CL, dL/h

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

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

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F d

Pharmacokinetic parameters of MBZ-OS and MBZ-1% tragacanth in plasma and tissues of mice after oral administration at a single dose of 25 mg/kg

a: Tmax was time to the drug peak concentration.b: Cmax was the peak concentration of the drug.c: AUC0-t was the area under the drug concentration-time curve.d: F (relative bioaviability) = AUC0-t of MBZ-1% tragacanth/AUC0-t of MBZ-OS.

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CL (L/h)

Pharmacokinetic parameters – Cycle 1

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

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AUC0–t, μg × hr/ml

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

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

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

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

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Cmax (ng/mL)

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

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<bold>Study Population</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>HV</bold>

<bold>Dosing Day</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>14</bold>

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

<bold>50</bold>

<bold>50</bold>

<bold>100</bold>

<bold>100</bold>

<bold>150</bold>

<bold>200</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

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

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

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

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

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

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

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

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

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

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

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

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

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CL (L/h/kg)

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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MAT (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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AUC0-∝ (ng.h/ml)

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

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

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tmax(h)

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

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C240h, IU/mL*

Pharmacokinetic endpoints

The aPTT reagents used for the one‐stage clotting assay were SynthAFax and Actin FSL for N9‐GP and rFIXFc, respectively. The ROX factor IX kit was used for the chromogenic assay with both treatments. All assays were calibrated using NHP.aPTT, activated partial thromboplastin time; AUC0‐inf,norm, area under the FIX activity–time curve from 0 to infinity, dose‐normalized to 50 IU/kg; C168h, FIX activity at 168 h; C240h, FIX activity at 240 h; CL, clearance; Cmax,norm, maximum FIX activity dose‐normalized to 50 IU/kg; IR30min, incremental recovery at 30 min; CV, geometric coefficient of variation; NHP, normal human plasma; PK, pharmacokinetic; rFIXFc, recombinant factor IX‐Fc fusion protein; t ½, terminal half‐life; V ss, apparent volume of distribution at steady state.*N = 12; two patients missed the last two PK time‐points and were excluded from the analysis for these parameters.

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Tmax (h)

Point Estimates of Anagrelide

Point estimates (90% confidence intervals) of PK parameter are presented. Except for the MRT of the metabolite RL603, no PK parameter lies within the predefined margins (0.8–1.25). Thus, PK parameters are significantly different between AER and the commercially available reference product (CARP), and food intake has a significant impact on the PK of AER (P < .001 for all tests); n = 28.

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Cmax

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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Bioavailability

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

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

Mean	95 % CI	Mean	95 % CI

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

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

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

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

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

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

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k on (nM−1 min−1)

Kinetic characterization of [3H]INCB3344 and 15a in membranes of CHO cells transiently expressing murine CCR2 (mCCR2).

Values are means ± S.E.M of three separate experiments performed in duplicate. *Values of [3H]INCB3344 for hCCR2b were taken from Vilums et al. 25. †Values of 15a for hCCR2b were taken from Vilums et al. 24. ‡Kinetic rate index (KRI) = Bt1/Bt2 (see Materials and Methods). § K D = k off/k on. ||RT = 1/k off.

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AUClast (h*ng/mL)

Summary statistics: oxycodone PK parameters

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

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θCL/F, Medium CYP3A4 inhibitor

Parameter estimates in the final population pharmacokinetic model

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

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

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

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

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

θV/F, weight
	Power	0.216	17.4	0.143	0.278

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

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

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

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

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

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

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

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

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

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

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

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

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

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

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Cmax(ng mL-1)

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Ae, mg

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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C MAX

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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ALAG1: Lag time (d)

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

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Parameter	Final parameter estimate	Between‐subject variability

Typical value	%RSE	Magnitude	%RSE

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

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

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

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

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

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

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

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

F1: Bioavailability	0.658	FIXED	NE	NA

ALAG1: Lag time (d)	0.0803	FIXED	NE	NA

Residual variability iv	0.0467	32.6	NA	NA

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

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

Minimum value of the objective function = 73303.561

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

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t1/2 (min)

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

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

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Kel (1/h)

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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t1/2 (h)

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

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V T2 (L)

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

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

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

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

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

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

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

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

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

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

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

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

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CsA

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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Mean Cavg0–168h—ng/dL (SD) ¶

Summary of steady‐state pharmacokinetic parameters by treatment

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

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t1/2 (hours)

Non-compartmental PK parameters (geometric means ± geometric coefficients of variation, unless otherwise stated) for the first and second infusions of BI 831266

aMedian (minimum, maximum)–Insufficient data to calculate descriptive statistics AUC 0–24 area under the plasma concentration–time curve over the time interval from 0 to 24 h after the start of infusion; AUC 0–∞ area under the plasma concentration–time curve over the time interval from 0 extrapolated to infinity; CL total clearance of analyte in plasma after intravenous administration; C max maximum measured concentration; norm dose normalized; PK pharmacokinetic; t 1/2 terminal half-life; t max time from dosing to maximum measured concentration

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AUC [g*days/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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Control AUCss (pg/ml)

Simulated (10 trials × 10 female HV) population mean (range of trial means) steady state AUC for different doses of EE (20 μg, 35 μg, 50 μg) alone and in the presence of various degrees of CYP modulation

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EE dosing	Control AUCss (pg/ml)	CYP3A4 inhibition<xref ref-type="fn" rid="cpt1085-note-0006">a</xref>AUCss (pg/ml)	Complete CYP inhibition<xref ref-type="fn" rid="cpt1085-note-0007">b</xref> AUCss (pg/ml)	Strong CYP3A4 induction<xref ref-type="fn" rid="cpt1085-note-0008">c</xref> AUCss (pg/ml)	Moderate CYP3A4 induction<xref ref-type="fn" rid="cpt1085-note-0009">d</xref> AUCss (pg/ml)

20 µg multiple dosing	670 (578–737)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>
	902 (779–1054)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>
	1169 (972–1334)	244 (205–395)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>
	412 (367–437)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>

<italic>N</italic> of individuals below lower threshold value	86	59	36	100	99

<italic>N</italic> of individuals above upper threshold value	0	3	7	0	0

35 µg multiple dosing	1172 (1012–1290)	1579 (1404–1844)	2046 (1702–2335)<xref ref-type="fn" rid="cpt1085-note-0011">f</xref>
	427 (310–520)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>
	720 (632–765)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>

<italic>N</italic> of individuals below lower threshold value	38	13	5	95	90

<italic>N</italic> of individuals above upper threshold value	13	40	64	0	1

50 µg multiple dosing	1675 (1446–1844)	2256 (1949–2634)<xref ref-type="fn" rid="cpt1085-note-0011">f</xref>
	2923 (2431–3336)<xref ref-type="fn" rid="cpt1085-note-0011">f</xref>
	609 (443–743)<xref ref-type="fn" rid="cpt1085-note-0010">e</xref>
	1029 (902–1161)

<italic>N</italic> of individuals below lower threshold value	12	4	2	87	49

<italic>N</italic> of individuals above upper threshold value	41	74	89	1	7

aSimulation was done in the presence of multiple doses of 200mg ketoconazole BD (CYP3A4 Ki = 0.015 µM) as perpetrator.bSimulation was done in the presence of a hypothetical compound as perpetrator with potent inhibition against CYP1A2, CYP2C8, CYP2C9, CYP3A4 (Ki = 0.015 µM) as perpetrator.cSimulation was done in the presence of multiple doses of 600mg rifampicin QD, a strong CYP3A4 inducer as perpetrator (Indmax = 16, IndC50 = 0.32 µM).dSimulation was done in the presence of multiple doses of 600mg efavirenz QD, a moderate CYP3A4 inducer as perpetrator (Indmax = 9.9, IndC50 = 3.8 µM).eSimulations in which the population mean is below the threshold of 1000pg/ml.h.fSimulations in which the population mean is above that of a 50 µg dose of EE.

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Terminal t1/2, h

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

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

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

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

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

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

Clearance, L/week	13.3 (9.17, 22.8)

Volume, L	4.58 (4.14, 4.99)

First‐phase t1/2, h	38.2 (23.2–56.7)

Terminal t1/2, h	12200 (3990–50200)

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

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

Clearance, L/week	14.0 (12.7–14.6)

Terminal t1/2, h	38.2 (36.5–41.9)

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

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

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

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

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

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      0
      1
      2
      3
      4

      0
      Parameter
      Study
      Study
      Study
      Study

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

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

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

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

      5
      t max (h)b
      4.0 (1.0–5.0)
      4.0 (3.0–6.0)
      3.0 (0.5–5.0)
      1.75 (1.0–5.0)

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

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

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

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

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

CAPTION: Summary of amenamevir pharmacokinetic parameters after administration of a single 400-mg dose of amenamevir alone and with ketoconazole at a dosage of 400 mg once daily or rifampicin at a dosage of 600 mg once daily
FOOTER: All values are presented as the arithmetic mean ± standard deviation unless stated otherwise AUC inf area under the plasma concentration versus time curve from time zero to infinity, CL/F clearance, C max maximum plasma concentration, LS GMR least squares geometric mean ratio, t ½ half-life, t max time to maximum plasma concentration aValues are presented as the geometric mean ± standard deviation bValues are presented as the median, with the range in parentheses cThe 90% confidence interval is given in parentheses

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      0
      1
      2

      0
      Parameters
      Units
      Values

      1
      Emax
      Log CFU/mL
      2.71 ± 0.37

      2
      E0
      Log CFU/mL
      −4.61 ± 0.69

      3
      Emax−E0
      Log CFU/mL
      7.32 ± 1.06

      4
      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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      0
      1
      2
      3
      4
      5

      0
      Unnamed: 0
      Group
      T0
      T1
      T2
      T3

      1
      BIS
      Male (n = 10)
      95 ± 3
      92 ± 5
      44 ± 13
      43 ± 17

      2
      nan
      Female (n = 11)
      94 ± 5
      94 ± 5
      43 ± 15
      44 ± 14

      3
      MAP
      Male (n = 10)
      100 ± 17
      106 ± 15
      90 ± 12
      88 ± 10

      4
      nan
      Female (n = 11)
      102 ± 18
      117 ± 22
      91 ± 12
      95 ± 13

      5
      HR
      Male (n = 10)
      67 ± 14
      58 ± 8
      60 ± 14
      64 ± 13

      6
      nan
      Female (n = 11)
      69 ± 13
      61 ± 12
      57 ± 10
      61 ± 11

CAPTION: Hemodynamic and bispectral index data for successful i-gel insertion
FOOTER: Values are represented as mean ± SD. BIS, bispectral index; MAP, mean arterial blood pressure (mmHg); HR, heart rate (beats/min). T0, baseline value (before anesthesia induction); T1, after dexmedetomidine administration; T2, immediately before i-gel insertion; T3, 3 min after i-gel insertion

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k

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

AMS amisulpride, IS internal standard (metoclopramide)

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tvKa (h-1)

Values of parameter estimates of sunitinib

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Tmax

Pharmacokinetic parameters in plasma after 4 mg/kg i.v. and i.m. administration, respectively.

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Parameters	Units	i.v	i.m

AUC24 h	μg∗h/ml	7.10 ± 0.91	3.94 ± 0.62

AUC	μg∗h/ml	7.94 ± 1.11	6.79 ± 0.45

<italic>T</italic>max	h	–	0.25 ± 0.06

<italic>T</italic>1/2	h	24.02 ± 3.12	44.04 ± 4.56

<italic>C</italic>max	μg/ml	–	0.98 ± 0.11

CLb	L/h	0.46 ± 0.08	0.43 ± 0.07

MRTlast	h	8.06 ± 1.6	22.85 ± 2.96

<italic>F</italic>	%	85.5 ± 7.11

AUC24 h, the area under the curve within 24 h; AUC, the area under the curve; Tmax, the time to peak concentration; T1/2, the eliminate half-life; Cmax, the peak concentration; CLb, relative total systemic clearance; MRT, the mean residence time; F, the bioavailability.

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C0 (µg/mL)

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T max (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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Vp/F, L

Final population model estimates of pantoprazole

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

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T max, h

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

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

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AUCinf

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Parameter	Study

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

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

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

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

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

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

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

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

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

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

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Cmax (ng/mL)

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

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

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

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

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Cmax (pg/mL)

Summary of glycopyrronium pharmacokinetic parameters (mITT population)

aMedian (Min, Max); bn = 11; cn = 10; dn = 12; en = 19; fn = 16.AUCx-y = area under the concentration-time curve from time x to time y; CL/F = apparent oral clearance; Cmax = maximum plasma concentration; CV% = coefficient of variation; GP MDI = glycopyrronium metered-dose inhaler; t1/2 = apparent terminal elimination half-life; tmax = time to maximum concentration; Vz/F = apparent volume of distribution; mITT=modified intention to treat.

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M + F

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

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AUC0–30 (ng · day/ml)

MEDI4893 nasal pharmacokinetic parameters for each dose determined by noncompartmental analysisa

aData are expressed as the mean ± standard deviation.

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t (4;14)

Demographics and Other Baseline Characteristics.

ASCT: autologous stem cell transplantation, IMiDs: immunomodulatory drugs

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tvV (mL)

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Cmax (ng/mL)

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

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AUC∞ (ng·h/mL)

Plasma pharmacokinetic parameters of fexinidazole (single-dose studies)

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

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AUC

Baseline clinical characteristics and their effects on pharmacokinetics and the recovery of platelet function in 51 healthy subjects.

BMI, body mass index; FIB, fibrinogen; APTT, activated partial thromboplastin time; TT, thrombin time; PT-A, prothrombin activity; PT, prothrombin time; INR, international normalized ratio; WBC, white blood cell count; RBC1, red blood cell count; MCH, mean corpuscular hemoglobin; PLT, platelet count; URIC, uric acid; CREA, creatinine; ALT, alanine aminotransferase; TP, total protein; ALB, albumin; DBIL, direct bilirubin; TBIL, total bilirubin; ADP, RBC2, red blood cell in urine; ERY, erythrocyte; OB, stool occult blood test; C max, Peak concentration; T max, time of peak concentration; t1/2, elimination half-life; AUC, area of plasma concentration–time curve; RT50, time to 50% recovery of maximum drug effect; RECDAY, recover day to the baseline PA. All correlation analyses were undertaken using Spearman correlation coefficients except those variables marked a, b.aRepeated measures data ANOVA.bMann-Whitney U-test.†RT50 and RECDAY were successfully acquired in 47 subjects.The color values refer to the results with P < 0.05 that considered as significant.

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Frel (%)*

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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Citrate half-life (min)

Pharmacokinetic data

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

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

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

Citrate mass removal (%)	83 ± 5

Citrate half-life (min)	60 ± 29

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

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

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

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

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AUC, mg.h/l

Pharmacokinetic profile across study groups

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

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AR

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

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

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AUC0–12 (pg•h/mL)

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V u,brain (WT) (mL/g brain)

      0
      1
      2
      3
      4

      0
      Parameters
      SLOH
      SLOH
      SLM
      SLM

      1
      Parameters
      Mouse
      Human
      Mouse
      Human

      2
      Blood to plasma ratio
      1.30 ± 0.250
      0.760 ± 0.0800
      1.40 ± 0.100
      0.820 ± 0.0800

      3
      f u,plasma %
      3.50 ± 0.700$
      0.170 ± 0.0400
      1.70 ± 0.380$
      0.100 ± 0.0100

      4
      f u,mic %
      17.0 ± 2.40$
      6.60 ± 1.60
      11.0 ± 1.06$
      7.30 ± 0.150

      5
      f u,hep, %
      16.0 ± 5.50
      5.50 ± 0.730$$
      15.0 ± 4.60
      11.0 ± 0.870$$

      6
      V u,brain (WT) (mL/g brain)
      1.40 ± 0.400
      —
      2.10 ± 0.650
      —

      7
      V u,brain (AD) (mL/g brain)
      1.20 ± 0.240
      —
      1.50 ± 0.580
      —

CAPTION: Blood cell partitioning, non-specific plasma, microsomes, hepatocytes and brain distribution by slices of SLM and SLOH (n = 3, Mean ± SD).
FOOTER: Statistical significance in parameters was estimated by student’s t-test. $ p < 0.05 and $$ p < 0.01, (SLOH vs SLM).

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Vd

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

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Apparent central volume of distribution

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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Q2/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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Cmax [ng/L]

Descriptive statistics of pharmacokinetic and pharmacodynamic parameters following epinephrine administration grouped by treatment (uncorrected values, per protocol population of n = 8)

aarithmetic means and standard deviations (SD); AUC area under the concentration vs. time profile (indices apply for the postdose time interval); AUEC area under the effect curve; Cmax maximal concentration; Emax maximal effect; MRTlast mean residence time calculated from concentrations up to the last point of observation; tmax, time of Cmax; BP blood pressure. Fractional AUC values for blood pressure are presented in the supplementary material

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MRTlast (h)

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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C max (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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θCL/F, VTE ≤72 h

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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F1 dihydrotestosterone (ng/mL)

      0
      1
      2
      3
      4

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

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

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

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

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

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

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

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

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QP1 (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
M
	27.2 (6)	—

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

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

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

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

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

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Parameters	 	Canagliflozin	DPTQ	DPTQ‐O‐glucuronide

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

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

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

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

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

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

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

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Final population PK model parameter estimates

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Population parameters	Interindividual variation (std. dev.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sex on km
	Covariate effect	0.15	0.05	31	0.001

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

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

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

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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T1/2, hours

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

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

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AUC0-inf (pg•h/mL)

Summary of glycopyrronium pharmacokinetic parameters (mITT population)

aMedian (Min, Max); bn = 11; cn = 10; dn = 12; en = 19; fn = 16.AUCx-y = area under the concentration-time curve from time x to time y; CL/F = apparent oral clearance; Cmax = maximum plasma concentration; CV% = coefficient of variation; GP MDI = glycopyrronium metered-dose inhaler; t1/2 = apparent terminal elimination half-life; tmax = time to maximum concentration; Vz/F = apparent volume of distribution; mITT=modified intention to treat.

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Cmax (μg/mL)

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

<!DOCTYPE html>

Body weight

5 to < 10 kg	10 to < 15 kg

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

Dispersible tablet	N = 171	N = 352

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

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

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

Crushed tablet	N = 183	N = 37

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

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

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

<bold>Lumefantrine</bold>

Dispersible tablet	N = 24	N = 78

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

Cmax (μg/mL)	6.55	5.55

AUC0-last (μg·h/mL)	550	393

Crushed tablet	N = 26	N = 75

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

Cmax (μg/mL)	5.50	6.29

AUC0-last (μg·h/mL)	578	558

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

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AUCnorm (kg·h/L)

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

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Parameter	Geometric mean/%CV	Range

Primary pharmacokinetic parameters

AUC∞ (μg·h/L)	354.4/30.3	209.7–458.0

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

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

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

MRT (h)	10.68/14.8	8.823–13.34

Secondary pharmacokinetic parameters

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

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

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

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

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

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Cmax artemether (ng/mL)

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Vss (liters)

Plazomicin plasma pharmacokinetic parameters by renal function groupa

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PK parameter	Normal renal <break/>function (<italic>n</italic> = 6)	Mild renal <break/>impairment (<italic>n</italic> = 6)	Moderate renal <break/>impairment (<italic>n</italic> = 6)	Severe renal <break/>impairment (<italic>n</italic> = 6)

Cmax (mg/liter)	37.9 ± 5.01	32.8 ± 4.30	39.2 ± 6.43	41.4 ± 7.83

AUC0–∞ (mg · h/liter)	136 ± 17.2	138 ± 23.7	281 ± 96.0	647 ± 259

Vss (liters)	36.0 ± 7.76	28.5 ± 2.17	25.8 ± 6.96	25.1 ± 7.89

CLT (liters/h)	4.64 ± 1.17	3.98 ± 0.481	2.25 ± 0.685	0.96 ± 0.379

aAll values are reported as mean ± SD. PK, pharmacokinetics; Cmax, maximum concentration of drug in plasma; AUC0–∞, area under the concentration-time curve from 0 h to infinity; Vss, volume of distribution at steady state; CLT, total clearance.

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Baseline clinical characteristics and their effects on pharmacokinetics and the recovery of platelet function in 51 healthy subjects.

BMI, body mass index; FIB, fibrinogen; APTT, activated partial thromboplastin time; TT, thrombin time; PT-A, prothrombin activity; PT, prothrombin time; INR, international normalized ratio; WBC, white blood cell count; RBC1, red blood cell count; MCH, mean corpuscular hemoglobin; PLT, platelet count; URIC, uric acid; CREA, creatinine; ALT, alanine aminotransferase; TP, total protein; ALB, albumin; DBIL, direct bilirubin; TBIL, total bilirubin; ADP, RBC2, red blood cell in urine; ERY, erythrocyte; OB, stool occult blood test; C max, Peak concentration; T max, time of peak concentration; t1/2, elimination half-life; AUC, area of plasma concentration–time curve; RT50, time to 50% recovery of maximum drug effect; RECDAY, recover day to the baseline PA. All correlation analyses were undertaken using Spearman correlation coefficients except those variables marked a, b.aRepeated measures data ANOVA.bMann-Whitney U-test.†RT50 and RECDAY were successfully acquired in 47 subjects.The color values refer to the results with P < 0.05 that considered as significant.

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tmaxb (hr)

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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CL/F (L/h)

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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Log CFU/mL

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      Emax
      Log CFU/mL
      2.71 ± 0.37

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      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

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      N (slope)
      /
      4.62 ± 0.72

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      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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Maximum elimination rate Vmax (mg/day)

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

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

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Total bilirubin on CL/F

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Covariate 1: ALB on CL

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CL/F or CL (mL/hr)

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

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

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Other malignancies on CL/Fb

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

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

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C max [ng/mL; mean ± SD]

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

<!DOCTYPE html>

Parameter	Clopidogrel	H3	H4 (active)	CLPM

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

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

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

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

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

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

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

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

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

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

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max [h; mean ± SD]	1.17 ± 0.76	0.83 ± 0.29	0.83 ± 0.29	1.61 ± 1.21

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½ [h; mean ± SD]	1.99 ± 0.44	0.72 ± 0.18	0.84 ± 0.20	7.11 ± 3.50

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

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

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

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

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

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

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

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Time to second treatment (TST)

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      Unnamed: 0_level_0
      Unnamed: 1_level_0
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      Kout (day-1)
      V1(L)
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      0.90
      0.99

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      Sex male versus female
      23 versus 21
      0.59
      0.53
      0.34
      0.37

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

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

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      Treatment RB versus RFC
      17 versus 28
      0.48
      0.82
      0.76
      0.99

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      Lymphocytosis
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      0.59
      0.30
      0.96
      0.99

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      Areas of lymphadenopathy
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      0.39
      0.96
      0.51

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

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

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

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      Cytogenetics
      Cytogenetics
      Cytogenetics
      Cytogenetics
      Cytogenetics
      Cytogenetics

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

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      Trisomy 12 versus others
      10 versus 34
      0.59
      0.92
      0.76
      0.37

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      Normal caryotype versus others
      4 versus 40
      0.89
      0.39
      0.96
      0.66

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

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

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      Time to relapse (TTR)
      44
      0.59
      0.82
      0.96
      0.99

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

CAPTION: Univariate analysis of pharmacokinetic parameters and biological or clinical variables
FOOTER: 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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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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Tmax (h)

The pharmacokinetic parameters of nicergoline for two preparations in 20 healthy volunteers after administration of a single 30 mg oral dose (Mean±SD).

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Parameter	Test	Reference	<italic>P</italic> value<xref rid="tbl3fna" ref-type="table-fn">a</xref>

<italic>T</italic>1/2 (h)	8.427±1.217	9.305±1.797	NS

<italic>T</italic>max (h)	3.400±0.417	3.300±0.479	NS

<italic>C</italic>max (ng/mL)	34.504±10.231	32.851±10.869	NS

<italic>AUC</italic>0−<italic>t</italic> [ng/(h mL)]	353.752±67.617	340.047±64.966	NS

<italic>AUC</italic>0−<italic>∞</italic> [ng/(h mL)]	388.380±66.735	382.912±62.208	NS

T1/2: elimination half time; Tmax: time to maximum concentration; Cmax: maximum concentration; AUC0−t: area under the plasma concentration–time curve from 0 h to the last concentration observed; AUC0−∞: area under the plasma concentration–time curve from 0 h to infinity.

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Cmax (ng/mL)

Pharmacokinetic parameters of eribulin (cycle 1, day 1)

Mean ± SD AUC (0-inf) area under the concentration-time curve from time zero to infinity, CL total clearance, C max maximum plasma concentration, t ½ terminal half-life, V ss steady-state volume of distribution

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IC50 (μM) ± SEMa

Inhibition potency of coumarinyl thiazoles 6(a–o) against AChE and BuChE.

aSEM, Standard mean error of three experiments.

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Chow et al. (2005); 1200 mg PE

      0
      1
      2
      3
      4
      5

      0
      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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C max (μg/dL)

Geometric mean and ratio of Aln-NEF and LT4 concurrently to LT4 alone for LT4

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Pharmacokinetic parameter (units)	Estimated geometric meana
	Ratio of meansb
	90% CI

Aln-NEF + LT4 (<italic>n</italic> = 29)	Aln-NEF (<italic>n</italic> = 29)	Lower limit	Upper limit

<italic>C</italic>
max (μg/dL)	3.694	3.437	1.075	1.006	1.148

AUC0–48 (μg·h/dL)	97.457	92.931	1.049	0.983	1.119

aEstimated geometric means are from the statistical model using terms for sequence, subject, period, and treatment b \documentclass[12pt]{minimal} 				\usepackage{amsmath} 				\usepackage{wasysym}  				\usepackage{amsfonts}  				\usepackage{amssymb}  				\usepackage{amsbsy} 				\usepackage{mathrsfs} 				\usepackage{upgreek} 				\setlength{\oddsidemargin}{-69pt} 				\begin{document}$$ \frac{\mathrm{Aln}-\mathrm{NEF}+\mathrm{LT}4}{\mathrm{LT}4} $$\end{document}Aln−NEF+LT4LT4

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

      0
      Unnamed: 0_level_0
      Unnamed: 1_level_0
      Unnamed: 2_level_0
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper
      Correlation degree of target proteins in C–T–D network/fit scores of proteins in target fishing by PharmMapper

      1
      Protein or gene
      Uniprot ID
      Closely relative diseases to myocardial ischemia
      Rg1
      Rb1
      Rd
      R1
      CTS
      DHI
      TS I
      TS IIA
      Total (all ingredients against one target)

      2
      F2
      P00734
      Myocardial infarction, coronary ischemic syndrome, coronary heart disease
      12/2.899
      12/2.915
      12/3.169
      –
      –
      12/2.746
      –
      12/2.858
      60/14.587

      3
      MAPK10
      P53779
      Angina
      –
      10/2.984
      10/2.964
      8/2.963
      8/2.752
      8/2.71
      9/2.752
      9/2.735
      62/19.86

      4
      ESR1
      P03372
      Myocardial infarction, coronary heart disease
      6/2.904
      6/3.008
      –
      6/3.149
      6/2.866
      6/2.852
      8/2.866
      8/2.581
      46/20.226

      5
      HSD11B1
      P28845
      ∗
      7/3.155
      –
      –
      –
      7/3.142
      7/3.805
      8/3.142
      –
      29/13.244

      6
      CASP3
      P42574
      Ischemia
      7/2.92
      7/2.948
      7/2.928
      7/2.978
      –
      –
      –
      –
      28/11.774

      7
      CMA1
      P23946
      Heart failure
      –
      –
      8/2.693
      8/2.681
      –
      –
      –
      –
      16/5.374

      8
      SEC14L2
      O76054
      ∗
      –
      –
      –
      3/3.972
      3/3.61
      3/3.636
      3/3.61
      3/3.502
      15/18.33

      9
      MAOB
      P27338
      Ischemia
      6/4.359
      –
      –
      –
      –
      –
      –
      –
      6/4.359

      10
      SOD2
      P04179
      Oxidative injury
      5/3.447
      –
      –
      –
      –
      –
      –
      –
      5/3.447

      11
      PLAU
      P00749
      ∗
      –
      –
      3/3.52
      –
      –
      –
      –
      –
      3/3.52

      12
      PDE5A
      O76074
      ∗
      –
      –
      2/2.954
      –
      –
      –
      –
      –
      2/2.954

      13
      CTSS
      P25774
      ∗
      –
      –
      –
      2/2.845
      –
      –
      –
      –
      2/2.845

      14
      RTN4R
      Q9BZR6
      ∗
      –
      –
      –
      2/2.511
      –
      –
      –
      –
      2/2.511

      15
      HMGCR
      P04035
      ∗
      –
      2/3.744
      –
      –
      –
      –
      –
      –
      2/3.744

      16
      Total (closely relative to myocardial ischemia issues)
      Total (closely relative to myocardial ischemia issues)
      Total (closely relative to myocardial ischemia issues)
      36/16.529
      35/11.855
      37/11.754
      29/11.771
      14/5.618
      26/8.308
      17/5.618
      29/8.174
      nan

      17
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan
      nan

CAPTION: The results of systems pharmacology investigation for the eight ingredients in GDPP.
FOOTER: ∗Means the others related-cardiovascular affairs excluded.–Represents the protein failed to be selected in the target fishing due to negative z′-score by PharmMapper.

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T1/2 (h)

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Body weight on Vm/F

Final population PK model parameter estimates

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T½ (hr)

A comparison between the pharmacokinetic parameters of moxifloxacin obtained by microbiological & HPLC methods with those reported previously

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Pharmacokinetic parameters	Values by microbiological assay	Values by HPLC assay	Reported values

Cmax (µg/ml)	3.14 ± 0.28	3.06 ± 0.26	3.10 ± 1.0<xref ref-type="table-fn" rid="tf6-1">*</xref>	3.34<xref ref-type="table-fn" rid="tf6-2">‡</xref>

Tmax (hr)	1.50 ± 0.32	1.58 ± 0.38	1.4 ± 0.20<xref ref-type="table-fn" rid="tf6-1">*</xref>	1.70<xref ref-type="table-fn" rid="tf6-2">‡</xref>

AUC0^M (µg.hr/ml)	30.8 ± 3.60	31.3 ± 6.33	36.1 ± 9.10<xref ref-type="table-fn" rid="tf6-1">*</xref>	33.8<xref ref-type="table-fn" rid="tf6-2">‡</xref>

T½ (hr)	14.04 ± 1.71	13.2 ± 1.39	11.5 – 15.6<xref ref-type="table-fn" rid="tf6-1">*</xref>	12.1<xref ref-type="table-fn" rid="tf6-2">‡</xref>

*Data obtained from (6).‡Data summarized from (18, 32).

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AUC0-0.75 (ng•h/mL)

Mean (SD) pharmacokinetic parameters for hydrocodone by treatment

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

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      0
      1
      2
      3
      4
      5

      0
      Unnamed: 0
      Group
      T0
      T1
      T2
      T3

      1
      BIS
      Male (n = 10)
      95 ± 3
      92 ± 5
      44 ± 13
      43 ± 17

      2
      nan
      Female (n = 11)
      94 ± 5
      94 ± 5
      43 ± 15
      44 ± 14

      3
      MAP
      Male (n = 10)
      100 ± 17
      106 ± 15
      90 ± 12
      88 ± 10

      4
      nan
      Female (n = 11)
      102 ± 18
      117 ± 22
      91 ± 12
      95 ± 13

      5
      HR
      Male (n = 10)
      67 ± 14
      58 ± 8
      60 ± 14
      64 ± 13

      6
      nan
      Female (n = 11)
      69 ± 13
      61 ± 12
      57 ± 10
      61 ± 11

CAPTION: Hemodynamic and bispectral index data for successful i-gel insertion
FOOTER: Values are represented as mean ± SD. BIS, bispectral index; MAP, mean arterial blood pressure (mmHg); HR, heart rate (beats/min). T0, baseline value (before anesthesia induction); T1, after dexmedetomidine administration; T2, immediately before i-gel insertion; T3, 3 min after i-gel insertion

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CL/F ∼ proof-of-concept

Parameter estimates of final dolutegravir population PK model

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

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t ½, abs-2 (days)

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

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<colgroup span="1"><col valign="top" align="left" span="1"/><col valign="top" align="char" char="" span="1"/><col valign="top" align="char" char="" span="1"/></colgroup>

Parameter	Mean	Bootstrap, median (95% CI)

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

Structural model parameters

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

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

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

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

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

Variable model parameters (shrinkage%)

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

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

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

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

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

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

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

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

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tvCl/F (mL/h)

Values of parameter estimates of sunitinib

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Auc0-12 (ng.h/ml)

PHARMACOKINETIC PARAMETERS OF COMPOUNDS LM 13765 AND LM 13765-C

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

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Systolic BP AUEC0-tlast*

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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F

Pharmacokinetics of S3643 in Male (n = 4) and Female (n = 4) Sprague-Dawley Rats.

Male rat: CL = 5.97 mL/min/kg; Vss = 337 mL/kg Female rat: CL = 8.03 mL/min/kg; Vss = 325 mL/kg.CL = clearance; Vss = steady-state volume of distribution; % F = bioavailability.

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