t1/2, days

Pharmacokinetic parameters following single doses of RN317 or bococizumab in subjects with hypercholesterolemia receiving ongoing statin therapy

Data shown are geometric mean (coefficient of variation; %CV) for all parameters except for Tmax where median (min, max) is shown, and t1/2 where arithmetic mean ± SD is shown.*n is the number of subjects in the treatment group and contributing to the mean; N is the number of subjects with a well‐characterized terminal phase. AUCinf, area under the plasma concentration–time curve from time zero to infinity; Cmax, maximum concentration; NR, not reported where <3 subjects had reportable parameter values; SD, standard deviation; t1/2, terminal half‐life; Tmax, time to reach maximum concentration.

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AUC(0-∞) (mg·h/L)

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

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ω2 ka

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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VAS, Physician, global

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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AUMC (μg·min2/mL)

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}
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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}
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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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AUCt [ng·h/mL; mean ± SD]

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

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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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t max (h)

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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AUMC0 -∞ (μg · h2/mL)

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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AUClast (h µg/mL)

Mean pharmacokinetic parameters of SHS15 oligomers after intravenous administration of SHS15 at 1.00 g/kg in male Sprague Dawley rats.

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Cmax, μg/ml

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Vc (L)

Model Parameters for the Final Integrated Model

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

ADC

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

 Km (nmol/L)	0.959 (1.68)	––

 Vc (L)	0.0996 (2.6)	0.0118 (36.9)

 CLd (L/h)	0.00197 (1.9)	–

 Vp (L)	0.183 (8.7)	0.230 (25.4)

 λ [Weibull scale parameter]	1.51 (0.9)	–

 κ [Weibull shape parameter]	1.10 (0.6)	–

 Fmp	0.783 (2.2)	–

 Fmd	0.0242 (30.9)	1.78 (34.2)

MMAE

 CLm (L/h)	2.27 (8.3)	0.333 (20.2)

 Vm (L)	1.00 (0.3)	–

 CLmd (L/h)	23.0 (0.7)	–

 Vmp (L)	88.4 (4.8)	0.0670 (31.9)

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

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

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

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

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Predicted Exposures With Nivolumab 240 mg Q2W in Chinese Patients and 10 mg/kg Q2W in the Global Population

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Chinese Patients 240 mg Q2W (n = 314)<xref ref-type="fn" rid="jcph1432-tbl4-note-0002">a</xref>
	Global Population 10 mg/kg Q2W (n = 148)<xref ref-type="fn" rid="jcph1432-tbl4-note-0003">b</xref>

Predicted Exposure (µg/mL)	Geometric Mean	CV (%)	Geometric Mean	CV (%)	Difference in Geometric Means (%)

Cmin1
	20.7	24.1	53.6	27.5	−61.0

Cmax1
	71.2	18.9	178.0	25.2	−60.0

Cavg1
	32.4	18.3	85.7	22.0	−62.0

Cminss
	78.3	71.8	206.0	64.0	−62.0

Cmaxss
	152.0	44.7	393.0	39.6	−61.0

Cavgss
	101.0	58.1	268.0	52.3	−62.0

Cavg1 indicates postdose 1 time‐averaged serum concentration; Cavgss, time‐averaged serum concentration at steady‐state; Cmax1, postdose 1 peak serum concentration; Cmaxss, peak serum concentration at steady state; Cmin1, postdose 1 trough serum concentration; Cminss, trough serum concentration at steady state; CV, coefficient of variation; Q2W, every 2 weeks.aPredicted data for all Chinese patients in CheckMate 077 and 078 receiving nivolumab 3‐mg/kg (n = 294) or 240‐mg Q2W (n = 20) doses.bPredicted data for global patients receiving 10 mg/kg Q2W from global studies MDX‐1106‐01 and CA209‐003.

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