Cmax (mean, SD)b ng/mL

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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Ve (L/kg)

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

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Lanabecestat t1/2λz (h)

PK Parameters for Each Treatment Group

AUC0–∞, area under the plasma drug concentration–time curve from zero to infinity; AUC0–t, area under plasma drug concentration–time curve from zero to time t, the last quantifiable concentration; CI, confidence interval; CL/F, oral clearance; Cmax, maximum observed plasma drug concentration; SD, standard deviation; t1/2λz, half‐life associated with the terminal elimination rate constant.

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V P (L)

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

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

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

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

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

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

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

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

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

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

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

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

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T½ (h)

Summary of plasma remogliflozin and GSK279782 PK parameters in healthy subjectsa

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

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MRT (hours)

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

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

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

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

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

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

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

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

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

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

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

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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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Final parameter estimates describing the piperaquine population pharmacokinetics in women with uncomplicated P. falciparum malaria

Coefficient of variation (%CV) for between-subject variability (BSV) and (†) between occasion variability (BOV) were calculated as the [exp(estimated variance)-1]1/2. Relative standard errors (RSE) and the 95% confidence intervals (CI) were based on 868 successful stratified bootstrap runs (out of 1000) and presented as 100×(standard deviation/mean value) and as 2.5 to 97.5 percentiles, respectively.CL/F is the apparent elimination clearance. Vc/F is the apparent volume of distribution of the central compartment. Q1/F and Q2/F is the inter-compartment clearance between the central and first and second peripheral compartment, respectively. VP1/F and VP2/F is the apparent volume of distribution of first and second peripheral compartment, respectively. MTT is the mean transit time of the absorption model. RUV is the variance of the residual variability. No. of trans comp is the number of transit compartments used in the absorption phase. F represents the relative bioavailability.

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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.

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CL/F (l/h)

Population Pharmacokinetic Parameters, Passive Membrane Permeability, Physiological Parameters and In Vitro Binding Values Used for the Simulations

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Parameter	Values used in human D2RO Simulations	Source

CL/F (l/h)	19.5 (58)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

V/F (l)	1,150 (75)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

Ka (h−1)	0.600 (32)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

koff (h−1)	2.34	(<xref ref-type="bibr" rid="CR37">37</xref>)

Kd (nM)	5.10b	(<xref ref-type="bibr" rid="CR38">38</xref>)

fraction unbound in plasma	0.0700	(<xref ref-type="bibr" rid="CR22">22</xref>)

fraction unbound in brain	0.034	(<xref ref-type="bibr" rid="CR19">19</xref>)

Human cerebral blood flow (l/h)	36.0	(<xref ref-type="bibr" rid="CR24">24</xref>)

Human brain extravascular volume (l)	1.4	(<xref ref-type="bibr" rid="CR23">23</xref>)

Human brain vascular volume (l)	0.150	(<xref ref-type="bibr" rid="CR23">23</xref>)

CLbev (l/h)	11.3	–c

CL/F clearance; Ka absorption rate constant; V/F central volume of distributionaPopulation mean (inter-individual variability as %CV)bIn vitro Ki value assumed as KdcCalculated as Papp* human brain endothelial surface area

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

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

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Vc / F (l)

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

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Parameter (unit)	Definition of parameter	Bootstrap

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Population parameter estimates for the final model

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

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

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

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

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

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

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

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

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

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

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

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

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

Residual variability (%)

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

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

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

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

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

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–Cl

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

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

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V d/F (L)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Kel (mean, SD) 1/h

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AUC0–t (ng/ml h)

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

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

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

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

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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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Tmax (h)

S3643 and Metabolites M344A, M314A, and M314B Observed from 0.25–24 h in Rat Plasma (Males and Females Combined, n = 8).

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

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Cmax

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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t½app, hours

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

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

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Tmax (h)

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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Cmax (μg/ml)

Summary of in vitro potency and in vivo pharmacokinetic parameters of spiroindolone analogs following single oral dosing at 25 mg/kg and i.v. dosing at 5 mg/kg to female CD-1 micea

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Compound<xref ref-type="table-fn" rid="T2F2"><italic>b</italic></xref>	IC50 (mean ± SD) (nM) for:
	Oral PK parameter<xref ref-type="table-fn" rid="T2F3"><italic>c</italic></xref>
	i.v. PK parameter<xref ref-type="table-fn" rid="T2F4"><italic>d</italic></xref>

<named-content content-type="genus-species">P. falciparum</named-content> NF54 (<italic>n</italic> = 3)	<named-content content-type="genus-species">P. berghei</named-content> GFP ANKA PbGFPCON (<italic>n</italic> = 3)	<italic>C</italic>max (μg/ml)	<italic>T</italic>max (h)	AUC0–24 (μg · h/ml)	<italic>t</italic>1/2 (h)<xref ref-type="table-fn" rid="T2F3"><italic>c</italic></xref>	<italic>F</italic> (%)	<italic>V</italic>ss (liters/kg)	CL (ml/min/kg)	<italic>t</italic>1/2 (h)

(+)-1	13 ± 2.2	242 ± 124	1.2	0.25	1.3	0.7	13	0.9	49.7	0.4

(+)-2	5.6 ± 0.9	75 ± 32	0.6	1	2.9	4.3	62	9.9	92.6	4.6

(+)-3	5.6 ± 0.7	140 ± 54	0.7	2	5.8	6.2	91	13.7	60.1	4.3

(+)-4	5.9 ± 0.9	104 ± 53	1.0	0.25	3.9	5.6	26	1.9	24.0	4.7

(+)-5	4.3 ± 0.4	88 ± 26	3.1	0.25	17.7	4.0	47	1.6	11.8	3.8

(+)-6	0.33 ± 0.06	7.5 ± 2.5	3.1	2	26.8	3.2	53	1.6	8.5	2.9

(+)-7 (KAE609)	1.2 ± 0.2	26 ± 14	0.1<xref ref-type="table-fn" rid="T2F5"><italic>e</italic></xref>	1	1.0	8.7	44	2.1	9.7	3.4

0.25<xref ref-type="table-fn" rid="T2F5"><italic>e</italic></xref>	2	2.6	7.5	32

3.6	1	43.3	10.0	100

10.8<xref ref-type="table-fn" rid="T2F5"><italic>e</italic></xref>	24	186.9	9.4	100

(−)-6	105 ± 20	2,851 ± 897	5	2	68.2	7.9	78	2.8	4.2	13.2

(−)-7	210 ± 19	4,908 ± 1,445	8.3	1	107.3	9.1	92	1.3	2.6	5.6

aIC50s were determined at least three times in independent assays (16 h + 8 h of incubation periods, as indicated in Materials and Methods). i.v., intravenous.bThe data in parentheses indicate whether the compound is the (+) or (−) optical isomer.cCmax, maximum concentration of drug in plasma; Tmax, time to Cmax; AUC0–24, area under the concentration-time curve from 0 to 24 h; t1/2, elimination half-life; F, oral bioavailability.dVss, volume of distribution at steady state; CL, total systemic clearance.eDose proportionality PK for KAE609 at 1.5 mg/kg, 5.6, and 105 mg/kg for Cmax values of 0.1, 0.25, and 10.8, respectively, using the formulation 1.1 equimolar 1 N HCl, 5 % Solutol HS15 in 50 mM (pH 3) citrate acid buffer.

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C max, ng/mL

Summary of irinotecan and SN‐38 pharmacokinetics parameters by nal‐IRI dose regimen in NAPOLI‐1

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Analyte	Pharmacokinetic parameter<xref ref-type="fn" rid="cpt720-note-0005">a</xref>

70 (80) mg/m2
<break/>
Q2W<xref ref-type="fn" rid="cpt720-note-0006">b</xref>

100 (120) mg/m2
<break/>
Q3W<xref ref-type="fn" rid="cpt720-note-0006">b</xref>

Total irinotecan	Cavg, mg/L	1.19 (0.91–1.55)	1.66 (1.33–2.05)

<italic>C</italic>
max, mg/L	26.6 (24.1–29.3)	41.5 (39.8–43.2)

Clearance, L/week	13.3 (9.17, 22.8)

Volume, L	4.58 (4.14, 4.99)

First‐phase t1/2, h	38.2 (23.2–56.7)

Terminal t1/2, h	12200 (3990–50200)

Total SN‐38	Cavg, ng/mL	0.721 (0.667–0.778)	0.870 (0.821–0.922)

<italic>C</italic>
max, ng/mL	2.64 (2.47–2.83)	3.99 (3.77–4.23)

Clearance, L/week	14.0 (12.7–14.6)

Terminal t1/2, h	38.2 (36.5–41.9)

Unencapsulated SN‐38	Cavg, ng/mL	0.589 (0.543–0.639)	0.702 (0.661–0.745)

<italic>C</italic>
max, ng/mL	2.07 (1.93–2.23)	3.05 (2.89–3.21)

tuSN38>thr, weeks (first 6 weeks, based on actual doses)	4.77 (4.59–4.95)	4.28 (4.12–4.44)

tuSN38>thr, weeks (first 6 weeks, based on simulated doses)	5.71 (5.64–5.79)	4.80 (4.69–4.92)

Cavg, average concentration; C max, maximum concentration; tuSN38>thr, time uSN38>threshold.aFor Cavg, Cmax, and tuSN38>thr, median values and 95% prediction intervals (representing interpatient variabilities) were obtained from NAPOLI1 patients; for Clearance, Volume, and t1/2, median values and 95% confidence intervals (representing precision of parameter estimates) were obtained from bootstrapping.bDose is given based on irinotecan free base with the original protocol dose (based on irinotecan hydrochloride trihydrate) is in parentheses.

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AUC(0–24) (µg h/ml)**

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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t ½ (h)

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

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

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

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

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

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

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

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

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

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

 <italic>C</italic>
max
	1.02 (0.98–1.06)	1.08 (1.02–1.15)	1.04 (1.01–1.07)	1.07 (1.01–1.13)

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

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Va/F (mL/kg)

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)

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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}
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				\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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Central volume of distribution of morphinea

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AUC 0 - ∞ (min. μmol/L)

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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μ

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Tmax (h)

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Amount of acetonitrile (%)

Dependence of amisulpride retention on the amount of acetonitrile in the mobile phase

AMS amisulpride, IS internal standard (metoclopramide)

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CSS/Dose (ng/mL/mg)

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

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

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

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

CL (L/h)	39 ± 11	39 ± 11	28 ± 9

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

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F

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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Cmax (ng/mL)

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

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

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MRTpo (h)

Effect of food and parasite infection on the oral absorption of N-251 in mice

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Conditions	Pharmacokinetic parameters

<italic>C</italic>max (ng/mL)	<italic>T</italic>max (h)	AUCpo (ng/mL·h)
<italic>F</italic>
	MRTpo (h)

Normal-fasted (control)	1677.33 ± 811.23	2	3768.25	0.2277	2.46

Infected-fasted	1767.17 ± 1649.75	2	3273.35	0.1978	2.45

Normal-fed	952.50 ± 332.49	1.5	2282.17	0.1379	3.01

The Cmax with SD and Tmax were the observed values. AUC and MRT were calculated from 0 to infinity using the trapezoidal rule. F was calculated utilizing the AUC value of 2433.64 ng/mL·h after the intravenous administration of 10 mg/kg

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AUC0‐inf (ng·h/mL)

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

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

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MRT

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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Cmax

Pharmacokinetic variability in single‐dose (SD) and steady‐state (SS) studies of 13 beta‐adrenergic blocking agents

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Drug	Study type	CV parameter	Doses (mg)	CV 0%‐20%	CV 20%‐40%	CV 40%‐60%	CV 60%‐80%	CV > 80%	References (Supplementary Materials)

Atenolol	SD	Cmax
	25‐200	5	20	10	1
35‐56

 	 	AUC	25‐200	8	23	4	 	1
35‐56

 	SS	Cmax
	25‐100	1	4	2
37,57‐60

 	 	AUC	50‐100	1	3
37,58‐60

Betaxolol	SD	Cmax
	20	 	1
61

 	 	AUC	20	 	1
61

 	SS	Cmax
	20	1
62

 	 	AUC	20	 	1
62

Bisoprolol	SD	Cmax
	5‐100	10	2
63‐70

 	 	AUC	5‐40	7	3
64‐69

 	SS	Cmax
	10	 	2
71,72

 	 	AUC	10	 	2
71,72

Carvedilol	SD	Cmax
	6,25‐128	1	 	5	6	1
73‐81

 	 	AUC	6,25‐128	2	 	4	6
73‐76,78‐81

 	SS	Cmax
	25	 	 	1
73

 	 	AUC	25	 	 	1
73

Labetalol	SD	Cmax
	100‐400	4	2	8	2
55,82‐86

 	 	AUC	100‐200	3	6	4	1
55,82,84‐86

 	SS	Cmax
	400	 	2
87

 	 	AUC	100‐400	 	3	 	1
87‐89

Metoprolol	SD	Cmax
	25‐200	1	9	24	6	5
38,65,90‐118

 	 	AUC	25‐200	1	7	18	11	12
38,65,91‐123

 	SS	Cmax
	50‐400	2	13	19	9	6
17,58,124‐141

 	 	AUC	50‐400	3	5	12	6	14
17,58,119,126‐131,133‐141

Nadolol	SD	Cmax
	30‐120	 	2	3
142‐144

 	 	AUC	30‐80	 	5	1
142‐145

 	SS	Cmax
	10‐80	2	1	2
143,146

 	 	AUC	10‐80	 	3	3
143,145,146

Nebivolol	SD	Cmax
	5‐10	1	1	8	1
147‐154

 	 	AUC	5‐10	1	2	 	2	6
147‐154

 	SS	Cmax
	20	 	 	1
155

 	 	AUC	20	 	 	 	1
155

Oxprenolol	SD	Cmax
	80‐260	2	1
156,157

 	 	AUC	80‐260	2	1	1
122,156,157

 	SS	Cmax
	160	 	1	2
126,158

 	 	AUC	160	 	1	2
126,158

Pindolol	SD	Cmax
	5‐30	4	5	1	 	2
159‐165

 	 	AUC	5‐30	4	4	1	 	2
159‐165

 	SS	Cmax
	1‐5	 	2	4
166,167

 	 	AUC	1‐15	 	3	3	1
166‐168

Propranolol	SD	Cmax
	0,5‐320	3	8	29	7	4
38,42,51,70,93,95,169‐191

 	 	AUC	0,5‐320	3	15	23	8	9
38,42,51,93,95,169‐186,188‐198

 	SS	Cmax
	40‐180	 	5	11	6
59,62,128,171,180,188,199‐209

 	 	AUC	40‐180	 	3	23	8	5
59,62,128,166,171,180,188,195,197,199‐214

Sotalol	SD	Cmax
	40‐320	9	4	1
215‐220

 	 	AUC	40‐320	10	4
215‐220

 	SS	Cmax
	160‐320	1	 	 	 	1
218,221

 	 	AUC	80‐400	4	 	1
217,218,221,222

Timolol	SD	Cmax
	10‐120	1	3	1	1
223‐225

 	 	AUC	0,4‐60	 	2	2	3
142,193,223‐225

Cmax maximum serum concentration, AUC area under the concentration‐time curve.

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k01 t1/2 (h)

Pharmacokinetics of oral administration of 5 μg/kg misoprostol in five horses

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Tmax (h)	0.39 ± 0.04	k01 t1/2 (h)	0.12 ± 0.04

Cmax (ng/mL)	0.29 ± 0.07	k10 t1/2 (h)	0.67 ± 0.20

k01 (per h)	6.27 ± 1.57	AUC0−∞ (h ng/mL)	0.40 ± 0.12

k10 (per h)	1.10 ± 0.31	Vd/F	12.49 ± 2.38

Cl/F	224.84 ± 59.89

Data represent five different horses. Tmax, time to maximum concentration; Cmax, maximum concentration; k01, first‐order absorption rate constant; k10, first‐order elimination rate constant; k01 t1/2α, half‐life of absorption; k10 t1/2, half‐life of elimination; AUC0−∞, area under the concentration–time curve extrapolated to infinity; Vd/F, apparent volume of distribution dependent on bioavailability; Cl/F, clearance dependent on bioavailability.

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Vd (L/kg)

Pharmacokinetic profile of NAT after intravenous administration in NZ rabbit.

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Parameters	Estimates

<italic>C</italic>0 (ng/mL)	537±322

AUC0−<italic>∞</italic> (h*ng/mL)	162±55

<italic>t</italic>1/2 (h)	1.4±0.4

<italic>V</italic><italic>d</italic> (L/kg)	8.3±2.8

Cl (L/h/kg)	6.6±1.9

Abbreviation: C0: concentration at time zero, AUC: area under the curve from 0 to ∞, Vd: volume of distribution, Cl: clearance, t1/2: terminal half-life, n=3.

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AUC0–∞ (h · ng/ml)

Bioequivalence analysis of artesunate, dihydroartemisinin, pyronaridine, primaquine, and carboxyprimaquine after pyronaridine-artesunate and primaquine were administered as single oral doses alone or in combination

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Parameter<xref ref-type="table-fn" rid="T4F1"><italic>a</italic></xref>	Geometric mean ratio (% [90% confidence interval]) for:

Artesunate (<italic>n</italic> = 15)	Dihydroartemisinin (<italic>n</italic> = 15)	Pyronaridine (<italic>n</italic> = 15)	Primaquine (<italic>n</italic> = 15)	Carboxyprimaquine (<italic>n</italic> = 15)

<italic>C</italic>max (ng/ml)	120 (76.8–188)	109 (87.3–137)	101 (91.4–112)	130 (117–146)	109 (104–115)

AUC0–last (h · ng/ml)	101 (89.3–114)	110 (104–116)	101 (95.9–106)	115 (107–125)	104 (98.6–111)

AUC0–∞ (h · ng/ml)	101 (89.5–114)	110 (104–116)	99.3 (93.9–105)	115 (106–124)	98.1 (93.0–104)

aCmax, maximum observed plasma or whole-blood concentration after oral administration; AUC0–last, observed area under the plasma or whole-blood concentration-time curve from zero time to last observed concentration; AUC0–∞, predicted area under the plasma or whole-blood concentration-time curve after the last dose from zero time to infinity.

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Cmax

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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AUC(0-t) (mg·h/L)

Pharmacokinetic parameters of 4-O-methylhonokiol after oral administration of 4-O-methylhonokiol (0.6 mg/kg) (n =6)

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Parameters	Mean ± SD

Cmax(mg/L)	1.37 ± 0.23

<italic>t</italic>max (h)	0.85 ± 0.12

t 1/2u (h)	0.35 ± 0.05

CL/F (LIb/kg)	0.17 ± 0.03

Ka(l/h)	3.47 ± 0.58

AUC(0-t) (mg·h/L)	3.46 ± 0.61

AUC(0-∞) (mg·h/L)	3.56 ± 0.64

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CL/Fb, 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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θCL/F, Strong CYP3A4 inhibitor

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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CL/F (mL/min)

Summary of Methotrexate (MTX) Plasma Pharmacokinetic Parameters after Administration of Methotrexate Along (i.e., Day 1) and after Co-Administration of Methotrexate and Apremilast (i.e., Day 8)

N, number of subjects; CV, coefficient of variation; Cmax, maximum observed plasma concentration; tmax, time to maximum plasma concentration; t1/2, estimate of the terminal elimination half-life in plasma; AUC0–t, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration; AUC0–∞, area under the plasma concentration-time curve from time 0 extrapolated to infinity; CL/F, apparent total plasma clearance when dosed orally; Vz/F, apparent total volume of distribution when dosed orally; NA, not applicable.aArithmetic mean when appropriate (i.e., N > 1).btmax is summarized by median and range (minimum to maximum), when appropriate.cMean excludes data with R2 < 0.9.dMedian difference (“MTX + Apremilast” − “MTX”).e90% CI of the median difference are from Hodges–Lehmann Estimate.fP-value is from Wilcoxon signed-rank test.

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T1/2λz (h)

Comparative mean (±SD) kinetic parameters of (−) ABZ-SO and (+) ABZ-SO in goats and sheep following subcutaneous administrations at dose rates of 5, 10 and 15 mg/kg (n = 8)

T 1/2λz terminal half-life; T max time to reach peak plasma concentration; C max peak plasma concentration; AUC last area under the (zero moment) curve from time 0 to the last detectable concentration; MRT last mean residence time*Differences between the enantiomers in the same animals and dose rates (P < 0.05)

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tmax (h)a

Pharmacokinetic parameters of ciprofloxacin in plasma after a single dose of ciprofloxacin dry powder for inhalation (32.5 mg ciprofloxacin; n = 6)

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Parameter	Geometric mean/%CV	Range

Primary pharmacokinetic parameters

AUC∞ (μg·h/L)	354.4/30.3	209.7–458.0

<italic>C</italic>max (μg/L)	56.42/32.2	30.65–72.84

<italic>t</italic>max (h)a	0.625	0.250–1.500

<italic>t</italic>½ (h)	9.538/19.7	7.320–12.91

MRT (h)	10.68/14.8	8.823–13.34

Secondary pharmacokinetic parameters

AUCnorm (kg·h/L)	0.8645/41.8	0.4517–1.378

AUC/<italic>D</italic> (h/L × 10−3)	10.90/30.3	6.453–14.09

<italic>V</italic>z/<italic>F</italic> (<italic>L</italic>)	1,262/33.2	950.7–1,969

CL/<italic>F</italic> (L/h)	91.71/30.3	70.97–155.0

%CV geometric coefficient of variation, AUC∞ area under the plasma concentration–time curve from time zero to infinity after a single dose of study drug, AUC/D AUC divided by dose (mg), AUCnorm AUC divided by dose per kg body weight, CL/F apparent total clearance from plasma after non-intravenous administration, Cmax maximum plasma concentration, MRT mean residence time, t½ terminal elimination half-life, tmax time to reach maximum drug concentration in plasma after a single dose, Vz/F apparent volume of distribution during terminal phase after non-intravenous administrationaMedian (range)

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PSdif,inf,h

Initial Range and Theoretical Lower Limit of Parameters for CNM

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A. Common parameters

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

 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

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

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

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

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

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

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

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

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

B. Irinotecan parameters

Parameter	Unit	Value	Theoretical lower limit

 PSdif,inf,h
	L/kg	0.1 ~ 100	0

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

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

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

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

 CLbile
	L/h/kg	0.1 ~ 100	0

 PSdif,eff,ent
	L/h/kg	0.1 ~ 100	0

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

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

C. SN-38 parameters

Parameter	Unit	Value	Theoretical lower limit

 1/fglu
e
	-	1.1 ~ 10	1

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

D. SN-38G parameters

Parameter	Unit	Value	Theoretical lower limit

 kdec
	/h	0.06 ~ 6	0

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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Cmax (ng/mL)

Summary statistics: oxycodone PK parameters

aAQ parameters are calculated from Cmax/Tmax values separately determined for each subject and then summarized for all individuals within the respective treatment group.bDue to fluctuations in plasma concentrations at later time points, AUCINF and T1/2 could be accurately derived only for 31 DETERx IN subjects and 29 DETERx PO subjects.AQ = abuse quotient; AUCINF = area under the plasma concentration-time course profile from time 0 (dosing) to infinity; AUClast = area under the plasma concentration-time course profile from time 0 (dosing) to last quantifiable concentration; Cmax = maximum observed plasma concentration; CV = coefficient of variation; IN = intranasal; IR = immediate-release; max = maximum; mL = milliliter; N = number of observations; ng = nanogram; OXY = oxycodone; PK = pharmacokinetic; PO = per os; SD = standard deviation; Tmax = time from dosing to maximum observed concentration; T1/2 = terminal elimination half-life.

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

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

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V ss (L)

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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C max (μM)

PK parameters of NP046

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CLM,NR (L/hr)a

Individual parameter and exposure estimates stratified by disease status

Values are expressed as median (range).NASH, nonalcoholic steatohepatitis; M3G, morphine‐3‐glucuronide; VM3G, central volume of distribution of M3G; VM, central volume of distribution of morphine; CLM,R, renal clearance of morphine; CLM,NR, non‐renal clearance of morphine; CLM3G, systemic clearance of M3G; AUCM, area under the concentration time curve of morphine in serum; AUCM3G, area under the concentration time curve of M3G in serum.aCLM (total systemic clearance of morphine)= CLM,R (renal clearance of morphine) + CLM,NR (non‐renal clearance of morphine).bSingle dose area under the concentration versus time curve for morphine (AUCM,0‐∞) and M3G (AUCM3G,0‐∞) were estimated using model‐derived parameters and according to the following equations:  AUCM,0−∞=(DOSECLM) AUCM3G,0−∞=(fM3G∗CLMCLM3G)∗AUCM,0−∞ where the fraction of the morphine dose metabolized to M3G was assumed to be 1.

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ω2 V/F

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IIV CL/F (%)

Nevirapine parameter estimates and standard errors obtained from the basic population pharmacokinetic model and the final pharmacokinetic/pharmacogenetic model (n = 180)a

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Parameter (unit)	Basic model
	Final model

Estimate	RSE<italic><xref ref-type="table-fn" rid="TF1-2">b</xref></italic> (%)	Estimate	RSE<italic><xref ref-type="table-fn" rid="TF1-2">b</xref></italic> (%)

CL/F (liters/h)	2.74	3.76	3.02	4.44

<italic>V/F</italic> (liters)	113	23.2	114	22.8

<italic>ka</italic> (h−1)	0.569	26.7	0.578	26.1

IIV CL/F (%)	33.5	26.9	33.2	27.4

IOV CL/F (%)	34.9	23.3	31.8	24.2

Covariates

    θ1
<italic>CYP2B6</italic> 983TT/516TT	−0.696	36.6

    θ2
<italic>CYP2B6</italic> 983TC/516GG or GT	−1.08	22.3

Residual error

    Proportional (%)	13.1	17.0	13.1	17.0

aAbbreviations: CL/F, apparent oral clearance of nevirapine (basic model) or apparent oral clearance of nevirapine in patients with reference genotype wt983T>C/wt or het516G>T (final model); V/F, apparent volume of distribution; ka, absorption rate constant; IIV, interindividual variability; IOV, interoccasion variability; RSE, relative standard error; SE, standard error; θ1, absolute change in CL/F for CYP2B6 983TT/516TT genotype compared to reference genotype (CYP2B6 983TT/516GG or GT); θ2, absolute change in CL/F for het983T>C/wt or het516G>T genotype compared to reference genotype.bRSE = (SEestimate/estimate) × 100.

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β (h-1)

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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h


t1/2 (h)

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

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AUC0–t (h.ng ml−1)

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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AUC0–∞, μg × hr/ml

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

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

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CL/F (L/h)

Final parameter estimates describing the piperaquine population pharmacokinetics in women with uncomplicated P. falciparum malaria

Coefficient of variation (%CV) for between-subject variability (BSV) and (†) between occasion variability (BOV) were calculated as the [exp(estimated variance)-1]1/2. Relative standard errors (RSE) and the 95% confidence intervals (CI) were based on 868 successful stratified bootstrap runs (out of 1000) and presented as 100×(standard deviation/mean value) and as 2.5 to 97.5 percentiles, respectively.CL/F is the apparent elimination clearance. Vc/F is the apparent volume of distribution of the central compartment. Q1/F and Q2/F is the inter-compartment clearance between the central and first and second peripheral compartment, respectively. VP1/F and VP2/F is the apparent volume of distribution of first and second peripheral compartment, respectively. MTT is the mean transit time of the absorption model. RUV is the variance of the residual variability. No. of trans comp is the number of transit compartments used in the absorption phase. F represents the relative bioavailability.

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Tmax c, hr

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

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

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

<italic>BUP</italic>

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

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

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

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

<italic>NorBUP</italic>

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

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

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

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

<italic>NAL</italic>

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

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

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

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

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

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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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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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Protein binding (%)a

Mean (±standard deviation) non-compartmental pharmacokinetic parameters of telavancin and the excipient hydroxypropylbetadex in subjects with varying degrees of renal function (see Table 1 for definitions CLcr (ml/min) from study A and eGFR (ml/min/1.73 m2) from study B)

The CL reported for ESRD is the CL for the subjects (i.e., includes residual clearance and any dialysis clearance) AUC area under concentration-time curve, ESRD end-stage renal disease, C max maximum plasma concentration, CL clearance, CL cr creatinine clearance, t ½ terminal elimination half-life, V ss apparent volume of distribution at steady state aStudy A only

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Heart rate AUEC0-1.5h [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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AUC0–24 (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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Cmax (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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CL/F (liters/h)

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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k (h−1)

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

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C168h, IU/mL*

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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Dose-normalized b  Cmax (μg/mL)

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

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 	Mean values ± SD (range)

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

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

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

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

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

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

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

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AUC0-τ, ng•h/ma

Pharmacokinetic parameters of TAK-285 after multiple-dose administration

AUC 0-τ area under the plasma concentration-time curve from time zero to the end of the dosing interval; BID twice daily; C max maximum plasma concentration; NA not applicable; PTR peak-trough ratio; QD once daily; R ac accumulation ratio; T max time of first occurrence of Cmax  aGeometric mean (% coefficient of variation) bMedian (range) cMean (standard deviation) d n = 4 e n = 8 f n = 6

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fraction unbound in brain

Population Pharmacokinetic Parameters, Passive Membrane Permeability, Physiological Parameters and In Vitro Binding Values Used for the Simulations

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Parameter	Values used in human D2RO Simulations	Source

CL/F (l/h)	19.5 (58)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

V/F (l)	1,150 (75)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

Ka (h−1)	0.600 (32)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

koff (h−1)	2.34	(<xref ref-type="bibr" rid="CR37">37</xref>)

Kd (nM)	5.10b	(<xref ref-type="bibr" rid="CR38">38</xref>)

fraction unbound in plasma	0.0700	(<xref ref-type="bibr" rid="CR22">22</xref>)

fraction unbound in brain	0.034	(<xref ref-type="bibr" rid="CR19">19</xref>)

Human cerebral blood flow (l/h)	36.0	(<xref ref-type="bibr" rid="CR24">24</xref>)

Human brain extravascular volume (l)	1.4	(<xref ref-type="bibr" rid="CR23">23</xref>)

Human brain vascular volume (l)	0.150	(<xref ref-type="bibr" rid="CR23">23</xref>)

CLbev (l/h)	11.3	–c

CL/F clearance; Ka absorption rate constant; V/F central volume of distributionaPopulation mean (inter-individual variability as %CV)bIn vitro Ki value assumed as KdcCalculated as Papp* human brain endothelial surface area

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CL (L/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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AUC0-∞ (h · ng/ml)

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Cmax, ng/mLa

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AUC0-last (ng·h/mL)

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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CL/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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Cmax (ng/mL)

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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Apparent terminal T½ d , f, hr

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Cmax (dn), ng/mL/mg

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

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

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CL (L/h)

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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Cmax, ng/mL

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

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

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

Arithmetic mean	129	1050	9.23

Arithmetic mean CV%	62	86

Median	103	4	1050	9.23

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

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

Arithmetic mean	727	13 300	20

Arithmetic mean CV%	79	106	68

Median	444	2.47	5220	27.5

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

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

Arithmetic mean	1940	15 800	16 900	12.6

Arithmetic mean CV%	54	58	54	54

Median	1480	1.92	12 900	14 700	10.9

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

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

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If Weight 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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CL (L/min)

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

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

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

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

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

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

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

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

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

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

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

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

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AUC(0,tlast) (μg ml−1 h)

Statistical comparison of primary pharmacokinetic endpoints between MSB11022 and reference products

AUC(0,∞), area under the concentration–time curve from time 0 extrapolated to infinity; AUC(0,t last), AUC from time 0 to the last quantifiable concentration; CI, confidence interval; C max, maximum observed concentration; EU‐RMP, Europe‐approved reference medicinal product; LS, least‐squares; US‐RP, US‐licensed reference product.

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AUC (μg × h/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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C24 (pg/mL)

Effect of FTR 600 mg ER BID on dose‐normalized buprenorphine PK

AUCτ, area under the plasma concentration–time curve over the dosing interval; BID, twice daily; C24, concentration in plasma at 24 hours; Cmax, maximum concentration in plasma; CI, confidence interval; ER, extended release; FTR, fostemsavir; GMR, geometric mean ratio; PK, pharmacokinetics; Tmax, time to maximum plasma concentration.Median (range) Tmax for Treatment C and Treatment D: buprenorphine (1.0 h [1.0–2.0] and 2.0 h [1.0–2.0]); norbuprenorphine (2.0 h [1.0–2.0] and 2.0 h [1.0–4.0]).aMR‐AUCτ, ratio of metabolite AUCτ to parent AUCτ corrected for molecular weight, for norbuprenorphine to buprenorphine presented as geometric mean (coefficient of variation, %).

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