DRUG1 ON CL/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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Vd/Fa, 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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T1/2 (h)

Pharmacokinetic parameters of free curcumin (CCM) and TPGS/CCM.

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CLM,NR (L/hr)

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
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	27.2 (6)	—

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

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

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

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

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CL/F (L/h/kg)

Difference in pharmacokinetic parameters of sildenafil between the two combination therapies

Data are expressed as the median (interquartile range). S+B, coadministration of sildenafil with bosentan; S+A, coadministration of sildenafil with ambrisentan; tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; AUC0‐8, area under the plasma concentration‐time curve from 0 to 8 hours; CL/F, oral clearance.

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Q 1 (L/min)

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

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

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

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

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

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

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

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

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

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

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

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

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

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Cmax (ng ml−1)

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

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

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Cmax (ng/ml)

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CL0–8 hour,renal (mL/min)d

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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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Cmax, ng/mL

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

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

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CL / F (l / h)

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

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Parameter (unit)	Definition of parameter	Bootstrap

Median	95% CI<xref rid="tfn1" ref-type="table-fn">
a
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<bold>𝜽−<italic>Estimates</italic></bold>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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The PK parameters of FF after I.M and I.V administrations (30 mg/kg) in pigs (n = 8).

Ke, presented elimination rate constant; t1/2ke, presented elimination half-life; Clb, presented body clearance; AUC, presented area under the curve; AUC0-24h, presented area under the curve from 0 to 24 h; Cmax, peak concentration; Tmax, the time of maximum serum concentration; the MRT, presented mean residence time; F, the bioavailability.

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Vm (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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Cmax (μg/L)

Pharmacokinetic parameters of the seven components of Shengjiang decoction

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

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C av,72 (ng/mL)

Noncompartmental pharmacokinetic parameters of prexasertib

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

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Tmax a (h)

Summary statistics of midazolam plasma PK parameter values

AUC0−12 h, 0–12‐hour area under the concentration‐time curve; AUCinf, area under the concentration‐time curve to infinity; CL/F, total clearance; Cmax, peak plasma concentration; CV%, percentage of coefficient of variation; PK, pharmacokinetic; t1/2, terminal half‐life; Tmax, time of maximum plasma concentration; Vz/F, volume of distribution based on the terminal phase.aMedian and range is given for Tmax.

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MAT (hours)

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

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

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

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

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

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

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

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

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

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

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

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tmax (h)

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

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Parameters	Mean ± SD

Cmax(mg/L)	1.37 ± 0.23

<italic>t</italic>max (h)	0.85 ± 0.12

t 1/2u (h)	0.35 ± 0.05

CL/F (LIb/kg)	0.17 ± 0.03

Ka(l/h)	3.47 ± 0.58

AUC(0-t) (mg·h/L)	3.46 ± 0.61

AUC(0-∞) (mg·h/L)	3.56 ± 0.64

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AUC,0-48h (ng∙h/mL)

Model-predicted variation in panobinostat exposure across covariates

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Vc/F, L

Final population model estimates of pantoprazole

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

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AUC0‐12h, ng ⋅ h/mLa

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

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

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

Arithmetic mean	129	1050	9.23

Arithmetic mean CV%	62	86

Median	103	4	1050	9.23

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

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

Arithmetic mean	727	13 300	20

Arithmetic mean CV%	79	106	68

Median	444	2.47	5220	27.5

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

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

Arithmetic mean	1940	15 800	16 900	12.6

Arithmetic mean CV%	54	58	54	54

Median	1480	1.92	12 900	14 700	10.9

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

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

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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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AUCa (μg ⋅ h/mL)

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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C max (ng/mL)

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

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

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CLcr [ml/min]

Concentrations of retinol, α-tocopherol and β-carotene (mean ± SD) in relation to MMF, CNI co-administered and patients’ clinical condition

MMF – mycophenolate mofetil, CNI – calcineurin inhibitors, CsA – cyclosporine, Tac – tacrolimus, CLcr – creatinine clearance, Ccr – plasma creatinine, ALT – alanine aminotransferase, AST – aspartate aminotransferase

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DRUG0 ON CL/F

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

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

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AZ13569724 AUC0–t (ng·h/mL)

PK Parameters for Each Treatment Group

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

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AUC/D (h/L × 10−3)

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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β (1/h)

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

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

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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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k10 (per h)

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

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

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

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

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

Cl/F	224.84 ± 59.89

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

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CLbev (l/h)

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

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Parameter	Values used in human D2RO Simulations	Source

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

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

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

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

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

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

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

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

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

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

CLbev (l/h)	11.3	–c

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

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MRT0 -∞ (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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Time to peak value (hrs)

Area under the curve, basal diurnal variation (DV), serum iron and plasma folate by treatment

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Basal Diurnal Variation (DV)	Powdered Supplement	Tablet Supplement

<bold>Iron</bold>

 AUC (μmol·h/L)	104.5 ± 34.1

 Adjusted AUC(after DV) (μmol·h/L)	10.0 ± 43.3*	41.8 ± 45.9*

 Peak value (μmol/L)	14.6	3.0	8.9

Time to peak value (hrs)	3	4

<bold>Folate</bold>

 Incremental AUC (nmol·h/L)	NA	271.8 ± 110.9	248.7 ± 140.2

 Peak value (nmol/L)	NA	54.4	53.1

Time to peak value (hrs)	NA	4	3

AUC, area under the curve. All values are mean ± SD; n(iron) = 17; n(folate) = 18 (sample size differed according to subject exclusion for iron variables). *p = 0.0003.

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      Parameters
      Units
      Values

      1
      Emax
      Log CFU/mL
      2.71 ± 0.37

      2
      E0
      Log CFU/mL
      −4.61 ± 0.69

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      Emax−E0
      Log CFU/mL
      7.32 ± 1.06

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      EC50
      h
      30.07 ± 6.94

      5
      N (slope)
      /
      4.62 ± 0.72

      6
      AUC24h/MIC for bacteriostatic effect
      h
      26.72 ± 6.28

      7
      AUC24h/MIC for bactericidal effect
      h
      39.54 ± 7.31

      8
      AUC24h/MIC for eradication effect
      h
      50.69 ± 9.16

CAPTION: PK-PD modeling of ex vivo cyadox after oral administration at a dose of 30 mg/kg.
FOOTER: []

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Vd/F (L)

Population pharmacokinetic parameters of baclofen.

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<bold>Parameters</bold>	<bold>Estimation</bold>	<bold>Rse</bold>	<bold>Bootstrap</bold>

<bold>(%)</bold>	<bold>95% CI</bold>

CL/F (L/h)	11.6	3	10.8–12.3

Vd/F (L)	72.8	5	66.5–80.4

Ka (1/h)	1.64	10	1.34–2.00

<bold>BETWEEN SUBJECT VARIABILITY</bold>

ω(CL/F)	0.21	14	0.16–0.27

ω(Vd/F)	0.22	31	0.11–0.36

ω(Ka)	0.44	24	0.19–0.65

<bold>RESIDUAL VARIABILITY</bold>

σ exponential	0.24	5	0.21–0.26

Rse, relative standard error; CL/F, clearance; Vd/F, volume of distribution; Ka, absorption constant; CI, confidence interval.

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Specificity

      0
      1
      2
      3

      0
      Efficacy end point
      SGC time point
      ROC analysis metric
      Estimate

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      Clinical responsea during
      Week 2
      Threshold, µg/ml
      8.900000

      2
      induction at Week 6
      nan
      Sensitivity
      49.100000

      3
      nan
      nan
      Specificity
      71.500000

      4
      nan
      nan
      PPV
      65.400000

      5
      nan
      nan
      NPV
      56.100000

      6
      nan
      Week 4
      Threshold, µg/ml
      7.400000

      7
      nan
      nan
      Sensitivity
      56.600000

      8
      nan
      nan
      Specificity
      68.300000

      9
      nan
      nan
      PPV
      58.000000

      10
      nan
      nan
      NPV
      67.100000

      11
      nan
      Week 6
      Threshold, µg/ml
      2.500000

      12
      nan
      nan
      Sensitivity
      59.000000

      13
      nan
      nan
      Specificity
      67.200000

      14
      nan
      nan
      PPV
      67.700000

      15
      nan
      nan
      NPV
      58.400000

      16
      Clinical remissionb at both
      Week 28
      Threshold, µg/ml
      0.900000

      17
      Week 30 and Week 54 of
      during maintenance
      Sensitivity
      78.700000

      18
      maintenance
      [steady-state trough]
      Specificity
      48.000000

      19
      nan
      nan
      PPV
      43.400000

      20
      nan
      nan
      NPV
      81.600000

      21
      nan
      Week 30
      Threshold, µg/ml
      3.700000

      22
      nan
      during maintenance
      Sensitivity
      41.300000

      23
      nan
      nan
      Specificity
      75.500000

      24
      nan
      nan
      PPV
      47.000000

      25
      nan
      nan
      NPV
      71.100000

      26
      nan
      Week 44
      Threshold, µg/ml
      1.400000

      27
      nan
      during maintenance
      Sensitivity
      54.100000

      28
      nan
      [steady-state trough]
      Specificity
      77.600000

      29
      nan
      nan
      PPV
      58.800000

      30
      nan
      nan
      NPV
      74.000000

      31
      nan
      Week 54
      Threshold, µg/ml
      3.700000

      32
      nan
      during maintenance
      Sensitivity
      39.500000

      33
      nan
      nan
      Specificity
      82.400000

      34
      nan
      nan
      PPV
      58.800000

      35
      nan
      nan
      NPV
      68.100000

Optimal SGC thresholds and ROC curve analysis estimates for key efficacy endpoints in PURSUIT.

aClinical response was defined as a decrease from baseline in the Mayo score ≥ 30% and ≥ 3 points, accompanied by either a rectal bleeding subscore of 0 or 1 or a decrease from baseline in the rectal bleeding subscore ≥ 1. bClinical remission was defined as a Mayo score ≤ 2 points, with no individual subscore > 1.NPV, negative predictive value; PPV, positive predictive value; PURSUIT, Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment; ROC, receiver operating characteristic; SGCs, serum golimumab concentrations.

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Univariate analysis of pharmacokinetic parameters and biological or clinical variables

<!DOCTYPE html>

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

<italic>n</italic>

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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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Cmax [g/L]

Pharmacokinetic parameters for IGSC 20% and IGIV 10% treatments

*Patients aged 12 years and older †Apparent clearance for SC administration.95% CI = 95% confidence interval; IGSC = s.c.immunoglobulin; IGIV = intravenous immunoglobulin; AUC = area under the curve

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LDX + VXRb

      0
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      2
      3

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      Vital signs
      Treatment Arm A
      Treatment Arm B
      Combination

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

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

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

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

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

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AUC(0–inf), µg⋅h/mL

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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C3hr (ng/mL)

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

<!DOCTYPE html>
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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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Concentration (ng/mL)

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

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T1/2 (h)

PHARMACOKINETIC PARAMETERS OF COMPOUNDS LM 13765 AND LM 13765-C

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

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Cmax

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

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

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Total serum concentration (MIC/unbound fraction)

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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T1/2γ (h)

Pharmacokinetic parameters

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

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T max (h)

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

<!DOCTYPE html>

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

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

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

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

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

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

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

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

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Systolic BP Emax

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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Tmax (h)

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

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

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Main pharmacokinetic parameters of oral tryptanthrin in KM mice.

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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Cmax (mg/L)

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

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E0 (log10CFU/lung)

      0
      1

      0
      Parameter
      Mean ±SD

      1
      E0 (log10CFU/lung)
      4.16 ± 0.43

      2
      Imax (log10CFU/lung)
      8.66 ± 1.10

      3
      IC50
      21.57 ± 8.38

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

      5
      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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T½ab(h)

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

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

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Covariate 6: tumor size on CL

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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The PK parameters of FF after I.M and I.V administrations (30 mg/kg) in pigs (n = 8).

Ke, presented elimination rate constant; t1/2ke, presented elimination half-life; Clb, presented body clearance; AUC, presented area under the curve; AUC0-24h, presented area under the curve from 0 to 24 h; Cmax, peak concentration; Tmax, the time of maximum serum concentration; the MRT, presented mean residence time; F, the bioavailability.

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AUCINF_obs (h µg/mL)

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

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Weight on Vc/Fc

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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Chow et al. (2005); 800 mg PE

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      2
      3
      4
      5

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      GT solids and PE pharmacokinetic studies in humans
      Predicted and actual C max in the plasma (μg/mL)
      Predicted and actual C max in the plasma (μg/mL)
      Predicted and actual C max in the plasma (μg/mL)
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

      1
      GT solids and PE pharmacokinetic studies in humans
      EGCG
      EGC
      EC
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

      2
      Lee et al. (2002); 20 mg/kg GT solids
      0.06a (0.08)b
      0.07 (0.22)c
      0.04 (0.12)c
      0.200000
      6.060000

      3
      Chow et al. (2005); 400 mg PE
      0.11 (0.14)
      0.01 (0.02)
      0.01 (0.00)
      0.130000
      8.420000

      4
      Chow et al. (2001); 600 mg PE
      0.21 (0.17)
      0.02 (0.01)
      0.01 (0.01)
      0.210000
      12.460000

      5
      Chow et al. (2005); 800 mg PE
      0.21 (0.29)
      0.02 (0.03)
      0.01 (0.00)
      0.250000
      15.710000

      6
      Chow et al. (2005); 1200 mg PE
      0.35 (0.92)c
      0.04 (0.04)
      0.02 (0.01)
      0.420000
      26.700000

CAPTION: Using C max as a dose surrogate to predict plasma dosimetry of TCM in humans
FOOTER: aValues without brackets are predicted C max of unchanged TCs based on PBPK modeling.bBracketed values are C max from the literature. These C max usually are determined from free tea catechin concentrations except those of Lee et al. (2002) study, which are determined from total tea catechin concentrations (free plus conjugated forms).cCmax is under‐predicted when compare with the observed value.dTotal TCM concentrations are expressed as μg EGCg equivalents/mL plasma; they are calculated using predicted C max and the concentration/dose additivity model (ATSDR, 2004).eAdministered dose metrics are expressed as mg EGCg equivalents/kg BW; they are calculated using the concentrations of individual TCs in PE and the additivity model (ATSDR, 2004).

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CL (mL/h)

Pharmacokinetic Evaluation for Total YM155 Levels in Whole Blood after a Single i.v. Administration to Female Mice Bearing Subcutaneous KCNR Tumor Xenografts

The PK values are calculated by non-compartmental analysis (NCA) using a linear-logarithmic trapezoidal methodC0, concentration at t = 0, extrapolated, t1/2 = elimination half-life; AUC0-∞, extrapolated area under the curve from zero to infinity; CL, plasma clearance; Vz, volume of distribution during terminal phase, derived from slope (λz) in terminal phase; Vss, volume of distribution at steady state; MRT0-∞, mean residence timea PK analysis for free YM155 is based on data points until t = 2 h. Inclusion of the t > 2 h data points will result in an unrealistic estimate of the terminal slope λz (see main text for details)

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t max (h)

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

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

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Cmin—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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Clearance (l/h)

Overview of the pharmacokinetics of intravenous (iv) paracetamol in cohorts of women as retrieved in literature

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Author	Study characteristics	Clearance (l/h)	Distribution volume (l/kg)

Ochs et al. [<xref ref-type="bibr" rid="CR18">18</xref>]	single iv, 650 mg, young women, age matched study design

Controls (<italic>n</italic> = 10), 21–30 year, 54 (SE 2.1) kg	16.8 (SE 0.6)	0.98 (SE 0.08)

Oral contraceptives (<italic>n</italic> = 10), 62 (SE 2.5) kg	22.7 (SE 2.3)	0.98 (SE 0.06)

Sonne et al. [<xref ref-type="bibr" rid="CR19">19</xref>]	single iv, 1 000 mg, 2 episodes in each individual	16.6	1.01

3 women 54–56 kg, 29–33 years

Scaveno et al. [<xref ref-type="bibr" rid="CR14">14</xref>]	single iv, 650 mg, 30 post-menopausal women

controls (<italic>n</italic> = 18): 45 (SE 3.9) years, 64.9 (SE 3.3) kg	16.6 (SE 0.69)	0.85 (SE 0.04)

conjugated oestrogens (<italic>n</italic> = 12): 46 (3.4) years, 60.2 (1.7) kg	16.6 (SE 0.25)	0.82 (SE 0.05)

Abernethy et al. [<xref ref-type="bibr" rid="CR9">9</xref>]	single iv, 650 mg, 16 women

controls (<italic>n</italic> = 8): 23–32 years, 48–66 kg	13.7 (SD 1.26)	0.96 (SD 0.08)

oral contraceptives (<italic>n</italic> = 8): 21–36 years, 48–77 kg	20.0 (SD 1.68)	1.04 (SD 0.08)

Wynne et al.[<xref ref-type="bibr" rid="CR10">10</xref>]	single iv, 500 mg, 42 female/5 male volunteers, <italic>.</italic>all results pooled

healthy, young:	25 (SE 1) years, 59 (SE 2) kg	16.6 (SE 0.71)	1.00 (SE 0.04)

healthy, elderly:	73 (SE 1) years, 66 (SE 2) kg	14.6 (SE 0.79)	1.07 (SE 0.03)

frail, elderly:	82 (SE 2) years, 53 (SE 4) kg	7.9 (SE 0.32)	0.81 (SE 0.03)

Kulo et al. [<xref ref-type="bibr" rid="CR16">16</xref>]	single iv, 2 000 mg

28 cases, at delivery	31.5 (20–42) years, 79 (57–110) kg	20.3 (11.8–62.8)	0.72 (0.52–1.56)

SE standard error, SD standard deviation

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MRT (h)

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

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

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t1/2 (hour)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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)

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VWD, n (%)

Study participant baseline characteristics

n, number of study participants with characteristic; N, total number of study participants; PK, pharmacokinetic; VWD, von Willebrand disease. Among other bleedings, one study participant experienced ulorrhagia after each meal, that is, 2–3 times per day; such bleedings also occurred during the study, but were not reported as they were considered too minor.aBody weight measured at month 12 (start of prophylactic treatment for arm 3 study participants).

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k01 (per h)

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

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

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A (µg/L)

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

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

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MRT (h)

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

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

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AUC

Linear mixed effects regression results.

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 	Regression coefficient (SE)	<italic>p</italic> value	–Log likelihood<xref ref-type="table-fn" rid="TF4">a</xref>	<italic>R</italic>2a

Model A

 Duration	0.17 (0.11)	0.16	2.35	0.19

 Temperature	0.12 (0.11)	0.30	–	–

Model B

 AUC	2.6e-3 (6.8e-4)	0.003	3.36	0.56

 Temperature	0.18 (0.09)	0.07	–	–

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Tmax [h]

Pharmacokinetic parameters for IGSC 20% and IGIV 10% treatments

*Patients aged 12 years and older †Apparent clearance for SC administration.95% CI = 95% confidence interval; IGSC = s.c.immunoglobulin; IGIV = intravenous immunoglobulin; AUC = area under the curve

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CL0–τ,secretion (mL/min)d

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F

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).

F


k 10 half‐life

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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Q (l / h)

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

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Parameter (unit)	Definition of parameter	Bootstrap

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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t1/2, h

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

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

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

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Pharmacokinetic parameter	Mean	Median	CV%

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

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

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

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

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

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Cmax (μg/mL)

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

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

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AI Cmin (μg/mL) geomean (CV%)

The trough (Cmin) and end of infusion (Ceoinf) concentrations of SHR-1210 after the first dose (C1D1) and the dose at steady state (C5D1) and the corresponding accumulation index (AI)

Only 1 infusion was administered in C1 (4 weeks); Q2W dosing starts from C2.AI accumulation index, calculated as concentration (Cmin or Ceoinf) at C5 divided by the corresponding concentration at C1 of each dose, C Cycle, Cminday 14 concentration at C1 and C5, CV% coefficient of variation %, n number of subjects contributing to the mean, Q2W every 2 weeks.an = 11bn = 6cn = 11dn = 10en = 4

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V

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.

V


CSF concentration (ng/mL)

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

      0
      Unnamed: 0_level_0
      Multiple dose (mg)
      AUC(0–12 h) day 7/11 (ng.h/mL)
      AUC(0–12 h) day 7/11 (ng.h/mL)
      AUC(0–12 h) day 7/11 (ng.h/mL)
      CSF t1/2 (h)
      CSF concentration (ng/mL)
      CSF concentration (ng/mL)
      CSF concentration (ng/mL)
      CSF: QC inhibition (%)
      CSF: QC inhibition (%)
      CSF: QC inhibition (%)

      1
      Unnamed: 0_level_1
      Multiple dose (mg)
      AUC(0–12 h) day 7/11 (ng.h/mL)
      AUC(0–12 h) day 7/11 (ng.h/mL)
      AUC(0–12 h) day 7/11 (ng.h/mL)
      CSF t1/2 (h)
      Mean (AUC/12 h)
      Max (C 3 h)
      Min (C 12 h)
      Mean
      Max
      Min

      2
      Unnamed: 0_level_2
      Multiple dose (mg)
      Plasma
      CSF
      CSF/AUC (%)
      CSF t1/2 (h)
      Mean (AUC/12 h)
      Max (C 3 h)
      Min (C 12 h)
      Mean
      Max
      Min

      3
      Nonelderly healthy subjects
      20 (n = 8)
      120 (32.5)
      6
      5
      nan
      0.500000
      0.8
      0.3
      5
      8
      3

      4
      Nonelderly healthy subjects
      50 (n = 8)
      413 (37.3)
      17.3 (34.8)
      4.19 (13.0)
      6.21 (7.9)
      1.700000
      2.32 (34.5)
      0.75 (40.4)
      15
      19
      7

      5
      Nonelderly healthy subjects
      100 (n = 8; fed)
      969 (26.5)
      44.7 (27.2)
      4.65 (12.1)
      6.38 (6.9)
      4.000000
      6.02 (27.4)
      1.92 (29.6)
      29
      38
      16

      6
      Nonelderly healthy subjects
      200 (n = 8)
      1833 (35.1)
      91.7
      5
      nan
      7.600000
      12.2
      4.0
      44
      56
      29

      7
      Nonelderly healthy subjects
      400 (n = 8) capsule
      5946 (16.1)
      236 (25.0)
      3.97 (12.6)
      6.45 (9.7)
      24.800000
      31.4 (23.3)
      10.5 (33.0)
      72
      76
      52

      8
      Nonelderly healthy subjects
      500 (n = 8; fed) capsule
      9302 (63.0)
      465
      5
      nan
      38.800000
      62.0
      20.5
      80
      86
      68

      9
      Elderly healthy subjects
      200 (n = 6) capsule
      3891 (35.1)
      195
      5
      nan
      16.200000
      25.9
      8.6
      62
      73
      47

      10
      Elderly healthy subjects
      300 (n = 8) capsule
      5658 (48.1)
      275 (40.7)
      4.86 (11.8)
      6.22 (42.6)
      23.600000
      37.7
      12.5
      71
      79
      56

      11
      Elderly healthy subjects
      500 (n = 12) tablet
      11,851 (39.4)
      530 (36.6)
      5.27 (9.7)
      6.91 (5.2)
      49.400000
      79.0
      26.2
      84
      89
      73

      12
      Elderly healthy subjects
      800 (n = 6) tablet
      24,549 (46.0)
      1230
      5
      nan
      102.000000
      163.7
      54.2
      91
      94
      85

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

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Q1/F (L/h)

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

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

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AUC∞, mg*h/L

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

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

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t1/2, hr

Pharmacokinetic parameters of prasugrel active metabolite

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Prasugrel alone	Prasugrel + ritonavir	Ratio (prasugrel + ritonavir <italic>versus</italic> prasugrel alone)	CI 90%	<italic>p</italic>-value

<italic>t</italic>max, hr	0.5 (0.5–1)	0.5 (0.25–1.5)	1	0.5–2	0.73

<italic>t</italic>1/2, hr	1.62 (0.54)	1.42 (0.66)	0.94	0.66–1.22	0.33

<italic>C</italic>max, ng/ml	389.8 (226.2)	185.4 (83.1)	0.55	0.40–0.7	<bold>0.007</bold>

AUC, hr ng/ml	339.6 (144.7)	207.5 (91.1)	0.62	0.54–0.7	<bold>0.005</bold>

Values are presented as the means (±S.D.) for t1/2, Cmax and AUC and as median (range) for tmax values or mean ratios (prasugrel + ritonavir versus prasugrel alone) with 90% confidence intervals (CI 90%).tmax, time to reach maximal concentration; t1/2, elimination half-life; Cmax, maximal concentration; AUC, area under the concentration-time curve; Significant values (p < 0.05) were highlighted in bold.

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Final population PK model parameter estimates

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Population parameters	Interindividual variation (std. dev.)

Parameter	Description	Estimate	Std. error	Rel. std. error (%)
<italic>P</italic>‐value	Estimate	Std. error	Rel. std. error (%)

tlag (h)	Absorption lag time	0.67	‐	‐	1.92	0.20	10

ka (1/h)	Absorption rate constant	0.71	0.04	5	0.39	0.05	12

Vp/F (L)	Apparent volume of distribution, central compartment selexipag	12.90	2.00	16	0.31	0.12	38

Body weight on Vp/F	Covariate effect	1.20	0.30	25	<0.001

CL/F (L/h)	Apparent selexipag clearance	19.10	1.60	8	0.73	0.03	4

Body weight on CL/F	Covariate effect	0.61	0.15	25	<0.001

Total bilirubin on CL/F	Covariate effect	−0.40	0.07	18	<0.001

k12 (1/h)	Transfer rate constant central to peripheral compartment selexipag	0.09	0.02	18	0.25	0.18	73

k21 (1/h)	Transfer rate constant peripheral to central compartment selexipag	0.06	0.01	17	1.06	0.13	12

Vm/F (L)	Apparent volume of distribution, central compartment ACT‐333679	4.65	0.80	17	0.10	0.25	241

Body weight on Vm/F	Covariate effect	0.88	0.18	21	<0.001

kmet (1/h)	Metabolism rate constant selexipag to ACT‐333679	0.67	0.12	18	0.05	0.42	788

k34 (1/h)	Transfer rate constant central to peripheral compartment ACT‐333679	1.04	0.23	22	0.47	0.18	39

k43 (1/h)	Transfer rate constant peripheral to central compartment ACT‐333679	0.18	0.03	14	0.89	0.14	16

km (1/h)	Elimination rate constant ACT‐333679	0.49	0.08	16	0.27	0.06	20

Sex on km
	Covariate effect	0.15	0.05	31	0.001

PAH comedication on km (ERA)	Covariate effect	0.15	0.06	38	0.008

PAH comedication on km (PDE5 inh.)	Covariate effect	0.07	0.05	77	0.190

PAH comedication on km (ERA and PDE5 inh.)	Covariate effect	0.37	0.05	14	<0.001

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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% of unbound to plasma proteins

Volume of Distribution, Percentage of Unbound Plasma Proteins, log D, and log BBB Coefficient Partition of VLB and Its Metabolites

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

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

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VM (L)

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
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	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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θCL/F, ACS

Parameter estimates in the final population pharmacokinetic model

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

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

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

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

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

θV/F, weight
	Power	0.216	17.4	0.143	0.278

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

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

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

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

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

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

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

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

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

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

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

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

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

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

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If GFR 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‐t/dose, d·μg/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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If Age affect CL ?

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t maxa (h)

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

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

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c.1172 T > A p.I391N

Genetic variants distribution in different profiles of propofol metabolism rate.

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AUC0-∞ (µg/mL·h)

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

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