If Body surface area affect CL ?

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

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<bold>Hypothesis test</bold>

<bold>OBJ</bold>

<bold>ΔOBJ</bold>

<bold>P-value</bold>

<bold>Comments</bold>

Basic model	2206.3

If Gender affect CL ?	2205.0	-1.3	>0.05	NO

If Age affect CL ?	2097.6	-108.7	<0.01	YES

If Weight affect CL ?	2094.0	-112.3	<0.01	YES

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

If ALT affect CL ?	2204.8	-1.5	>0.05	NO

If AST affect CL ?	2204.8	-1.5	>0.05	NO

If CRE affect CL ?	2197.5	-8.8	<0.01	YES

If BUN affect CL ?	2205.6	-0.7	>0.05	NO

If GFR affect CL ?	2140.6	-65.7	<0.01	YES

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AUC0–∞/dose (h · μg/ml/[mg/kg])

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

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

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

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

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

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

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

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

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

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

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

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

AUC0–∞ (h · μg/ml)	61.4 (33.0–231)

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

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

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

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MTT (h)

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

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

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θk 10

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

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

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

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

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

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

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

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

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

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

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

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

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

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AUClast (h·ng/mL)

Liver Microsomal Stability and in Vivo Pharmacokinetic Properties of Selected Compoundsa

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 	% of parent compound
remaining at 60 min vs <italic>T</italic> = 0 min

 	human liver microsomes
	mouse liver microsomes
	mouse in vivo pharmacokinetics properties

compd	1 μM	10 μM	1 μM	10 μM	route of
administration (dose, mg/kg)	<italic>C</italic>max (ng/mL)	AUClast (h·ng/mL)	<italic>T</italic>1/2 (plasma) (h)	<italic>B</italic>/<italic>P</italic>

<bold>5a</bold> (TG4-155)	0.1	10.6	0.2	4.8	iv (3)	2400 ± 350	749 ± 24	0.45	0.3

ip (3)	738 ± 207	457 ± 64	0.58

<bold>5c</bold> (TG7-98)	20.9	24.0	18.3	13.0	nd	ND	ND	ND	ND

<bold>5d</bold> (TG6-10-1)	2.3	39.9	2.0	23.1	ip (5)	115 ± 44	453 ± 49	1.6	1.8

po (10)	248 ± 61	475 ± 60	1.8	1.6

<bold>5g</bold> (TG7-74)	0.8	5.8	0	0.2	nd	ND	ND	ND	ND

<bold>5h</bold> (TG7-76)	12.4	18.6	0.2	0.1	nd	ND	ND	ND	ND

<bold>5j</bold> (TG7-186)	0.4	21.4	0.1	51.7	nd	ND	ND	ND	ND

<bold>6a</bold> (TG8-4)	16.2	43.8	1.7	8.7	ip (5)	1510 ± 142	1050 ± 58	1.49	<0.1

po (10)	128 ± 23	197 ± 26	1.44	<0.1

<bold>6c</bold> (TG8-21)	58.5	70.4	7.1	19.3	ND	ND	ND	ND	ND

aMale or female C57Bl/6 mice were used for in vivo pharmacokinetic study. Formulation used: 5% DMA, 50% PEG400, and 45% saline for compound 5a; 10% DMSO, 50% PEG400, 40% sterile water for 5d; and 2.5% DMA, 12.5% propylene glycol, and 85% phosphate-buffered saline (pH 7.4) for 6a. DMA = N,N-dimethylacetamide. Cmax is the maximum observed concentration that occurs at Tmax. T1/2 is the terminal half-life. AUC = area under the curve from time zero to the time of the last measurable observation (AUClast). B/P = brain to plasma ratio, calculated from drug concentrations in plasma and brain tissue at 1 and 2 h. ND = not determined.

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CLR, mL/min

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

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

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Vd/Fb, L/m2

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

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

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AUC

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C max/dose, μ/mL·mg

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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Fluconazole elimination rate (1/hour)

Population pharmacokinetic parameter estimates

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Base model	Final model	Bootstrap <break/>(977/1000 successful)

Parameters	Population mean (%RSE)	Median (2.5 to 97.5 percentile)

 Elimination rate (1/hour)	0.0317 (13%)	0.0408 (15%)	0.0411 (0.0318 to 0.0558)

 Volume (L)	216 (22%)	233 (17%)	228 (167 to 312)

 Absorption rate (1/hour)	3.43 (fixed)	3.43 (fixed)	3.43 (fixed)

 Volume: age exponent	–	0.775 (13%)	0.780 (0.601 to 1.01)

 Elimination rate: creatinine clearance exponent	–	0.850 (24%)	0.842 (0.470 to 1.25)

 Fluconazole elimination rate (1/hour)	–	0.0268 (5%)	0.0267 (0.0234 to 0.0321)

Between-subject variability

 <italic>ωke</italic>2	0.219 (51%)	0.262 (40%)	0.256 (0.0858 to 0.590)

 <italic>ωV</italic>2	0.991 (27%)	0.329 (35%)	0.291 (0.0637 to 0.518)

Residual error	SD (%RSE)

 Additive (µg/L)	4.24 (14%)	3.69 (13%)	3.65 (3.16 to 4.14)

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Vss/F (mL/kg)

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

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

<inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
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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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Time min (Q90%)

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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MRT (h)

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

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

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

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

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

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

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

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

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

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

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

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

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

α (h-1)
	1.2 ± 0.0
	-
	-

β (h-1)
	9.2 ± 0.0
	-
	-

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

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

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

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

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MRT

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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Vc/F (L)

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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t1/2, h

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

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<col align="left" span="1"/><col align="center" span="1"/><col align="left" span="1"/><col align="center" span="1"/><col align="center" span="1"/><col align="center" span="1"/><col align="center" span="1"/><col align="center" span="1"/>

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

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

Arithmetic mean	129	1050	9.23

Arithmetic mean CV%	62	86

Median	103	4	1050	9.23

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

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

Arithmetic mean	727	13 300	20

Arithmetic mean CV%	79	106	68

Median	444	2.47	5220	27.5

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

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

Arithmetic mean	1940	15 800	16 900	12.6

Arithmetic mean CV%	54	58	54	54

Median	1480	1.92	12 900	14 700	10.9

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

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

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h


CLZnano

      0
      1
      2
      3
      4

      0
      Formulation
      Content (w/v %)
      Content (w/v %)
      Content (w/v %)
      Treatment

      1
      Formulation
      CLZ Microparticles
      MC
      DS
      Treatment

      2
      CLZmicro
      0.500000
      0.5
      0.2
      —

      3
      Milled-CLZMC
      0.500000
      0.5
      —
      Ball mill + Bead mill

      4
      Milled-CLZDS
      0.500000
      —
      0.2
      Ball mill + Bead mill

      5
      CLZnano
      0.500000
      0.5
      0.2
      Ball mill + Bead mill

CAPTION: Formulations of particle dispersions containing CLZ.
FOOTER: []

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C max

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

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

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

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

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

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

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

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

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

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

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

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

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a

x


AUC0-∞ (ng mL-1⋅h-1)

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

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F%

Ortho-fluoro and ortho-methyl (3-chloro-4,5-dialkoxybenzamido)benzoic acids.

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Potency and Selectivity
	PK

Compd	R1O	R2O	R3	RAR<italic>α</italic><break/><italic>rel</italic> EC50<xref rid="tblfn22" ref-type="table-fn">a</xref>	<italic>β</italic>/<italic>α</italic><break/>ratio <xref rid="tblfn23" ref-type="table-fn">b</xref>	<italic>γ</italic>/<italic>α</italic><break/>ratio<xref rid="tblfn23" ref-type="table-fn">b</xref>	LogDpH 7.4<xref rid="tblfn24" ref-type="table-fn">d</xref>	intrinsic Clint<xref rid="tblfn25" ref-type="table-fn">e</xref>
	rat pof

mouse	human	AUC	Cl	F%

<bold>53</bold>	iPrO	MeO	F	6.7	609	17,600	1.0	11	0.3	10,871	15	15

<bold>54</bold>	iPrO	EtO	F	1.1	487	6169	1.4	17.9	3.3	15,376	12	12

<bold>43</bold>	iPrO	iPrO	F	2.7	34	300	2.0	18.8	6.9	–	–	–

<bold>55</bold>	iPrO	MeO	Me	4.7c	241	509	1.3	10.6	1.5	–	–	–

<bold>44</bold>	iPrO	iPrO	Me	0.97	45	2947	2.3	26.2	15	77,670	5.4	66

<bold>56</bold>	iPrO	EtO	Me	1.6	200	11,000	1.8	37.6	5.3	70,765	7	40

<bold>57</bold>	EtO	iPrO	Me	7	286	1675	1.9	25.7	8.7	–	–	–

<bold>58</bold>	MeO	EtO	Me	33	210	>250	–	18.4	–	–	–	–

<bold>59</bold>	<inline-graphic xlink:href="fx15.gif"/>	EtO	Me	2.6	58	38,461	–	42.3	–	–	–	–

<bold>45</bold>	<italic>t</italic>BuO	<italic>t</italic>BuO	Me	0.64	13,200	128	2.9	36.2	28.7	–	–	–

F


Me

      0
      1
      2
      3
      4
      5
      6
      7
      8
      9
      10
      11
      12

      0
      Unnamed: 0_level_0
      Unnamed: 1_level_0
      Unnamed: 2_level_0
      Unnamed: 3_level_0
      Potency and Selectivity
      Potency and Selectivity
      Potency and Selectivity
      Unnamed: 7_level_0
      PK
      PK
      PK
      PK
      PK

      1
      Compd
      R1O
      R2O
      R3
      RARαrel EC50a
      β/αratio b
      γ/αratiob
      LogDpH 7.4d
      intrinsic Clinte
      intrinsic Clinte
      rat pof
      rat pof
      rat pof

      2
      Compd
      R1O
      R2O
      R3
      RARαrel EC50a
      β/αratio b
      γ/αratiob
      LogDpH 7.4d
      mouse
      human
      AUC
      Cl
      F%

      3
      53
      iPrO
      MeO
      F
      6.7
      609
      17600
      1.0
      11.000000
      0.3
      10871
      15
      15

      4
      54
      iPrO
      EtO
      F
      1.1
      487
      6169
      1.4
      17.900000
      3.3
      15376
      12
      12

      5
      43
      iPrO
      iPrO
      F
      2.7
      34
      300
      2.0
      18.800000
      6.9
      –
      –
      –

      6
      55
      iPrO
      MeO
      Me
      4.7c
      241
      509
      1.3
      10.600000
      1.5
      –
      –
      –

      7
      44
      iPrO
      iPrO
      Me
      0.97
      45
      2947
      2.3
      26.200000
      15
      77670
      5.4
      66

      8
      56
      iPrO
      EtO
      Me
      1.6
      200
      11000
      1.8
      37.600000
      5.3
      70765
      7
      40

      9
      57
      EtO
      iPrO
      Me
      7
      286
      1675
      1.9
      25.700000
      8.7
      –
      –
      –

      10
      58
      MeO
      EtO
      Me
      33
      210
      >250
      –
      18.400000
      –
      –
      –
      –

      11
      59
      nan
      EtO
      Me
      2.6
      58
      38461
      –
      42.300000
      –
      –
      –
      –

      12
      45
      tBuO
      tBuO
      Me
      0.64
      13200
      128
      2.9
      36.200000
      28.7
      –
      –
      –

CAPTION: Ortho-fluoro and ortho-methyl (3-chloro-4,5-dialkoxybenzamido)benzoic acids.
FOOTER: aRelative EC50.

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e


θk 01

θ

k


Half life [h]

Comparison of population median plasma profile and experimental plasma profile pharmacokinetics

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Parameters	Population median CPT-11 plasma conc- profile	CPT-11 experimental data	Predictive error (%)

AUC_tEnd [μmol*min/l]	1296.06	1504.96	13.88

Cmax μmol/l	9.86	11.6	15

Tmax [h]	1.5	1.56	3.846

Half life [h]	29.21	Infinity	__

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      0
      1
      2
      3
      4

      0
      Parameter
      Study
      Study
      Study
      Study

      1
      Parameter
      15L-CL-008
      15L-CL-008
      15L-CL-009
      15L-CL-009

      2
      Parameter
      Amenamevir alone (n = 22)
      Amenamevir + ketoconazole (n = 22)
      Amenamevir alone (n = 22)
      Amenamevir + rifampicin (n = 22)

      3
      AUCinf (ng h/mL)a
      19,917 ± 5561
      51,483 ± 12048
      18,658 ± 4935
      3115 ± 930

      4
      C max (ng/mL)a
      1448 ± 329
      1886 ± 448
      1325 ± 282
      563 ± 218

      5
      t 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)

      6
      t ½ (h)
      8.1 ± 1.9
      17.5 ± 2.9
      8.0 ± 1.2
      2.9 ± 0.6

      7
      CL/F (L/h)
      20.8 ± 5.9
      8.0 ± 2.1
      22.1 ± 5.9
      133.5 ± 40.0

      8
      LS GMRc
      Amenamevir + ketoconazole vs amenamevir alone
      Amenamevir + ketoconazole vs amenamevir alone
      Amenamevir + rifampicin vs amenamevir alone
      Amenamevir + rifampicin vs amenamevir alone

      9
      AUCinf
      2.58 (2.32–2.87)
      2.58 (2.32–2.87)
      0.17 (0.15–0.19)
      0.17 (0.15–0.19)

      10
      C max
      1.30 (1.17–1.45)
      1.30 (1.17–1.45)
      0.42 (0.37–0.49)
      0.42 (0.37–0.49)

CAPTION: 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
FOOTER: 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

L

C

L


r (t½, abs-1, t½, abs-2)

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

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Parameter	Mean	Bootstrap, median (95% CI)

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

Structural model parameters

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

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

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

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

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

Variable model parameters (shrinkage%)

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

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

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

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

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

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

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

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

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½

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t

½

a

b

s


Volume, L

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

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

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

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

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

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

Clearance, L/week	13.3 (9.17, 22.8)

Volume, L	4.58 (4.14, 4.99)

First‐phase t1/2, h	38.2 (23.2–56.7)

Terminal t1/2, h	12200 (3990–50200)

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

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

Clearance, L/week	14.0 (12.7–14.6)

Terminal t1/2, h	38.2 (36.5–41.9)

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

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

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

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

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

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AUC0-1h [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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GB on CL/Fb

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

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

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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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CL: Allometric exponent for weight (−)c

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

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Parameter	Final parameter estimate	Between‐subject variability

Typical value	%RSE	Magnitude	%RSE

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

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

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

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

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

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

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

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

F1: Bioavailability	0.658	FIXED	NE	NA

ALAG1: Lag time (d)	0.0803	FIXED	NE	NA

Residual variability iv	0.0467	32.6	NA	NA

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

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

Minimum value of the objective function = 73303.561

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

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Volume: age exponent

Population pharmacokinetic parameter estimates

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Tmax, hb

Pharmacokinetic parameters of TAK-285 after multiple-dose administration

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

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AUC0-t (h·ng/mL)

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

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Between‐subject variability CL ω (CV%)

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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AUC(0–∞) (ng h/ml)

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

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PK parameter	LCDP polymeric micelles	LCDP oral suspension	Statistical test

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

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

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

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

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

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

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Univariate analysis of pharmacokinetic parameters and biological or clinical variables

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CL(L/day)	Kout (day-1)	V1(L)	V2(L)

<italic>n</italic>

<italic>p</italic>

Age	44	0.86	0.82	0.90	0.99

Sex male versus female	23 versus 21	0.59	0.53	0.34	0.37

Body surface area (BSA, m2)	44	0.59	0.82	0.76	0.99

Binet stage A or B versus C	27 versus 17	0.89	0.82	0.34	0.99

Treatment RB versus RFC	17 versus 28	0.48	0.82	0.76	0.99

Lymphocytosis	44	0.59	0.30	0.96	0.99

Areas of lymphadenopathy	44	0.59	0.39	0.96	0.51

CD38 positivity (≥30%) versus negativity	21 versus 22	0.88	0.82	0.90	0.99

FCGR F/F versus V/F and <italic>V</italic>/V	25 versus 19	0.86	0.68	0.90	0.99

IGHV unmutated versus mutated status	10 versus 6	0.37	0.82	0.96	0.99

Cytogenetics

 Isolated del(13q) versus others	8 versus 36	0.37	0.02	0.76	0.23

 Trisomy 12 versus others	10 versus 34	0.59	0.92	0.76	0.37

 Normal caryotype versus others	4 versus 40	0.89	0.39	0.96	0.66

 Del(11q) versus others	10 versus 34	0.37	0.17	0.76	0.17

 Del(17p) versus others	9 versus 35	0.17	0.007	0.17	0.23

 Time to relapse (TTR)	44	0.59	0.82	0.96	0.99

 Time to second treatment (TST)	44	0.37	0.39	0.96	0.99

vs. versus, CL clearance, Kout first-order rate constant of rituximab independent death of latent target antigen, V1 central distribution volume, V2 peripheral distribution volume, RB rituximab bendamustine, RFC rituximab fludarabine cyclophosphamide, FCGR Fc gamma receptor, IGHV immunoglobulin heavy chain variable region. Values were adjusted for multiple testing using the Benjamini–Hochberg method (https://www.sdmproject.com/utilities/?show=FDR), and p < 0.05 considered as significant

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AUC∞ (μg·h/L)

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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tmax (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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C max (µmol/L)

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

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

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CL, L/h

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

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

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Cmax, ×103ng/mL

Predicted pharmacokinetics parameters of morphine in virtual neonates after the intravenous administration

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Age years	Body weight kg	Hepatic OCT1nmol/liver	Cmax, ×103ng/mL	AUC∞,ng/mL*hr	CLpediatric,i,L/hr	CL70kg,i, L/hr per 70kg

Predictions by PBPK modeling

Mean	0.10	4.2	10.0	1.80	188	3.55	29.4

SD	0.01	0.6	10.4	0.16	80	1.66	13.5

Minimum	0.08	2.7	0.38	1.41	48	1.14	9.7

Maximum	0.12	6.2	96.2	2.32	474	10.7	94.3

Clinical observations

Patient T.T.	0.1	4.0	NA	2.12	205	2.23	19.1

Patient A.J.	0.1	4.4	NA	2.54	99.7	5.04	40.1

AUC∞, area under the plasma concentration‐time curve extrapolated to infinity; CLpediatric,i, pediatric clearance; Cmax, maximum concentration for simulations (for clinical observations, concentration at time zero); NA, not available; OCT1, organic cation transporter 1; PBPK, physiologically based pharmacokinetic.CL70kg,i (L/hr per 70kg), an allometrically‐scaled clearance with standard body weight of 70kg (i.e., CL70kg, i in Eq. (5), as described in the Method section), which is calculated as follows: CL70kg,i=CLpediatric,i×70 kgBody Weightpediatric,i0.75

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MIC (mg/liter)

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

      0
      Strain
      Origin
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)
      MIC (mg/liter)

      1
      Strain
      Origin
      GEP
      AZM
      CLR
      OXA
      VAN
      LZD
      DAP
      MXF
      CIP
      GEN

      2
      ATCC 25923
      Laboratoryb
      0.5–1
      1
      0.25
      0.25
      1
      2–4
      1
      0.03–0.0625
      0.125–0.25
      0.5

      3
      SA040 LZDr
      In vitro mutant from clinical isolatec
      0.25–0.5
      2
      0.25
      0.25
      1–2
      16
      2
      0.125
      ND
      0.5

      4
      SA618 bis
      Clinicald
      0.25
      ND
      ND
      256
      4
      2
      32
      4
      ND
      0.125

      5
      NRS119
      Clinicale
      0.5–1
      4
      2
      >256
      1
      128
      2
      4
      ND
      64

      6
      MU50
      Clinicalf
      0.25
      >256
      >256
      >256
      8
      1
      8
      4
      ND
      64

      7
      SA1
      Laboratoryg
      0.25
      ND
      ND
      ND
      ND
      ND
      ND
      0.0625
      4
      ND

CAPTION: Strains used in the study, strain origin, and MIC in brotha
FOOTER: aData in bold indicate values greater than the EUCAST resistant (r) clinical breakpoint values (European Committee on Antimicrobial Susceptibility Testing, 2017). Abbreviations: GEP, gepotidacin; AZM, azithromycin; CLR, clarithromycin; OXA, oxacillin; DAP, daptomycin; VAN, vancomycin; LZD, linezolid; MXF, moxifloxacin; CIP, ciprofloxacin; GEN, gentamicin; ND, not determined.bLaboratory standard (ATCC, Manassas, VA).cFrom P. Appelbaum, Hershey Medical Center, Hershey, PA (41). Selected by in vitro exposure of a clinical isolate to increasing concentrations of linezolid; unknown resistance mechanism.dRespiratory tract infection. From P. Appelbaum, Hershey Medical Center, Hershey, PA (42). Described as a MRSA and heterogeneous vancomycin-intermediate S. aureus strain.ePeritonitis (43). Described as a MRSA and linezolid-resistant strain with a mutated domain V in 23S RNA.fATCC 700699 (ATCC, Manassas, VA). Surgical wound infection, vancomycin-intermediate S. aureus (44).gIn vitro mutant overexpressing NorA; selected by in vitro exposure of ATCC 25923 to increasing concentrations of ethidium bromide (45); from Claudine Quentin, Université de Bordeaux 2, Bordeaux, France.

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Aelast, %

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Tadalafil pharmacokinetic parameters by weight cohort and bosentan use on day 49

AUCτ, area under the plasma concentration–time curve during 1 dosing interval; CLss/F, apparent plasma clearance of drug after extravascular administration at steady state; Cmax, maximum plasma concentration; HW, heavy weight; LW, light weight; MW, middle weight; n, number of patients; tmax, time to maximum plasma concentration.

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Typical (median)

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      This study, patients
      Schnider, volunteers
      Schnider, volunteers
      Eleveld, volunteers
      Eleveld, volunteers
      Eleveld, patients
      Eleveld, patients

      1
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      Typical (median)
      Typical (median)
      Bias (%)
      Typical (median)
      Bias (%)
      Typical (median)
      Bias (%)

      2
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      5.11
      4.27
      16
      5.18
      −1.4
      8.16
      −60

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      2.38
      1.94
      28
      1.96
      18
      1.64
      31

      4
      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

      7
      Q 2 (L/min)
      0.608
      0.836
      −38
      1.38
      −127
      0.41
      32

      8
      MDPE
      −0.50
      −8.4
      −8.4
      −1.0 %
      −1.0 %
      −29.4
      −29.4

      9
      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 individual pharmacokinetic parameters and confidence intervals for IFN alpha-2b and IFN gamma (Model V)

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

Mean	95 % CI	Mean	95 % CI

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

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

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

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

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

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

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

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Pharmacokinetic profile across study groups

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

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fAUC0-24 h/MIC for 1 log10 kill

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      0
      Parameter
      Mean ±SD

      1
      E0 (log10CFU/lung)
      4.16 ± 0.43

      2
      Imax (log10CFU/lung)
      8.66 ± 1.10

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      IC50
      21.57 ± 8.38

      4
      fAUC0-24 h/MIC for bacteriostatic action
      19.93 h

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      fAUC0-24 h/MIC for 1 log10 kill
      31.89 h

      6
      fAUC0-24 h/MIC for 2 log10 kill
      53.27 h

CAPTION: The PK/PD parameter estimates for the fAUC0-24 h/MIC index and the fAUC0-24 h/MIC values required for various antibacterial effects.
FOOTER: []

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Cmin (ng/mL)

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

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<bold>Study Population</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>HV</bold>

<bold>Dosing Day</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>14</bold>

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

<bold>50</bold>

<bold>50</bold>

<bold>100</bold>

<bold>100</bold>

<bold>150</bold>

<bold>200</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

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

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

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

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

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

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

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

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

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

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

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

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

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Tmax (h)

ABT‐751 and Irinotecan Pharmacokinetic Parameters

Data are presented as the mean ± SD (n) or median (range, n) for Tmax. AUC, area under the concentration‐time curve; Cmax, maximum plasma concentration; NA, not applicable; NC, not calculated; Tmax, time of Cmax; SD, standard deviation.aFor ABT‐751, AUCτ is reported. For irinotecan, AUC∞ is reported.bRatio of unbound ABT‐751, ABT‐751 sulfate, or ABT‐751 glucuronide to ABT‐751 and SN‐38, APC, or SN‐38 glucuronide to irinotecan expressed as a percentage.cCmax and AUC∞ were dose normalized to 150 mg.dCmax and AUC∞ were dose normalized to 250 mg/m2.21 eSeven patients had undetectable SN‐38 glucuronide concentrations. Of the 10 with detectable levels, either the half‐life or percentage extrapolated for AUC was poor; thus, AUC∞ was not calculated. † P < .05 for matched pair comparison when administered alone or in combination with CAPIRI.

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AUC0‐48 (ng·h/mL)

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

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

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Stability, ng/mL

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

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

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Tmax (min)

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

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V1 (L)

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

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NASF effect on clearance of M3Gb

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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Cmax (μg/mL)

Pharmacokinetic parameters – Cycle 1

Data are mean (SD). Cmax = peak concentration. AUC∞ = area under the plasma concentration vs time curve extrapolated to infinity. t1/2 = half-life. CL = clearance. Vz = volume of distribution at terminal phase

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ARAUCtau

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

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Dose	Day 1	Day 7

1%	3%	1%	3%

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

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

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

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

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

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

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

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

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C max (DN), μg/mL/mg

Descriptive statistical summary of pharmacokinetic parameters following a single subcutaneous dose of bococizumab alone or in co‐mixture with rHuPH20

AUCinf, area under the plasma concentration‐time profile from time zero extrapolated to infinite time; CL/F, apparent clearance; C max, maximum plasma concentration; DN; dose‐normalized to a 300‐mg dose; rHuPH20, recombinant human hyaluronidase; T max, time to C max; V z/F, apparent volume of distribution; t ½, terminal half‐life.aData are presented as geometric mean (% coefficient of variation), except T max data which are median (range) and t ½ data which are arithmetic mean ± standard deviation.

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AUC0‐t, μg·h/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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IIV−Q/F

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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Cmax—ng/dL

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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Cmax, μg/ml

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

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

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AUCinf (DN), μg. day/mL/mg

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tlag , h

Final population model estimates of pantoprazole

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

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Css > 200 (µM)

Corresponding Dosimetry and Assay Information for Chemicals with OEDs < 1 µg/kg/day

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Chemical	<italic>C</italic>ss (µM)	Assay Endpoint	AC50 (µM)	Oral Equivalent (mg/kg/day)	<italic>C</italic>ss > 200 (µM)	AC50 < 0.5 (µM)

Heptadecafluorooctanesulfonic acid potassium salt	217.01	Inhibition of human CYP2C9 enzymatic activity	1.30E-02	5.99E-05	Yes	Yes

Mirex	70.82	Increased expression of prostaglandin E2 in human peripheral blood mononuclear cells	1.14E-02	1.61E-04	—	Yes

Diethylstilbestrol	0.46	Binding to human estrogen receptor	7.43E-05	1.61E-04	—	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor response element in transfected HepG2 cells	1.01E-04	2.19E-04	—	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor signaling pathway in transfected HEK293 cells	1.27E-04	2.76E-04	—	Yes

Potassium perfluorohexanesulfonate	266.56	Inhibition of human CYP2C9 enzymatic activity	8.25E-02	3.09E-04	Yes	Yes

Potassium perfluorohexanesulfonate	266.56	Inhibition of human CYP4F12 enzymatic activity	8.60E-02	3.23E-04	Yes	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor alpha signaling pathway in transfected HepG2 cells	1.80E-04	3.92E-04	—	Yes

Tannic acid	0.34	Inhibition of human GSK3b enzymatic activity	2.00E-04	5.83E-04	—	Yes

Dinoseb	485.94	Decreased mitochondrial membrane potential in HepG2 cells	3.50E-01	7.20E-04	Yes	Yes

Pentadecafluorooctanoic acid ammonium salt	269.96	Inhibition of human CYP2C9 enzymatic activity	2.02E-01	7.48E-04	Yes	Yes

Triphenyl phosphate	0.79	Binding to human peroxisome proliferator-activated receptor-gamma	6.09E-04	7.66E-04	—	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor signaling pathway in transfected HEK293 cells	4.02E-04	8.73E-04	—	Yes

Gentian violet	10.01	Decreased expression of interleukin-8 in human peripheral blood mononuclear cells	1.00E-02	9.99E-04	—	Yes

Gentian violet	10.01	Decreased expression of E-selectin adhesion protein in human endothelial cells	1.00E-02	9.99E-04	—	Yes

Gentian violet	10.01	Decrease expression of interleukin 1 alpha in human peripheral blood mononuclear cells	1.00E-02	9.99E-04	—	Yes

Endrin	238.20	Activation of estrogen receptor response element in transfected HepG2 cells	2.72E-01	1.14E-03	Yes	Yes

Dinoseb	485.94	Decreased expression of transforming growth factor-beta in human primary bronchial epithelial cells	6.28E-01	1.29E-03	Yes	—

2-Methyl-4,6-dinitrophenol	589.15	Decrease mitochondrial membrane potential in HepG2 cells	8.74E-01	1.48E-03	Yes	—

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CL ∼ AGE

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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      0
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      2
      3

      0
      Parameter (unit)
      Definition of parameter
      Bootstrap
      Bootstrap

      1
      Parameter (unit)
      Definition of parameter
      Median
      95% CI a

      2
      𝜽−Estimates
      𝜽−Estimates
      𝜽−Estimates
      𝜽−Estimates

      3
      CL / F (l / h)
      Apparent clearance
      62.8
      (54.4–71.2)

      4
      Vc / F (l)
      Apparent central volume of distribution
      254
      (226–281)

      5
      Vp / F (l)
      Apparent peripheral volume of distribution
      388
      (344–456)

      6
      Q (l / h)
      Intercompartmental clearance between central and peripheral compartment
      23.6
      (19.3–29.5)

      7
      Ka(h-1)
      Absorption rate constant
      12.4
      (6.57–33.9)

      8
      MTT (h)
      Mean transit time
      0.812
      (0.797–0.831)

      9
      N
      Number of transit compartment
      20.2
      (16.6–25.6)

      10
      𝝎2−Estimates
      𝝎2−Estimates
      𝝎2−Estimates
      𝝎2−Estimates

      11
      IIV CL (CV%)
      Interindividual variability on clearance
      12.6
      (3.69–20.4)

      12
      IIV Ka (CV%)
      Interindividual variability on absorption rate
      155
      (55.9–628)

      13
      IIV Q (CV%)
      Interindividual variability on distributional clearance
      25.7
      (7.74–42.0)

      14
      IIV N (CV%)
      Interindividual variability on number of transit compartments
      20.2
      (7.57–38.2)

      15
      IOV MTT (CV%)
      Inter-occasional variability on mean transit time
      4.39
      (2.31–6.18)

      16
      IOV N (CV%)
      Inter-occasional variability on number of transit compartments
      17.6
      (9.32–25.2)

      17
      𝝈2−Estimates
      𝝈2−Estimates
      𝝈2−Estimates
      𝝈2−Estimates

      18
      PRV (CV%)
      Proportional residual variability
      19.4
      (16.0–22.9)

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

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

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CL (ml/min/kg)

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

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

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

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

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

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

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

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

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

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

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

3.6	1	43.3	10.0	100

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

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

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

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

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F (%)

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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CL

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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Apparent selexipag clearance

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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t1/2 (h)

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

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

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Tmax (unitless)

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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AUC (min µg/mL)

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

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

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ESRDa (n = 6/0)

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      1
      2
      3
      4
      5

      0
      Parameter
      Study A/study B, mean ± standard deviation
      Study A/study B, mean ± standard deviation
      Study A/study B, mean ± standard deviation
      Study A/study B, mean ± standard deviation
      Study A/study B, mean ± standard deviation

      1
      Parameter
      Normal (n = 6/14)
      Mild (n = 6/13)
      Moderate (n = 6/8)
      Severe (n = 4/8)
      ESRDa (n = 6/0)

      2
      Telavancin
      Telavancin
      Telavancin
      Telavancin
      Telavancin
      Telavancin

      3
      Protein binding (%)a
      86.5 ± 1.3
      87.5 ± 1.0
      87.8 ± 1.1
      86.7 ± 1.2
      87.6 ± 1.0/0

      4
      t ½ (h)
      6.9 ± 0.6/6.5 ± 0.9
      9.6 ± 2.9/7.8 ± 2.0
      10.6 ± 2.4/8.1 ± 1.5
      14.5 ± 1.3/11.8 ± 6.7
      11.8 ± 2.8/0

      5
      C max (μg/mL)
      70.6 ± 11.2/76.7 ± 8.6
      65.9 ± 2.7/74.2 ± 7.3
      65.8 ± 12.1/78.0 ± 4.5
      71.8 ± 7.1/83.2 ± 13.1
      52.1 ± 10.1/0

      6
      AUC0–∞ (μg∙h/mL)
      560 ± 93/539 ± 99
      633 ± 101/606 ± 139
      721 ± 200/936 ± 182
      1220 ± 120/1397 ± 297
      1010 ± 341/0

      7
      CL (mL/h/kg)
      13.7 ± 2.1/17.0 ± 3.2
      12.1 ± 1.9/15.2 ± 4.6
      11.1 ± 3.3/9.5 ± 2.0
      6.18 ± 0.63/6.5 ± 1.5
      8.18 ± 2.65/0

      8
      V ss (mL/kg)
      131 ± 16/155.4 ± 30.2
      157 ± 19/159.5 ± 34.5
      156 ± 24/157.8 ± 41.7
      136 ± 10/ 141.9 ± 17.7
      157 ± 27/0

      9
      Hydroxypropylbetadex
      Hydroxypropylbetadex
      Hydroxypropylbetadex
      Hydroxypropylbetadex
      Hydroxypropylbetadex
      Hydroxypropylbetadex

      10
      t ½ (h)
      3.02 ± 1.56/2.15 ± 0.35
      4.96 ± 6.22/2.47 ± 0.55
      4.18 ± 1.27/5.09 ± 2.07
      9.84 ± 3.62/12.2 ± 2.8
      37.2 ± 8.72/0

      11
      C max (μg/mL)
      344 ± 61/386 ± 51
      476 ± 83/367 ± 37
      565 ± 172/453 ± 58
      517 ± 36/479 ± 57
      290 ± 59/0

      12
      AUC0–∞ (μg∙h/mL)
      946 ± 45/971 ± 199
      1880 ± 1050/1083 ± 275
      2720 ± 1190/2512 ± 921
      5440 ± 1460/6385 ± 1713
      8510 ± 2470/0

      13
      CL (mL/h/kg)
      79.5 ± 3.8/94.5 ± 19.0
      49.2 ± 22.7/85.1 ± 25.3
      32.5 ± 14.2/37.2 ± 11.0
      14.5 ± 3.3/14.6 ± 4.5
      9.8 ± 4.3/0

      14
      V ss (mL/kg)
      263 ± 101/277.7 ± 148.2
      182 ± 51/248.6 ± 61.8
      160 ± 71/228.2 ± 56.1
      183 ± 23/227.8 ± 32.7
      473 ± 70/0

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

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F1 free testosterone (pg/mL)

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

      1
      F1 total testosterone (ng/mL)
      5.65 ± 2.35
      0.256 ± 0.063
      6.41 ± 2.23
      0.726 ± 0.165

      2
      F2 total testosterone (ng/mL)
      7.84 ± 3.69*
      0.201 ± 0.043
      8.10 ± 2.49
      0.598 ± 0.080

      3
      F1 free testosterone (pg/mL)
      36.2 ± 14.9
      0.250 ± 0.083
      35.1 ± 18.8
      0.674 ± 0.187

      4
      F2 free testosterone (pg/mL)
      52.4 ± 20.8*
      0.194 ± 0.054
      55.5 ± 31.1*
      0.798 ± 0.247

      5
      F1 dihydrotestosterone (ng/mL)
      0.519 ± 0.222
      0.410 ± 0.105
      1.39 ± 0.87
      1.14 ± 0.49

      6
      F2 dihydrotestosterone (ng/mL)
      0.578 ± 0.245
      0.451 ± 0.066
      1.17 ± 0.47
      0.850 ± 0.336

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

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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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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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Elimination rate (1/hour)

Population pharmacokinetic parameter estimates

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Base model	Final model	Bootstrap <break/>(977/1000 successful)

Parameters	Population mean (%RSE)	Median (2.5 to 97.5 percentile)

 Elimination rate (1/hour)	0.0317 (13%)	0.0408 (15%)	0.0411 (0.0318 to 0.0558)

 Volume (L)	216 (22%)	233 (17%)	228 (167 to 312)

 Absorption rate (1/hour)	3.43 (fixed)	3.43 (fixed)	3.43 (fixed)

 Volume: age exponent	–	0.775 (13%)	0.780 (0.601 to 1.01)

 Elimination rate: creatinine clearance exponent	–	0.850 (24%)	0.842 (0.470 to 1.25)

 Fluconazole elimination rate (1/hour)	–	0.0268 (5%)	0.0267 (0.0234 to 0.0321)

Between-subject variability

 <italic>ωke</italic>2	0.219 (51%)	0.262 (40%)	0.256 (0.0858 to 0.590)

 <italic>ωV</italic>2	0.991 (27%)	0.329 (35%)	0.291 (0.0637 to 0.518)

Residual error	SD (%RSE)

 Additive (µg/L)	4.24 (14%)	3.69 (13%)	3.65 (3.16 to 4.14)

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Vp (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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AL dosing and pharmacokinetic parameters in patients weighing 5 to < 10 kg or 10 to < 15 kg

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5 to < 10 kg	10 to < 15 kg

<bold>Artemether & dihydroartemisinin (DHA)</bold>

Dispersible tablet	N = 171	N = 352

Total dose artemether (mg/kg)	14.8 ± 2.57	10.0 ± 1.30

Cmax artemether (ng/mL)	372 ± 251	110 ± 97.7

Cmax DHA (ng/mL)	107 ± 76.6	38.2 ± 42.4

Crushed tablet	N = 183	N = 37

Total dose artemether (mg/kg)	14.7 ± 1.94	10.0 ± 1.28

Cmax artemether (ng/mL)	295 ± 214	137 ± 111

Cmax DHA (ng/mL)	89.9 ± 83.5	36.6 ± 28.7

<bold>Lumefantrine</bold>

Dispersible tablet	N = 24	N = 78

Total dose lumefantrine (mg/kg)	90.4 ± 9.46	60.4 ± 7.37

Cmax (μg/mL)	6.55	5.55

AUC0-last (μg·h/mL)	550	393

Crushed tablet	N = 26	N = 75

Total dose lumefantrine (mg/kg)	88.6 ± 13.1	59.5 ± 6.87

Cmax (μg/mL)	5.50	6.29

AUC0-last (μg·h/mL)	578	558

Data are mean ± SD;1 N = 18 for DHA;2 N = 34 for DHA;3 N = 19 for DHA

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