported; Q2W+1, dosing at weeks 0, 1, 2 followed by dosing every 2 wk; t max, time to reach C max after last dose.

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C

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m

g

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W

µ

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L


Duration of zero order absorption

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

<!DOCTYPE html>

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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Heart rate AUEC0-0.5h [bpm*hr]

Descriptive statistics of pharmacokinetic and pharmacodynamic parameters following epinephrine administration grouped by treatment (uncorrected values, per protocol population of n = 8)

aarithmetic means and standard deviations (SD); AUC area under the concentration vs. time profile (indices apply for the postdose time interval); AUEC area under the effect curve; Cmax maximal concentration; Emax maximal effect; MRTlast mean residence time calculated from concentrations up to the last point of observation; tmax, time of Cmax; BP blood pressure. Fractional AUC values for blood pressure are presented in the supplementary material

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e

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t

r

a

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AUC0-last (h · ng/ml)

Bioequivalence analysis of primaquine, carboxyprimaquine, chloroquine, and desethylchloroquine after primaquine and chloroquine administered as a single oral dose alone and in combination

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Parameter	Value<italic><xref ref-type="table-fn" rid="TF5-1">a</xref></italic>

Primaquine (<italic>n</italic> = 16)	Carboxyprimaquine (<italic>n</italic> = 16)	Chloroquine (<italic>n</italic> = 16)	Desethylchloroquine (<italic>n</italic> = 16)

<italic>C</italic>max (ng/ml)	163 (147–181)	121 (115–126)	103 (92.1–116)	90.2 (77.3–105)

AUC0-last (h · ng/ml)	130 (120–141)	114 (108–120)	104 (95.4–114)	90.8 (75.9–109)

AUC0-∞ (h · ng/ml)	124 (113–135)	75.3 (62.5–90.7)	106 (97.7–115)	91.8 (71.2–118)

aData are presented as geometric mean ratios (90% CI).

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Pharmacokinetic (PK) parameters of recombinant human growth hormone (r-hGH) in serum (n = 28, PK population)

Geomean (geo CV%) and range, for tmax median and range are given.AUC0-t, area under the serum concentration-time curve from time 0 to the last measurable concentration time point after drug administration; AUC0-∞, total area under the serum concentration-time curve extrapolated to infinity; Cmax, maximum serum concentration; CL/f, apparent clearance; CV, coefficient of variation; t1/2, terminal elimination half life; tmax, time to reach Cmax; Vz/f, apparent volume of distribution.A = r-hGH liquid multi-dose, 5.83 mg/mL.B = r-hGH liquid multi-dose, 8.0 mg/mL.C = r-hGH freeze-dried 8.8 mg, reconstituted in 1.51 mL.

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Q/F

Summary of the results obtained from the final model and the bootstrap analysis

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Parameter<xref ref-type="table-fn" rid="T2F1"><italic>a</italic></xref>	Median value for<xref ref-type="table-fn" rid="T2F2"><italic>b</italic></xref>:

Estimate	%RSE	%CV	Bootstrap estimate (95% CI)

CL/<italic>F</italic> (liters/day)	377	6.58	371.7	(302–435)

<italic>V</italic>2/<italic>F</italic> (liters)	2,230	6.59	2,212	(1,930–2,580)

<italic>V</italic>3/<italic>F</italic> (liters)	3,230	15.0	3,298	(2,360–4,710)

<italic>Q</italic>/<italic>F</italic> (liters/day)	804	11.2	831	(651–1,130)

<italic>Ka</italic> (day−1)	17.9	11.7	17.7	(14.1–22.5)

θ6 age on <italic>V</italic>3/<italic>F</italic>	0.624	38.6	0.629	(0.224–1.05)

θ7 formulation on <italic>Ka</italic>	1.63	37.8	1.86	(0.517–4.11)

IIV

    CL/<italic>F</italic>	0.166	26.7	40.7	0.160	(0.055–0.318)

    <italic>V</italic>2/<italic>F</italic>	0.993	8.76	99.6	0.994	(0.805–1.170)

    <italic>V</italic>3/<italic>F</italic>	0.256	48.4	50.6	0.265	(0.033–0.593)

    <italic>Q</italic>/<italic>F</italic>

    <italic>Ka</italic>	0.433	26.6	65.8	0.413	(0.194–0.669)

RV (additive error)	0.195	12.1	0.195	(0.15–0.244)

aFor both of the derived parameters distribution half-life (T1/2α) and elimination half-life (T1/2β) for pediatric malaria patients, the mean value ± standard deviation was 0.9 ± 0.6. F, oral bioavailability; CL, clearance; V2, central volume of distribution; V3, peripheral volume of distribution; Q, intercompartmental clearance; Ka, first-order absorption rate constant; IIV, interindividual variability; RV, residual variability.b%RSE, relative standard error [(SE/mean) × 100%]; %CV, percent coefficient of variation [(SD/estimate) × 100%].

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

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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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Range Cmax

Mean PK parameters (SD) of ST zolpidem

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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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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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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.

I

I

V

i

n

t

½

a

b

s


Vss (L/m2)

Pharmacokinetic parameters of eribulin (cycle 1, day 1)

Mean ± SD AUC (0-inf) area under the concentration-time curve from time zero to infinity, CL total clearance, C max maximum plasma concentration, t ½ terminal half-life, V ss steady-state volume of distribution

V

s

s

L

m