t max (h)b

Summary of amenamevir pharmacokinetic parameters after administration of a single 400-mg dose of amenamevir alone and with ketoconazole at a dosage of 400 mg once daily or rifampicin at a dosage of 600 mg once daily

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Parameter	Study

15L-CL-008	15L-CL-009

Amenamevir alone (<italic>n</italic> = 22)	Amenamevir + ketoconazole (<italic>n</italic> = 22)	Amenamevir alone (<italic>n</italic> = 22)	Amenamevir + rifampicin (<italic>n</italic> = 22)

AUCinf (ng h/mL)a
	19,917 ± 5561	51,483 ± 12048	18,658 ± 4935	3115 ± 930

<italic>C</italic>
max (ng/mL)a
	1448 ± 329	1886 ± 448	1325 ± 282	563 ± 218

<italic>t</italic>
max (h)b
	4.0 (1.0–5.0)	4.0 (3.0–6.0)	3.0 (0.5–5.0)	1.75 (1.0–5.0)

<italic>t</italic>
½ (h)	8.1 ± 1.9	17.5 ± 2.9	8.0 ± 1.2	2.9 ± 0.6

CL/F (L/h)	20.8 ± 5.9	8.0 ± 2.1	22.1 ± 5.9	133.5 ± 40.0

LS GMRc
	Amenamevir + ketoconazole vs amenamevir alone	Amenamevir + rifampicin vs amenamevir alone

 AUCinf
	2.58 (2.32–2.87)	0.17 (0.15–0.19)

 <italic>C</italic>
max
	1.30 (1.17–1.45)	0.42 (0.37–0.49)

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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CL/F (LIb/kg)

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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Distribution volume: 32.7 (8.6) l/kg.

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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AUC (h μg ml−1)

Biophysical and in vivo murine PK data of PASylated proteins

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

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Summary of goodness-of-fit based on the minimum value of objective function (MVOF), of eight assumptions within the modeling of L-DOPA in plasma and brainECF.

The assumption 'NONE' is where all parameters were estimated.V = volume of distribution, Q = inter-compartmental clearance, k = elimination rate constant

Q


IC50 (mean ± SD) (nM) for:

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

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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t ½ [h; mean ± SD]

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

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Parameter	Clopidogrel	H3	H4 (active)	CLPM

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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AUC0-tlast [ng*hr/L]

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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θV/F, weight

Parameter estimates in the final population pharmacokinetic model

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

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

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

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

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

θV/F, weight
	Power	0.216	17.4	0.143	0.278

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

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

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

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

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

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

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

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

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

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

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

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

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

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

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Q/F (L h-1)

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

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Description	Estimate	RSE*	Bootstrap

Mean	95% CI

Ka (h–1)	2.85	8.7%	2.24	1.21 to 3.87

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

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

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

Vp/F (L)	168.	11.7%	175.9	135 to 239

ALAG1	0.877	4.7%	0.800	0.672 to 0.928

DRUG0 ON Ka	1.89	22.0%	2.00	1.23 to 2.88

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

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

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

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

WT ON Vc	0.579	25.7%	0.590	0.191 to 1.06

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

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

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

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

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

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

Prop-Error	0.216	5.0%	0.200	0.189 to 0.232

Add-Error	0.303	14.5%	0.300	0.215 to 0.382

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

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Ka (h–1)

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C max, μg/mL

Summary of pharmacokinetic parameters of durvalumaba

AUC0‐t, area under the concentration‐time curve from time zero to t; C max, maximum plasma concentration; CV, coefficient of variation; max, maximum; min, minimum; q2w, every 2 weeks; q3w, every 3 weeks; q4w, every 4 weeks; T max, time to C max.aPharmacokinetics analysis set.bAUC0‐14 for 1, 3 and 10 mg/kg, AUC0‐21 for 15 mg/kg, and AUC0‐28 for 20 mg/kg.

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Cmax/Db, ng/mL/mg

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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Plasma pharmacokinetic parameters of fexinidazole (single-dose studies)

Values are expressed as geometric mean (% coefficient of variation), except for t max which are median (range) AUC area under the plasma concentration–time curve, AUC last AUC from time zero to last measurable concentration, AUC ∞ AUC from time zero to infinity, C max maximum plasma concentration, F/FE food and formulation effect, FE food effect, S/F solution fasted, T/F tablet fasted, T/FD tablet fed (high-fat breakfast), T/FD1 tablet fed(Plumpy’Nut®), T/FD2 tablet fed (rice and beans), t ½β terminal elimination half-life, t max time to reach C max, SAD single ascending dose

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CL/F, L/h

Final population model estimates of pantoprazole

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

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Day 7 concn (μg/ml)c

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 (ng/mL)

Mean (SD) pharmacokinetic parameters for hydrocodone by treatment

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

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AUC(0-∞) (mg·h/L)

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Rdif,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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IIV−Vp/F

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Cmax, μg/mL

Plasma Pharmacokinetic Parameters for Omadacycline After a Single 300‐mg Oral Dose

Treatment A: participants fasted overnight (no food or drink except for water for at least 6 hours before dosing); a standard high‐fat (nondairy) meal was served 3 hours after dosing.Treatment B: a standard high‐fat (nondairy) meal was completed 4 hours before dosing.Treatment C: a standard high‐fat (nondairy) meal was completed 2 hours before dosing.Treatment D: a standard high‐fat meal including dairy was completed 2 hours before dosing.aMedian (minimum, maximum) values.bN = 30.

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Main pharmacokinetic parameters of oral tryptanthrin in KM mice.

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PK parameters	Unit	Value

AIC	–	−49.79

SBC	–	−47.36

V1_F	mL	343.89

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

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

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

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

AUC0–<italic>t</italic>	h μg/mL	9.38

AUC0–∞	h μg/mL	9.57

Alpha	1/h	1.19

Beta	1/h	0.30

Alpha_HL	h	0.57

Beta_HL	h	2.27

A	μg/mL	−208.93

B	μg/ml	2.60

CL_F	mL/h	204.58

<italic>T</italic>max	h	1.50

<italic>C</italic>max	μg/mL	3.13

MRT	h	3.06

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

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Major pharmacokinetic parameters of single i.v dose of 5 mg/kg DOX alone or in combination with 5 mg/kg of scutellarin (n = 8)

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AUC(0–12 h) day 7/11 (ng.h/mL)

Estimation of QC target inhibition in the CSF using plasma AUC

Abbreviations: QC, glutaminyl cyclase; CSF, cerebrospinal fluid; AUC, area under the concentration versus time curve; AUC0–12 h, area under the concentration versus time curve from time 0 h to the available and quantifiable sampling point closest to 12 h after dosing; t1/2, apparent terminal half-life; n, number of subjects; CV, coefficient of variation.NOTE. Doses administered as solutions under fasted conditions unless stated otherwise. Multiple doses administered twice daily (dose interval of 12 h). Geometric mean (CV%) data are presented and calculated/estimated values are presented in bold. Assumptions of model: AUC in CSF is 5% of that in plasma (CSF AUC = plasma AUC × 0.05); CSF mean concentrations defined as CSF AUC0–12h/12 h. CSF 3 h (max) and 12 h (min) concentrations were estimated by multiplying mean concentrations by 1.6 and 0.53, respectively. CSF target inhibition: Inhibition was calculated as %inhibition = 100×C/(Ki + C), where Ki = 29 nM and C is the concentration of PQ912 in the CSF.

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Parameter estimates of final dolutegravir population PK model

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

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Apparent terminal T½ d , g, hr

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CL/F (liters/h/kg)

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

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

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h


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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Tmax (h)

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

<!DOCTYPE html>
<colgroup><col align="center"/><col align="center"/><col align="center"/><col align="center"/></colgroup>

	<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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AUC0-7 (ng•h/mL)

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

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

C


ACTH

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

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

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CL/F, L/hr

Descriptive statistics for secondary PK parameters

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

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C max, day 1 (ng/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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AUC0‐ τ

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

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

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AUC0‐24, μg·h/mL

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MRTlast (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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V (L)

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

<!DOCTYPE html>

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

Mean	95 % CI	Mean	95 % CI

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

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

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

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

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

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

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AUC0–∞ (μg∙h/mL)

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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ESR, mm/hour

Clinical activity assessments in the multi dose phase at eight weeks

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

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ηka

Final population model estimates of pantoprazole

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

η

k

a


First pivotal

      0
      1
      2
      3
      4

      0
      Unnamed: 0_level_0
      Budesonide Cmax (pg/mL)
      Budesonide Cmax (pg/mL)
      Budesonide AUCt (h×pg/mL)
      Budesonide AUCt (h×pg/mL)

      1
      Unnamed: 0_level_1
      Mean (90% CI)
      Intra-subject CV (%)
      Mean (90% CI)
      Intra-subject CV (%)

      2
      Pilot
      Pilot
      Pilot
      Pilot
      Pilot

      3
      B/F Easyhaler (batch A)
      2030 (1744–2363)
      22
      4494 (4001–5048)
      17

      4
      B/F Easyhaler (batch B)
      1881 (1616–2190)
      nan
      4577 (4075–5141)
      nan

      5
      B/F Easyhaler (batch C)
      1841 (1582–2143)
      nan
      4955 (4411–5565)
      nan

      6
      Symbicort Turbuhaler
      1506 (1294–1753)
      nan
      3677 (3274–4130)
      nan

      7
      First pivotal
      First pivotal
      First pivotal
      First pivotal
      First pivotal

      8
      B/F Easyhaler
      1978 (1832–2135)
      34
      4867 (4618–5129)
      20

      9
      Symbicort Turbuhaler
      1543 (1430–1666)
      nan
      3881 (3683–4090)
      nan

      10
      B/F Easyhaler without CC
      2138 (1990–2298)
      30
      5403 (5144–5674)
      15

      11
      Symbicort Turbuhaler without CC
      1690 (1572–1816)
      nan
      4415 (4204–4637)
      nan

      12
      Second pivotal
      Second pivotal
      Second pivotal
      Second pivotal
      Second pivotal

      13
      B/F Easyhaler
      1709 (1599–1826)
      28
      4492 (4296–4697)
      17

      14
      Symbicort Turbuhaler
      1816 (1699–1940)
      nan
      4590 (4389–4799)
      nan

      15
      B/F Easyhaler without CC
      1966 (1824–2119)
      28
      5103 (4845–5376)
      16

      16
      Symbicort Turbuhaler without CC
      1875 (1739–2021)
      nan
      4937 (4687–5200)
      nan

      17
      Fourth study
      Fourth study
      Fourth study
      Fourth study
      Fourth study

      18
      B/F Easyhaler
      1823 (1661–2001)
      28
      4144 (3878–4428)
      20

      19
      Symbicort Turbuhaler (batch A)
      1730 (1576–1899)
      nan
      3787 (3544–4047)
      nan

      20
      Symbicort Turbuhaler (batch B)
      1996 (1818–2190)
      nan
      4242 (3970–4533)
      nan

Primary Pharmacokinetic Parameters of Formoterol After Single Dose of Two Inhalations of Budesonide/Formoterol Easyhaler 320/9 μg/Inhalation and Symbicort Turbuhaler Forte (PP Population)

B/F Easyhaler, budesonide/formoterol Easyhaler; CV%, coefficient of variation; mean, estimated geometric mean; 90% CI, the 90% confidence interval for the mean. Administration with concomitant charcoal except when separately mentioned (without CC).

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T1/2 (h)

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

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

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Cmax or C0 (μg/hr)

Pharmacokinetic parameters and incidence of anti-blisibimod antibodies in patients with systemic lupus erythematosus in the phase 1b study

Abbreviations: AR accumulation ratio, AUC 0-t plasma-concentration curve from time of treatment to the last measurable concentration, C max maximum observed serum concentration, C 0 estimated initial concentration after IV bolus dosing, CL clearance (CL), CL/F apparent clearance, IV intravenous, NA not applicable, NC not calculated, SC subcutaneous, SD standard deviation, t 1/2,z half-life, t max time to Cmax

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Kidneys

      0
      1
      2

      0
      Tissue
      Blood flow (ml/min)
      Weight or volume (g or ml)

      1
      Brain
      700
      1400

      2
      Muscle
      750
      35000

      3
      Kidneys
      1240
      310

      4
      Liver
      1450
      1800

      5
      Gut
      1100
      1650

      6
      Lungs
      5600
      1000

      7
      Remainder
      360
      24290

      8
      Arterial blood
      –
      1000

      9
      Venous blood
      –
      3550

CAPTION: Parameters for the PBPK model of LSF used for simulations of pharmacokinetics and tissue distribution of this compound in a 70-kg human subject (Brown et al. 1997; Davies and Morris 1993)
FOOTER: []

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2nd Intercompartmental clearance of morphinea

Population parameter estimates for the final model

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

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

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

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

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

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

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

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

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

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

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

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

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

Residual variability (%)

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

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

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

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

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

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AUC(0-∞) ng-hr/mL

Doxorubicin and doxorubicinol pharmacokinetics (geometric mean+/−standard error)

<!DOCTYPE html>

<bold>Doxorubicin</bold>

<bold>Doxorubicinol</bold>

<bold>With enalapril</bold>

<bold>Without enalapril</bold>

<bold>With enalapril</bold>

<bold>Without enalapril</bold>

Cmax (ng/mL)	88.79 ± 0.30	79.96 ± 5.16	27.81 ± 3.59	29.66 ± 4.68

AUC(0-∞) ng-hr/mL	1185.56 ± 44.64	1167.73 ± 45.26	1040 ± 80.6	1056.32 ± 92.03

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Cmax (ng/mL)

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

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VM3G (L)

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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Lanabecestat AUC0–∞ (ng·h/mL)

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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Vd/F

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/F (L)*

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

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

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DRUG1 ON Vc/F

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

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

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Vss (L/kg)

Individual and mean toxicokinetic parameters of DON estimated from a two-compartment model in the plasma of seven pigs following intravenous administration of a single dose of 100 µg/kg.

A: extrapolated zero-time plasma DON concentration in the α phase; B: extrapolated zero-time plasma DON concentration in the β phase; α: distribution rate constant; β: elimination rate constant; t1/2: biological half-life of α (distribution) or β (elimination); AUCINF: area under the curve; Cl: clearance; MRTINF: mean residence time; Vss: volume of distribution at steady state. a: mean is a harmonic mean with its SD.

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Cmax,norm, 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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CLM3G (L/hr)

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V ss, mL/kg*

Pharmacokinetic endpoints

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Central volume of distribution of M3G

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Time min (Q95%)

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

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

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Cmax (ng/ml)

PHARMACOKINETIC PARAMETERS OF COMPOUNDS LM 13765 AND LM 13765-C

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

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t½ (h)

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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λz (1/h)

Mean (SD) pharmacokinetic parameters for hydrocodone by treatment

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

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AUC0–inf (ng h ml−1)

Pharmacokinetic parameters

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

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ka (h–1)

Parameter estimates of final dolutegravir population PK model

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

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Cmax, μg/dL

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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t1/2β (h)

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Intercompartmental clearance Q (L/day)

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

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

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Tmax (h)

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Tmax (h)

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

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

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Calcium removal rate, mmol/min (mg/min)

Pharmacokinetic data

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      0
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      Plasma water flow rate (ml/min)
      118 ± 11

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

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

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      Citrate mass removal (%)
      83 ± 5

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      Citrate half-life (min)
      60 ± 29

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

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

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

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

Pharmacokinetic data

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AUC0-1.5h [ng*hr/L]

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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Semimechanistic time‐varying CL modela [95% CI]

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tmax (h)*

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MDAPE

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      6
      7

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

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      Parameter (unit)
      Typical (median)
      Typical (median)
      Bias (%)
      Typical (median)
      Bias (%)
      Typical (median)
      Bias (%)

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      V P (L)
      5.11
      4.27
      16
      5.18
      −1.4
      8.16
      −60

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

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      V T1 (L)
      14.2
      16.2
      −14
      10.5
      26
      31.4
      −121

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

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      V T2 (L)
      189
      238
      −26
      231
      −22
      105
      44

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

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      MDPE
      −0.50
      −8.4
      −8.4
      −1.0 %
      −1.0 %
      −29.4
      −29.4

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      MDAPE
      12.1
      13.6
      13.6
      9.3 %
      9.3 %
      29.4
      29.4

CAPTION: 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)
FOOTER: 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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Mean T½—h (SD)

Summary of steady‐state pharmacokinetic parameters by treatment

†Calculation for the 168‐h dosing interval for SC TE and 336‐h dosing interval for IM TE. ‡n = 1 due to rising T levels at later time points in 13/14 patients. §Ratio of AUC0–168h of metabolite to AUC0–168h of T. ¶Reference range was defined as 300–1,100 ng/dL for T, 4–57.5 ng/dL for DHT, and 10–50 pg/mL for E2. AUC = area under the concentration–time curve; DHT = dihydrotestosterone; E2 = estradiol; IM = intramuscular; ND = not determined; PK = pharmacokinetic; SC = subcutaneous; SD = standard deviation; T = testosterone; TE = testosterone enanthate

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Vz/F (L/kg)

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

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

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t 1/2

Plasma pharmacokinetic parameters for canagliflozin and DPTQ in bile‐duct cannulated and intact dog

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Parameters	 	Canagliflozin	DPTQ	DPTQ‐O‐glucuronide

BDC	Intact	BDC	Intact<xref ref-type="fn" rid="prp2502-note-0004">
b
</xref>
	Intact

AUC0‐48 hr
	µmol/L*hr	15.7 ± 5.4	20.7 ± 3.7	5.89 ± 3.3	7.94 ± 2.5	2.61 ± 1.5

AUCinf
	µmol/L*hr	16.4 ± 5.9	21.2 ± 3.9	5.89 ± 3.3	NA	2.6 ± 1.7

<italic>t</italic>
1/2
	hr	10.9 ± 1.8	8.05 ± 0.62	2.50 ± 2.3	NA

<italic>V</italic>
dss
	L/kg	0.87 ± 0.28	0.72 ± 0.13	0.33 ± 0.07<xref ref-type="fn" rid="prp2502-note-0003">
a
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	1.48 ± 0.25

CL	mL/min/kg	1.32 ± 0.50	0.93 ± 0.18	4.43 ± 3.1	2.73 ± 1.2

NoteDogs were given canagliflozin and DPTQ at 0.5 mg/kg by IV bolus. Values were derived from plots shown in Figure 2. Results shown represent mean ± SD from four animals.a P < 0.01 compared to the parameters in intact animals.bThe elimination phase was flat and AUCinf was not extrapolated, the CL and V dss was CL0‐48 h and V dss 0‐48 hr

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NASF on CLM3G

Population parameter estimates for the final model

%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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V2 (L)

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Tmax (min)

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

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

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t1/2 (h)

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

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

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AUCinf (h · mg/liter)

AUCinf and AUC%ext for subjects with mild and moderate hepatic impairmenta

aAUCinf, area under the curve to infinity; AUC%ext, percent extrapolation. Values are rounded to the nearest decimal.

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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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AUC0‐t, d·μg/mLb

Summary of pharmacokinetic parameters of durvalumaba

AUC0‐t, area under the concentration‐time curve from time zero to t; C max, maximum plasma concentration; CV, coefficient of variation; max, maximum; min, minimum; q2w, every 2 weeks; q3w, every 3 weeks; q4w, every 4 weeks; T max, time to C max.aPharmacokinetics analysis set.bAUC0‐14 for 1, 3 and 10 mg/kg, AUC0‐21 for 15 mg/kg, and AUC0‐28 for 20 mg/kg.

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Tmax (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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CLcreatinine (mL/min)c

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      With rifampicin (n = 24)
      Without rifampicin (n = 22)
      P value or GMR estimate (90% CI) (n = 22)

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      AUC0–τ (mg/L × hour)
      15.4 (7.8–32.8)
      12.1 (8.1–21.6)
      1.28 (1.13–1.44)a

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      Cmax (mg/L)
      2.3 (1.25–5.22)
      2.0 (1.10–3.86)
      1.19 (1.03–1.38)a

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

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      CL/F (L/hour)
      36 (21–69)
      47 (34–73)
      <0.001b

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      V d/F (L)
      332 (201–681)
      310 (87–477)
      0.586b

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      t1/2 (hour)
      6.4 (4.2–17.2)
      4.6 (1.6–6.6)
      0.002b

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

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

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      CLcreatinine (mL/min)c
      110 (88–155)
      106 (74–148)
      0.005b

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      CL0–8 hour,renal (mL/min)d
      309 (90–625)
      332 (126–659)
      0.836b

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      CL0–8 hour,secretion (mL/min)d
      205 (–1–494)
      219 (52–533)
      0.777b

      12
      CL0–τ,secretion (mL/min)d
      212 (27–494)
      216 (52–533)
      0.856b

CAPTION: Comparison of steady‐state metformin pharmacokinetic parameters and renal elimination parameters with and without co‐administration of rifampicin
FOOTER: 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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Mean (SD) pharmacokinetic parameters for hydrocodone by treatment

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

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