k d (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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Cmax (μg/ml)

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

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

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

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

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

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

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

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

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

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

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

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

AUC0–∞ (h · μg/ml)	61.4 (33.0–231)

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

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

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

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Cmax (µg/ml)

Pharmacokinetic parameters obtained after oral administration of optimized DRC (TAP-KyronT-134 complex) and TAP solution at a dose equivalent to 3 mg/Kg TAP.

*p < 0.05 level of significant difference; **p < 0.001 level of significant difference.

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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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T interval, ms

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

      0
      Variable
      N (%) or Mean ± SD
      Comparison with 7 days post-dosea
      P-value of ticagrelor
      P-value of ticagrelor
      P-value of ticagrelor
      P-value of ticagrelor
      P-value of M8
      P-value of M8
      P-value of M8
      P-value of M8
      RT50†
      RECDAY†

      1
      Unnamed: 0_level_1
      Unnamed: 1_level_1
      Unnamed: 2_level_1
      t1/2
      Tmax
      Cmax
      AUC
      t1/2
      Tmax
      Cmax
      AUC
      Unnamed: 11_level_1
      Unnamed: 12_level_1

      2
      Age (years)
      24.51 ± 2.32
      /
      0.632
      0.748
      0.137
      0.986
      0.163
      0.366
      0.107
      0.675
      0.109
      0.012

      3
      Male
      27 (52.94%)
      /
      0.004
      0.010
      0.122
      0.865
      0.497
      0.034
      0.007
      <0.001
      0.149
      0.014

      4
      BMI, kg/m2
      20.69 ± 2.32
      /
      0.986
      0.805
      0.079
      0.696
      0.358
      0.757
      0.125
      0.062
      0.130
      0.108

      5
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS

      6
      FIB, g/L
      2.74 ± 0.46
      0.880
      0.206
      0.072
      0.219
      0.165
      0.345
      0.198
      0.060
      0.003
      0.702
      0.469

      7
      APTT, sec
      38.24 ± 3.69
      0.108
      0.346
      0.838
      0.900
      0.859
      0.577
      0.798
      0.735
      0.208
      0.750
      0.284

      8
      TT, sec
      16.34 ± 0.90
      0.880
      0.079
      0.788
      0.601
      0.526
      0.769
      0.042
      0.788
      0.012
      0.551
      0.206

      9
      PT-A, %
      98.29 ± 8.68
      0.018
      0.209
      0.374
      0.624
      0.191
      0.253
      0.505
      0.245
      0.166
      0.989
      0.754

      10
      PT, sec
      13.3 ± 0.46
      <0.001
      0.531
      0.502
      0.864
      0.402
      0.456
      0.456
      0.190
      0.124
      0.369
      0.643

      11
      INR
      1.01± 0.05
      <0.001
      0.459
      0.209
      0.734
      0.349
      0.978
      0.560
      0.814
      0.204
      0.206
      0.983

      12
      WBC, 10∧9/L
      6.05 ± 1.06
      0.075
      0.472
      0.692
      0.167
      0.692
      0.580
      0.506
      0.150
      0.458
      0.675
      0.835

      13
      RBC1, 10∧9/L
      4.86 ± 0.62
      0.261
      0.069
      0.155
      0.174
      0.953
      0.420
      0.116
      0.014
      <0.001
      0.345
      0.353

      14
      MCH, pg
      29.30 ± 2.16
      0.698
      0.817
      0.768
      0.609
      0.493
      0.626
      0.394
      0.747
      0.449
      0.397
      0.921

      15
      PLT, 10∧9/L
      229.49 ± 47.84
      0.154
      0.483
      0.758
      0.923
      0.356
      0.937
      0.324
      0.751
      0.502
      0.269
      0.414

      16
      URIC, umol/L
      342.81 ± 76.14
      0.305
      0.004
      0.029
      0.996
      0.054
      0.529
      0.778
      0.121
      0.036
      0.198
      0.036

      17
      CREA, umol/L
      71.13 ± 13.97
      0.007
      0.064
      0.030
      0.009
      0.058
      0.960
      0.144
      0.055
      <0.001
      0.988
      0.326

      18
      ALT, U/L
      17.33 ± 9.86
      0.569
      0.312
      0.791
      0.011
      0.589
      0.414
      0.327
      0.003
      0.007
      0.794
      0.923

      19
      TP, g/L
      73.46 ± 5.01
      0.164
      0.985
      0.998
      0.975
      0.768
      0.682
      0.975
      0.312
      0.560
      0.558
      0.066

      20
      ALB, g/L
      46.01 ± 2.96
      0.205
      0.756
      0.457
      0.127
      0.427
      0.567
      0.835
      0.071
      0.407
      0.754
      0.004

      21
      DBIL, umol/L
      4.48 ± 0.92
      0.502
      0.806
      0.328
      0.168
      0.170
      0.136
      0.388
      0.286
      0.003
      0.576
      0.860

      22
      TBIL, umol/L
      15.80 ± 5.51
      0.004
      0.578
      0.386
      0.201
      0.500
      0.691
      0.975
      0.073
      0.018
      0.574
      0.590

      23
      Heart rate, bpm
      67.51 ± 9.31
      0.873
      0.302
      0.580
      0.304
      0.425
      0.008
      0.020
      0.491
      0.331
      0.365
      0.385

      24
      T interval, ms
      408.43 ± 25.45
      0.379
      0.226
      0.908
      0.368
      0.718
      0.046
      0.039
      0.378
      0.393
      0.660
      0.326

      25
      ADP, %
      68.18 ± 6.35
      /
      0.439
      0.724
      0.941
      0.829
      0.710
      0.950
      0.938
      0.350
      0.154
      0.038

      26
      ERYb
      6 (11.76%)
      /
      0.952
      0.339
      0.244
      0.492
      0.720
      0.731
      0.227
      0.698
      0.453
      0.576

      27
      RBC2
      –
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /

      28
      OB
      –
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /

CAPTION: Baseline clinical characteristics and their effects on pharmacokinetics and the recovery of platelet function in 51 healthy subjects.
FOOTER: 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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Cmax (ng/ml)

Mean PK parameters (SD) of ST zolpidem

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AUClast (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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CL (L/hr/kg)

A comparison of the artemether pharmacokinetic properties to literature values

aMedian and ranges were derived from the empirical Bayes estimates.bPopulation estimate (%RSE).cAfter a single dose of 300 mg artemether and four consecutive 100 mg artemether doses daily.dAfter a single dose of artemether-lumefantrine (Co-Artem).eAfter five doses artemether mono-therapy.AUC: area under the concentration-time curve, CMAX: maximum concentration, TMAX: time to maximum concentration and T1/2: elimination half-life. AUC and CMAX were normalized by artemether dose.

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T max, days

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

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

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C max b (μg/ml or μg/g)

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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koff (s−1)

Biophysical and in vivo murine PK data of PASylated proteins

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

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CLpediatric,i,L/hr

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

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

Predictions by PBPK modeling

Mean	0.10	4.2	10.0	1.80	188	3.55	29.4

SD	0.01	0.6	10.4	0.16	80	1.66	13.5

Minimum	0.08	2.7	0.38	1.41	48	1.14	9.7

Maximum	0.12	6.2	96.2	2.32	474	10.7	94.3

Clinical observations

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

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

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

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Fraction of dose in the first absorption depot F1a

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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Total clearance of M3G

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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Vss, L/m2

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

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

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Tmax/h

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

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C max (ng/mL)a

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

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

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

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

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

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

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

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

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

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

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

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

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Total clearance

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

<!DOCTYPE html>

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

Mean	95 % CI	Mean	95 % CI

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

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

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

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

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

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

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t1/2 (h)

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

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AUC (μMol × h/L)

Pharmacokinetic parameters of regorafenib and its metabolites M‐2 and M‐5 in NMRI Foxn1 nu/nu mice after oral administration at a dose of 10 mg/kg/day for 5 consecutive days

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<col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/><col style="border-right:solid 1px #000000" span="1"/>

Administered compound	Regorafenib	M‐2	M‐5

Analyte	Regorafenib	M‐2	M‐5	Regorafenib	M‐2	M‐5	M‐5<xref ref-type="fn" rid="cam4883-note-0008">a</xref>

AUC (<italic>μ</italic>g × h/L)	38,649	7490	772	11,601	52,101	3391	52,796

AUC (<italic>μ</italic>Mol × h/L)	80.0	15.0	1.6	24.0	104.4	7.0	108.9

AUC (% of total)<xref ref-type="fn" rid="cam4883-note-0009">b</xref>
	83	16	2	18	78	5	100

<italic>C</italic>
max (<italic>μ</italic>g/L)	4146	753	63	967	6150	342	5284

<italic>C</italic>
max (<italic>μ</italic>M/L)	8.6	1.5	0.1	2.0	12.3	0.7	10.9

aOnly M‐5 concentration was determined, because M‐2 and regorafenib formation does not occur.bTotal refers to the sum of the molar concentrations of regorafenib, M‐2, and M‐5 regardless of unbound fraction.

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AUClast (DN), μg. day/mL/mg

Comparison of the dose‐normalized pharmacokinetic parameters of bococizumab when administered alone or in co‐mixture with rHuPH20

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

Comparison and Pharmacokinetic Parameters	Test<xref ref-type="fn" rid="hsr261-note-0008">a</xref>
	Reference<xref ref-type="fn" rid="hsr261-note-0008">a</xref>
	Test/Reference Ratio, % (90% Confidence Interval)

Test: Bococizumab 150 mg + rHuPH20<break/>
Reference: Bococizumab 300 mg

AUCinf (DN), μg. day/mL/mg	1.238	1.047	118.32 (97.93‐142.95)

AUClast (DN), μg. day/mL/mg	1.197	1.023	117.03 (96.59‐141.81)

<italic>C</italic>
max (DN), μg/mL/mg	0.07919	0.05691	139.14 (116.67‐165.95)

Test: bococizumab 300 mg + rHuPH20<break/>
Reference: bococizumab 300 mg

AUCinf (DN), μg. day/mL/mg	1.430	1.047	136.64 (112.81‐165.50)

AUClast (DN), μg. day/mL/mg	1.405	1.023	137.37 (113.09‐166.86)

<italic>C</italic>
max (DN), μg/mL/mg	0.07385	0.05691	129.76 (108.55‐155.11)

Test: bococizumab 450 mg + rHuPH20<break/>
Reference: bococizumab 300 mg

AUCinf (DN), μg. day/mL/mg	1.428	1.047	136.42 (112.92‐164.81)

AUClast (DN), μg. day/mL/mg	1.407	1.023	137.56 (113.54‐166.67)

<italic>C</italic>
max (DN), μg/mL/mg	0.07208	0.05691	126.64 (106.19‐151.03)

AUCinf, area under the plasma concentration‐time profile from time zero extrapolated to infinite time; AUClast, area under the plasma concentration‐time profile from time zero to the time of the last quantifiable concentration; C max, maximum plasma concentration; DN; dose‐normalized to a 300‐mg dose; rHuPH20, recombinant human hyaluronidase.aData are presented as natural log‐transformed, adjusted geometric means obtained from an ANCOVA model with body mass index as a covariate.

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Cmax (μg/mL)

ABT‐751 and Irinotecan Pharmacokinetic Parameters

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

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F ∼ 10 mg§

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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Time to relapse (TTR)

      0
      1
      2
      3
      4
      5

      0
      Unnamed: 0_level_0
      Unnamed: 1_level_0
      CL(L/day)
      Kout (day-1)
      V1(L)
      V2(L)

      1
      Unnamed: 0_level_1
      n
      p
      p
      p
      p

      2
      Age
      44
      0.86
      0.82
      0.90
      0.99

      3
      Sex male versus female
      23 versus 21
      0.59
      0.53
      0.34
      0.37

      4
      Body surface area (BSA, m2)
      44
      0.59
      0.82
      0.76
      0.99

      5
      Binet stage A or B versus C
      27 versus 17
      0.89
      0.82
      0.34
      0.99

      6
      Treatment RB versus RFC
      17 versus 28
      0.48
      0.82
      0.76
      0.99

      7
      Lymphocytosis
      44
      0.59
      0.30
      0.96
      0.99

      8
      Areas of lymphadenopathy
      44
      0.59
      0.39
      0.96
      0.51

      9
      CD38 positivity (≥30%) versus negativity
      21 versus 22
      0.88
      0.82
      0.90
      0.99

      10
      FCGR F/F versus V/F and V/V
      25 versus 19
      0.86
      0.68
      0.90
      0.99

      11
      IGHV unmutated versus mutated status
      10 versus 6
      0.37
      0.82
      0.96
      0.99

      12
      Cytogenetics
      Cytogenetics
      Cytogenetics
      Cytogenetics
      Cytogenetics
      Cytogenetics

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

      14
      Trisomy 12 versus others
      10 versus 34
      0.59
      0.92
      0.76
      0.37

      15
      Normal caryotype versus others
      4 versus 40
      0.89
      0.39
      0.96
      0.66

      16
      Del(11q) versus others
      10 versus 34
      0.37
      0.17
      0.76
      0.17

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

      18
      Time to relapse (TTR)
      44
      0.59
      0.82
      0.96
      0.99

      19
      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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Cmax (µg/ml)

Pharmacokinetic parameters of Tolmetin Sodium estimated after oral and rectal administration of commercial capsule suspension (treatment I) and F8 hydrogel (treatment II) to six rats

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Parameter	Commercial capsule	Rectal hydrogel (F8)

Dose (mg/kg)	50	50

Cmax (µg/ml)	33.877 ± 2.16	45.425 ± 2.745

tmax (h)	1	4

t1/2el (h)	5.137 ± 0.027	6.910 ± 0.003

AUC0−24 (µg h/ml)	129.489 ± 13.55	463.481 ± 48.207

AUC0−∞ (µg.h/ml)	129.489 ± 13.55	514.033 ± 48.207

MRT (h)	3.923 ± 0.24	9.512 ± 0.233

Relative bioavailability	–	357.93%

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Diastolic BP Emax [mm Hg]

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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Dose normalized Cmax

Association between genetic polymorphisms and telatinib pharmacokinetic data. Dose normalized Cmax, T1/2 and Tmax

#=*801 number from termination codon TGA (5397). 3UTR

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AUC0-t (µg/mL·h)

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IMPDH1 expression

Data are given as median (range). The belatacept group includes 3 patients at week 13 and for the maximum, minimum and AUC calculations at week 2. E0, predose expression; Emax, maximum expression; Emin, minimum expression; AUC, area under the variable versus time curve.

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F (%)*

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)

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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CLz/L/h/kg

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C max, μg/mL

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

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Vd,ss/F (mL/kg) a

Pharmacokinetic parameters for caffeine in five studied conditions – means and ranges.

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 	Mean values ± SD (range)

Condition	Cmax (μg/mL)<xref rid="TF2" ref-type="table-fn">
a
</xref>	Dose-normalized<xref rid="TF3" ref-type="table-fn">
b
</xref> Cmax (μg/mL)	Tmax (min)	AUC0–∞ (μg/mL min)	Dose-normalized<xref rid="TF3" ref-type="table-fn">
b
</xref> AUC0–∞ (μg/mL min)	MRT (min)	MAT (min)	CL/F (mL/min/kg)	Vd,ss/F (mL/kg)<xref rid="TF2" ref-type="table-fn">
a
</xref>	t1/2 (min)

A (hot coffee – 20 min)	3.74 ± 1.09 (1.96–5.95)	1.69 ± 0.43 (1.07–2.40)	59 ± 27 (20–120)	2312 ± 1338	1035 ± 541	601 ± 263	12 ± 11	1.2 ± 0.6	623 ± 129	408 ± 178 (210–990)

B (cold coffee – 2 min)	3.64 ± 1.36 (1.81–8.17)	1.57 ± 0.59 (0.981–3.13)	62 ± 32 (40–120)	2447 ± 1781	1047 ± 725	607 ± 267	14 ± 10	1.3 ± 0.7	626 ± 145	411 ± 183 (187–966)

C (cold coffee – 20 min)	3.56 ± 1.06 (1.69–5.77)	1.60 ± 0.44 (0.917–2.79)	64 ± 20 (40–90)	2625 ± 2177	1172 ± 882	673 ± 362	16 ± 6	1.2 ± 0.6	642 ± 151	455 ± 249 (217–1386)

D (energy drink – 2 min)	3.36 ± 1.20 (1.40–5.78)	1.51 ± 0.48 (0.782–2.81)	70 ± 44 (20–240)	2473 ± 2302	1059 ± 834	665 ± 427	15 ± 16	1.4 ± 0.8	712 ± 194	450 ± 295 (154–1386)

E (energy drink – 20 min)	3.14 ± 0.95 (1.87–5.25)	1.41 ± 0.32 (0.940–1.96)	82 ± 42 (40–240)	2107 ± 1504	925.1 ± 565	593 ± 258	17 ± 8	1.5 ± 0.8	708 ± 144	399 ± 177 (187–990)

A: hot coffee 20 min; B: cold coffee 2 min; C: cold coffee 20 min; D: sugar-free energy drink 2 min; E: sugar-free energy drink 20 min.a -RM ANOVA p ≤ 0.05.b Values normalized by mg/kg dose of caffeine.

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C max (nmol·L -1 )

The effect of artemisinin (QHS) on the activity of CYP2B6 (bupropion hydroxylation) and CYP3A4 (midazolam hydroxylation) in humans

MDZ: midazolam; BUP: bupropion; OH-MDZ: hydroxymidazolam; OH-BUP: hydroxybupropion.*: P < 0.05; **: P < 0.01 (1-day compared with 2-day); N.A., not acquired.

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CL(L/day)

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

<italic>n</italic>

<italic>p</italic>

Age	44	0.86	0.82	0.90	0.99

Sex male versus female	23 versus 21	0.59	0.53	0.34	0.37

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

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

Treatment RB versus RFC	17 versus 28	0.48	0.82	0.76	0.99

Lymphocytosis	44	0.59	0.30	0.96	0.99

Areas of lymphadenopathy	44	0.59	0.39	0.96	0.51

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

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

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

Cytogenetics

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

 Trisomy 12 versus others	10 versus 34	0.59	0.92	0.76	0.37

 Normal caryotype versus others	4 versus 40	0.89	0.39	0.96	0.66

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

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

 Time to relapse (TTR)	44	0.59	0.82	0.96	0.99

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

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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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Cmax (μg/L)

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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Apparent peripheral volume of distribution

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

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

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fe

Mean administered doses (total mg) and mean (±SD) predicted values of Cmax (mg/L), AUC (mg*L/h), systemic CL (L/h) and fraction of dose excreted in urine (fe) for gadofosveset in simulated populations

*P < 0.05, **P < 0.01, ***P < 0.001 statistical significant differences with control group (healthy volunteers).

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Half-life (days)

ASN-1 and ASN-2 serum pharmacokinetic parameters for each dose by noncompartmental analysisa

aData are expressed as means (percent coefficients of variation [%CV]). IP, investigational product; NA, not applicable.

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CL0–8 hour,secretion (mL/min)d

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Free

Pharmacokinetics in the maximum tolerated dose cohort (sunitinib 25 mg/day on Schedule 2/2 + cisplatin + S-1)

AUC last area under the plasma concentration–time curve from time zero until last quantifiable observation; C max maximum concentration; CV coefficient of variation; 5-FU 5-fluorouracil; Schedule 2/2 2 weeks on treatment followed by 2 weeks off treatment; SP cisplatin 60 mg/m2 every 28 days + S-1 40 mg/m2 twice daily every 3/1 weeks; SU12662 sunitinib active metabolite

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      0
      1

      0
      Parameter
      Mean ±SD

      1
      E0 (log10CFU/lung)
      4.16 ± 0.43

      2
      Imax (log10CFU/lung)
      8.66 ± 1.10

      3
      IC50
      21.57 ± 8.38

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

      5
      fAUC0-24 h/MIC for 1 log10 kill
      31.89 h

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

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

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Michaelis‐Menten constant Km (mg/L)

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

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

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AUC (μmol·h/L)

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

<!DOCTYPE html>

Basal Diurnal Variation (DV)	Powdered Supplement	Tablet Supplement

<bold>Iron</bold>

 AUC (μmol·h/L)	104.5 ± 34.1

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

 Peak value (μmol/L)	14.6	3.0	8.9

Time to peak value (hrs)	3	4

<bold>Folate</bold>

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

 Peak value (nmol/L)	NA	54.4	53.1

Time to peak value (hrs)	NA	4	3

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

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AUCτ (pg h/mL)

Effect of FTR 600 mg ER BID on dose‐normalized buprenorphine PK

AUCτ, area under the plasma concentration–time curve over the dosing interval; BID, twice daily; C24, concentration in plasma at 24 hours; Cmax, maximum concentration in plasma; CI, confidence interval; ER, extended release; FTR, fostemsavir; GMR, geometric mean ratio; PK, pharmacokinetics; Tmax, time to maximum plasma concentration.Median (range) Tmax for Treatment C and Treatment D: buprenorphine (1.0 h [1.0–2.0] and 2.0 h [1.0–2.0]); norbuprenorphine (2.0 h [1.0–2.0] and 2.0 h [1.0–4.0]).aMR‐AUCτ, ratio of metabolite AUCτ to parent AUCτ corrected for molecular weight, for norbuprenorphine to buprenorphine presented as geometric mean (coefficient of variation, %).

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CL/F (L/hour)

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ka (h−1)

Nevirapine parameter estimates and standard errors obtained from the basic population pharmacokinetic model and the final pharmacokinetic/pharmacogenetic model (n = 180)a

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

Parameter (unit)	Basic model
	Final model

Estimate	RSE<italic><xref ref-type="table-fn" rid="TF1-2">b</xref></italic> (%)	Estimate	RSE<italic><xref ref-type="table-fn" rid="TF1-2">b</xref></italic> (%)

CL/F (liters/h)	2.74	3.76	3.02	4.44

<italic>V/F</italic> (liters)	113	23.2	114	22.8

<italic>ka</italic> (h−1)	0.569	26.7	0.578	26.1

IIV CL/F (%)	33.5	26.9	33.2	27.4

IOV CL/F (%)	34.9	23.3	31.8	24.2

Covariates

    θ1
<italic>CYP2B6</italic> 983TT/516TT	−0.696	36.6

    θ2
<italic>CYP2B6</italic> 983TC/516GG or GT	−1.08	22.3

Residual error

    Proportional (%)	13.1	17.0	13.1	17.0

aAbbreviations: CL/F, apparent oral clearance of nevirapine (basic model) or apparent oral clearance of nevirapine in patients with reference genotype wt983T>C/wt or het516G>T (final model); V/F, apparent volume of distribution; ka, absorption rate constant; IIV, interindividual variability; IOV, interoccasion variability; RSE, relative standard error; SE, standard error; θ1, absolute change in CL/F for CYP2B6 983TT/516TT genotype compared to reference genotype (CYP2B6 983TT/516GG or GT); θ2, absolute change in CL/F for het983T>C/wt or het516G>T genotype compared to reference genotype.bRSE = (SEestimate/estimate) × 100.

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T½ (h)

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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θV/F, Sex

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

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PK parameter	LCDP polymeric micelles	LCDP oral suspension	Statistical test

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

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

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

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

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

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

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Initial Range and Theoretical Lower Limit of Parameters for CNM

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A. Common parameters

Parameter	Unit	Irinotecan	SN-38	SN-38G	NPC	APC	Theoretical lower limit

 Vcentral
	L/kg	0.075 ~ 0.75	0.075 ~ 0.75	0.075 ~ 0.75	0.075 ~ 0.75	0.075 ~ 0.75	0.074a

 ka
	/h	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0

 kfeces
	/h	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0

 Rdif,h
	-	-b,c
	0.01 ~ 1.0	0.01 ~ 1.0	-c
	-c
	0

 1/β	-	-b
	1.1 ~ 10	1.1 ~ 10	1.1 ~ 10	1.1 ~ 10	1

 CLint,all
	L/h/kg	-b
	0.1 ~ 100	0.1 ~ 100	0.1 ~ 100	0.1 ~ 100	0

 1/fbile
	-	-b
	-e
	-d
	1.1 ~ 10	-d
	1

 kbile
	/h	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0.06 ~ 6.0	0

 Rdif,ent
	-	0.1 ~ 10	0.1 ~ 10	0.1 ~ 10	-c
	-c
	0

B. Irinotecan parameters

Parameter	Unit	Value	Theoretical lower limit

 PSdif,inf,h
	L/kg	0.1 ~ 100	0

 CLSN-38,h(irinotecan)
	L/h/kg	0.1 ~ 100	0

 CLNPC,h(irinotecan)
	L/h/kg	0.1 ~ 100	0

 CLAPC,h(irinotecan)
	L/h/kg	0.1 ~ 100	0

 CLothers,h(irinotecan)
	L/h/kg	0.1 ~ 100	0

 CLbile
	L/h/kg	0.1 ~ 100	0

 PSdif,eff,ent
	L/h/kg	0.1 ~ 100	0

 CLSN-38,h(irinotecan) /CLSN-38,ent(irinotecan)
	-	1.1 ~ 10	1

 CLNPC,h(irinotecan) / CLNPC,ent(irinotecan)
	-	1.1 ~ 10	1

C. SN-38 parameters

Parameter	Unit	Value	Theoretical lower limit

 1/fglu
e
	-	1.1 ~ 10	1

 CLSN-38G,h(SN-38) /CLSN-38G,ent(SN-38)
	-	1.1 ~ 10	1

D. SN-38G parameters

Parameter	Unit	Value	Theoretical lower limit

 kdec
	/h	0.06 ~ 6	0

aVcentral is larger than blood volume bHybrid parameters were not used. Instead of it, as shown in Table 1B. parameters for representing elementary steps were used cNo involvement of active uptake or efflux transporters for these compounds dfbile value was fixed as 1 eThe ratio (fglu) of metabolic clearance for glucuronidation of SN-38 to hepatic intrinsic clearance was estimated using the following equation, fglu = 1 - fblie

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      0
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      2
      3
      4

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      End point
      Precipitant
      Precipitant
      Precipitant
      Precipitant

      1
      End point
      13cisRA
      atRA
      4‐oxo‐13cisRA
      Combined parent and metabolitesa

      2
      f u,plasma b
      0.0004 (0.0001)
      0.0002 (5 × 10−5)
      0.012 (0.004)
      nan

      3
      f u,media b
      0.011 (0)
      0.027 (0.008)
      0.121 (0.013)
      nan

      4
      Cavg c (μM)
      0.69
      0.01
      5.4
      nan

      5
      Donor 1 d
      Donor 1 d
      Donor 1 d
      Donor 1 d
      Donor 1 d

      6
      Emin
      0.63 (0.57–0.68)
      0.64 (0.58–0.70)
      0.63 (0.58–0.69)
      nan

      7
      EC50,u (nM)
      0.18 (0.09–0.44)
      0.37 (0.16–0.81)
      3.8 (1.2–8.5)
      nan

      8
      Predicted % CYP2D6 remaining
      0.78
      1.0
      0.65
      0.65

      9
      Donor 3 e
      Donor 3 e
      Donor 3 e
      Donor 3 e
      Donor 3 e

      10
      Emin
      0.05
      0.07
      0.05
      nan

      11
      EC50,u (nM)
      0.91
      1.3
      17
      nan

      12
      Predicted % CYP2D6 remaining
      0.78
      1.0
      0.24
      0.23

Plasma and media unbound fractions for the studied retinoids, in vitro EC50,u values, and predicted magnitude of in vivo change in CYP2D6 based on clinical 13cisRA, atRA, and 4‐oxo‐13cisRA exposures

Donor 2 was excluded from quantitative predictions due to the wide confidence intervals of the determined EC50 values of retinoids on CYP2D6 mRNA in this donor (Figure  1 ). atRA, all‐trans‐RA; Cavg, average concentration; CYP, cytochrome P450; EC50,u, unbound half‐maximal effective concentration; Emin, minimum concentration; fu,plasma, fraction unbound in plasma; fu,media, fraction unbound in media; NA, not applicable; RA, retinoic acid. aThe combined effect of 13cisRA and its metabolites on CYP2D6 expression in vivo was predicted using Eq. (2). bBinding experiments were conducted in triplicate and data are presented as mean (SD). cCavg following administration of 20 mg b.i.d. 13cisRA reported in Amory et al.17 dThe concentration‐dependent effects of retinoids in donor 1 hepatocytes are presented as mean (90% confidence interval). eThe concentration‐dependent effects of retinoids in donor 3 hepatocytes were assessed in three replicate experiments, and the median value from the three experiments is reported.

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Tmax, hb

Summary of pharmacokinetic parameters following administration of single oral doses of PF‐04447943 5 mg and 25 mg a

AUC0−12, area under the concentration‐time curve from time 0−12 hours postdose; Cmax, maximum concentration; dn, dose normalized to 1 mg; Tmax, time to Cmax. aValues are geometric mean (geometric percent coefficient of variation) unless otherwise noted; bValues are median (range).

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b


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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% 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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AUC (nmoles ml−1 or g−1 min)

Area under the plasma or tissue concentration time curve (AUC) for resveratrol and DMU 212 in mice that received these agents (240mg/kg) i.g

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 	<bold>AUC (nmoles ml−1 or g−1 min)</bold>

<bold>Tissue</bold>	<bold>Resveratrol</bold>	<bold>DMU 212</bold>	<bold>AUCres/AUCDMU</bold>

Plasma	863	246	3.5

Liver	2150	432	5

Kidney	785	566	1.5

Lung	1123	778	1.5

Heart	2072	750	3

Brain	103	193	0.5

Intestinal mucosa	36 690	369 315	0.1

Colonic mucosa	2869	19 256	0.15

AUC values were calculated from the curves shown in Figure 2 using the mean plasma or tissue concentration values between 0 and 120 min postadministration.

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Cmax (ng/mL)

Summary statistics of midazolam plasma PK parameter values

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

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AUCINF (h*ng/mL)

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AUC0–30 coefficient (nasal/serum)

MEDI4893 nasal pharmacokinetic parameters for each dose determined by noncompartmental analysisa

aData are expressed as the mean ± standard deviation.

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Vss (mL/kg)

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

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

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MRT0-∞ (h)

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AUC0–48‐h (μM/h)a

Navoximod and its abundant metabolites in human plasma, urine, and feces after a single oral administration of 200 mg/600 μCi [14C]‐navoximod to healthy subjects

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<col align="left" span="1"/><col align="left" span="1"/><col align="char" char="." span="1"/><col align="char" char="." span="1"/><col align="char" char="." span="1"/><col align="char" char="." span="1"/><col align="char" char="." span="1"/>

Analyte	Biotransformation	Plasma	Urine	Feces	Total

% of TRA	AUC0–48‐h (μM/h)<xref ref-type="fn" rid="bcp13961-note-0014">a</xref>
	% of dose<xref ref-type="fn" rid="bcp13961-note-0015">b</xref>
	% of dose<xref ref-type="fn" rid="bcp13961-note-0015">b</xref>
	% of dose<xref ref-type="fn" rid="bcp13961-note-0015">b</xref>

Navoximod	Unchanged parent	7.00	4.40	1.66	3.79	5.45

M1 (thiocyanate)	Ring cleavage	5.54	3.54	0.614	0.138	0.752

M17	Oxidation (+ 34 Da)	D	D	1.78	1.54	3.32

M19	Glucuronidation	3.14	2.36	8.74	ND	8.74

M28	Glucuronidation	57.5	36.4	59.7	ND	59.7

M31	Oxidation (+16 Da)	D	D	1.71	D	1.71

M38	Glucuronidation	D	D	1.76	ND	1.76

D, only detected by mass spectrometry; ND, not detected; TRA, total radioactivity.aMean values from AUC 0–48 hour of pooled plasma (n = 8) adjusted with extraction recovery. The unextracted radioactivity accounted for 20.4% of the total radioactivity in the plasma sample.bMean values from eight subjects.

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Absorption rate (1/hour)

Population pharmacokinetic parameter estimates

<!DOCTYPE html>

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

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

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

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

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

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

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

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

Between-subject variability

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

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

Residual error	SD (%RSE)

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

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CLM,R (L/hr)a

Individual parameter and exposure estimates stratified by disease status

Values are expressed as median (range).NASH, nonalcoholic steatohepatitis; M3G, morphine‐3‐glucuronide; VM3G, central volume of distribution of M3G; VM, central volume of distribution of morphine; CLM,R, renal clearance of morphine; CLM,NR, non‐renal clearance of morphine; CLM3G, systemic clearance of M3G; AUCM, area under the concentration time curve of morphine in serum; AUCM3G, area under the concentration time curve of M3G in serum.aCLM (total systemic clearance of morphine)= CLM,R (renal clearance of morphine) + CLM,NR (non‐renal clearance of morphine).bSingle dose area under the concentration versus time curve for morphine (AUCM,0‐∞) and M3G (AUCM3G,0‐∞) were estimated using model‐derived parameters and according to the following equations:  AUCM,0−∞=(DOSECLM) AUCM3G,0−∞=(fM3G∗CLMCLM3G)∗AUCM,0−∞ where the fraction of the morphine dose metabolized to M3G was assumed to be 1.

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t max, day 7 (h)

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

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

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d

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V/F (liters)

Nevirapine parameter estimates and standard errors obtained from the basic population pharmacokinetic model and the final pharmacokinetic/pharmacogenetic model (n = 180)a

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Concentration (μg equiv·g−1 or mL)

      0
      1
      2
      3
      4
      5
      6

      0
      Unnamed: 0_level_0
      Concentration (μg equiv·g−1 or mL)
      Concentration (μg equiv·g−1 or mL)
      Concentration (μg equiv·g−1 or mL)
      Concentration (μg equiv·g−1 or mL)
      Concentration (μg equiv·g−1 or mL)
      Concentration (μg equiv·g−1 or mL)

      1
      Compound
      Plasma
      Liver
      Spleen
      Kidneys
      Testes
      Bone marrow

      2
      Total radioactivity
      2.44 (100)
      8.91 (100)
      23.4 (100)
      4.88 (100)
      4.05 (100)
      5.53 (100)

      3
      Peginesatide
      1.94 (79.6)
      5.63 (63.2)
      14.3 (61.2)
      2.64 (54.1)
      2.68 (66.0)
      3.22 (58.2)

      4
      Mono-PEG*
      0.122 (5.0)
      3.11 (34.9)
      7.59 (32.5)
      2.24 (45.9)
      1.31 (32.2)
      2.31 (41.8)

      5
      Other
      0.375 (15.4)
      0.162 (1.9)
      1.49 (6.3)
      0.00 (0.0)
      0.069 (1.8)
      0.00 (0.0)

Day 14 concentrations of peginesatide and associated radioactive compounds in rat plasma and tissues after a single IV administration of 5 mg/kg [14C]-peginesatide.

Values in parenthesis represent percent radioactivity for a given tissue/matrix. n = 3.

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Race (Other) 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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Cmax (ng/mL)

Difference in pharmacokinetic parameters of sildenafil between the two combination therapies

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

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IOV in t½, abs-2

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

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Parameter	Mean	Bootstrap, median (95% CI)

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

Structural model parameters

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

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

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

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

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

Variable model parameters (shrinkage%)

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

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

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

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

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

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

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

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

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VAS,

Clinical activity assessments in the multi dose phase at eight weeks

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

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AUC0–24 (μg · h/ml)

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

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

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

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

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

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

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

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

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

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

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

3.6	1	43.3	10.0	100

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

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

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

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

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CL

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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ALKS 3831

      0
      1
      2
      3

      0
      Unnamed: 0_level_0
      ALKS 3831
      OLZ
      B‐OLZ

      1
      Parameter Statistics
      (n = 46)
      (n = 45)
      (n = 48)

      2
      AUC0‐∞, ng·h/mL
      nan
      nan
      nan

      3
      Geometric mean
      627.9
      607.0
      610.4

      4
      Geometric mean ratio
      1.0
      0.994
      —

      5
      90%CI
      (0.995–1.063)
      (0.962–1.028)
      —

      6
      AUC0‐t, ng·h/mL
      nan
      nan
      nan

      7
      Geometric mean
      594.4
      578.9
      578.9

      8
      Geometric mean ratio
      1.0
      1.0
      —

      9
      90%CI
      (0.993–1.062)
      (0.967–1.034)
      —

      10
      Cmax, ng/mL
      nan
      nan
      nan

      11
      Geometric mean
      16.3
      16.3
      16.4

      12
      Geometric mean ratio
      0.994
      0.995
      —

      13
      90%CI
      (0.954–1.036)
      (0.955–1.037)
      —

CAPTION: Bioequivalence Evaluation of OLZ for Comparison of ALKS 3831 Versus B‐OLZ and OLZ Versus B‐OLZ
FOOTER: AUC0‐∞, area under the plasma concentration‐time curve from zero to infinity; AUC0‐t, area under the plasma concentration‐time curve from zero to the time of the last quantifiable concentration; B‐OLZ, brand olanzapine; Cmax, maximal plasma concentration; OLZ, olanzapine; PK, pharmacokinetics.

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V/F ∼ WT

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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V dss

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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AUC0-tlast (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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Age on CL/Fc

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TotalN = 317

      0
      1
      2
      3

      0
      Unnamed: 0
      AM + PQPN = 159
      ChloroquineN = 158
      TotalN = 317

      1
      Gender N (%)
      Gender N (%)
      Gender N (%)
      Gender N (%)

      2
      Male
      137 (86.2 %)
      145 (91.8 %)
      282 (89.0 %)

      3
      Female
      2 2 (13.8 %)
      13 (8.2 %)
      35 (11.0 %)

      4
      Race
      Race
      Race
      Race

      5
      Asian
      159 (100.0 %)
      158 (100.0 %)
      317 (100.0 %)

      6
      Age (years)
      Age (years)
      Age (years)
      Age (years)

      7
      Mean ± std
      33.2 ± 11.81
      33.7 ± 13.45
      33.5 ± 12.64

      8
      Median
      32
      30
      30

      9
      Min, max
      13.0, 65.0
      15.0, 65.0
      13.0, 65.0

      10
      Height (cm)
      Height (cm)
      Height (cm)
      Height (cm)

      11
      Mean ± std
      163.6 ± 7.83
      163.6 ± 8.67
      163.6 ± 8.24

      12
      Median
      164
      164
      164

      13
      Min, max
      130.0, 179.0
      131.0, 182.0
      130.0, 182.0

      14
      Weight (kg)
      Weight (kg)
      Weight (kg)
      Weight (kg)

      15
      Mean ± std
      57.6 ± 8.76
      58.8 ± 11.55
      58.2 ± 10.25

      16
      Median
      57
      56.4
      57

      17
      Min, max
      42.0, 81.0
      41.2, 128.9
      41.2, 128.9

      18
      No. of subjects having P. vivax asexual parasites (/µL) at screening
      No. of subjects having P. vivax asexual parasites (/µL) at screening
      No. of subjects having P. vivax asexual parasites (/µL) at screening
      No. of subjects having P. vivax asexual parasites (/µL) at screening

      19
      Mean ± std
      6458.9 ± 11,439.07
      5943.6 ± 10,401.49
      6202.9 ± 10,921.57

      20
      Median
      2704
      2880
      2750.5

      21
      GM
      2749.7
      2706.5
      2728.2

      22
      Min, max
      250.0, 90,049.0
      280.0, 80,000.0
      250.0, 90,049.0

      23
      Body temperature (degree celsius)
      Body temperature (degree celsius)
      Body temperature (degree celsius)
      Body temperature (degree celsius)

      24
      Mean ± std
      38.5 ± 0.62
      38.5 ± 0.61
      38.5 ± 0.61

      25
      Median
      38.6
      38.6
      38.6

      26
      Min, max
      36.1, 40.2
      36.8, 40.4
      36.1, 40.4

      27
      Fever >(38.0 degree celsius)
      122 (76.7 %)
      118 (74.7 %)
      240 (75.7 %)

      28
      No. of subjects having normal temperature (<37.5 degree celsius) at screening
      6 (3.8 %)
      3 (1.9 %)
      9 (2.8 %)

      29
      Hepatomegaly
      10 (6.3 %)
      12 (7.6 %)
      22 (6.9 %)

      30
      Splenomegaly
      10 (6.3 %)
      14 (8.9 %)
      24 (7.6 %)

      31
      Anemia <30 % at screening
      12 (7.55 %)
      11 (6.96 %)
      23 (7.26 %)

      32
      Hematocrit at screening
      Hematocrit at screening
      Hematocrit at screening
      Hematocrit at screening

      33
      Mean ± SD
      37.14 ± 5.35
      37.75 ± 5.30
      37.45 ± 5.33

      34
      Median
      37.4
      37.75
      37.5

      35
      Min, max
      19.8, 50
      2254.7
      19.8, 54.7

      36
      G6PD deficiency
      0
      0
      0

      37
      P. vivax infections in prior 12 months
      9 (5.66 %)
      8 (5.03 %)
      17 (5.36 %)

CAPTION: Demographic and baseline clinical characteristics
FOOTER: AM + PQP: FDC of arterolane maleate and PQP

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VP2/F (L)

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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AUC0‐t, μg · hr/dL

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

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

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AUClast (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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F2 free testosterone (pg/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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t1/2 (h)

Pharmacokinetic parameters of triptolide in rats after oral administration of triptolide (1 mg/kg, n = 6, mean ± S.D.) with or without puerarin pretreatment (100 mg/kg/day for seven days).

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Parameter	Triptolide	Triptolide + puerarin

<italic>T</italic>max (h)	0.51 ± 0.06	0.27 ± 0.2*

<italic>C</italic>max (ng/mL)	187.25 ± 15.36	219.67 ± 21.52*

<italic>t</italic>1/2 (h)	1.03 ± 0.12	1.18 ± 0.18*

AUC(0–<italic>t</italic>) (ng·h/mL)	201.55 ± 21.08	261.38 ± 31.27*

CL (L/h/kg)	4.92 ± 0.35	3.75 ± 0.19*

*p < 0.05 indicates significant differences from the control.

t

h


Tmax (h)

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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Ctrough (mg/L)

Observed meropenem concentrations in serum and cerebrospinal fluid

Abbreviations: C min Median observed serum trough concentration, C max Median observed serum peak concentration, C trough Median observed cerebrospinal fluid concentration at serum trough concentration, C after 4h Median observed cerebrospinal fluid concentration 4 h after serum trough concentration, N/A Not available (patient with only meropenem 1000 mg or only 2000 mg intravenously every 8 h), CrCL Estimated creatinine clearance (calculated using the Cockcroft-Gault equation [16])Observed meropenem concentrations after 1000 mg or 2000 mg intravenously every 8 h (4-h infusion)

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AUC0‐∞/Db, ng·hr/mL/mg

Summary statistics of buprenorphine, norbuprenorphine, and naloxone plasma pharmacokinetics following stable maintenance doses of buprenorphine/naloxone 8/2 mg to 24/6 mg once daily with or without coadministration of multiple doses of grazoprevir 200 mg once daily for 10 days in adult participants receiving stable buprenorphine/naloxone substitution therapy

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BUP/NAL alone	BUP/NAL + GZR	BUP/NAL + GZR/ BUP/NAL alone

Pharmacokinetic parameter
<italic>n</italic>
	GM	95% CI
<italic>n</italic>
	GM	95% CI	GMR	90% CI	Pseudo within‐participant %CV<xref ref-type="fn" rid="cts12565-tbl3-note-0004">a</xref>

<italic>BUP</italic>

AUC0‐∞/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng·hr/mL/mg	12	4.65	3.64–5.95	12	4.57	3.35–6.23	0.98	0.81–1.19	26.4

Cmax/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng/mL/mg	12	0.802	0.628–1.02	12	0.722	0.509–1.02	0.90	0.76–1.07	23.4

Tmax
<xref ref-type="fn" rid="cts12565-tbl3-note-0006">c</xref>, hr	12	1.99	1.00, 3.00	12	2.01	1.00, 4.00

Apparent terminal T½
<xref ref-type="fn" rid="cts12565-tbl3-note-0007">d</xref>
,
<xref ref-type="fn" rid="cts12565-tbl3-note-0008">e</xref>, hr	10	10.71	73.09	11	13.43	30.71

<italic>NorBUP</italic>

AUC0‐∞/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng·hr/mL/mg	12	3.53	2.55–4.90	12	3.99	2.76–5.76	1.13	0.97–1.32	20.9

Cmax/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng/mL/mg	12	0.223	0.153–0.324	12	0.246	0.167–0.36	1.10	0.97–1.25	17.2

Tmax
<xref ref-type="fn" rid="cts12565-tbl3-note-0006">c</xref>, hr	12	3.00	1.00, 12.00	12	3.00	1.50, 6.00

Apparent terminal T½
<xref ref-type="fn" rid="cts12565-tbl3-note-0007">d</xref>
,
<xref ref-type="fn" rid="cts12565-tbl3-note-0009">f</xref>, hr	5	16.13	26.12	8	33.87	49.98

<italic>NAL</italic>

AUC0‐∞/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng·hr/mL/mg	12	0.352	0.257–0.482	12	0.387	0.256–0.584	1.10	0.82–1.47	39.6

Cmax/D<xref ref-type="fn" rid="cts12565-tbl3-note-0005">b</xref>, ng/mL/mg	12	0.149	0.113–0.196	12	0.149	0.110–0.204	1.00	0.80–1.27	31.7

Tmax
<xref ref-type="fn" rid="cts12565-tbl3-note-0006">c</xref>, hr	12	0.75	0.50, 3.00	12	1.24	0.50, 2.02

Apparent terminal T½
<xref ref-type="fn" rid="cts12565-tbl3-note-0007">d</xref>
,
<xref ref-type="fn" rid="cts12565-tbl3-note-0010">g</xref>, hr	10	3.33	92.14	12	5.20	107.25

BUP/NAL alone: BUP 8 mg / NAL 2 mg to 24/6 mg on day 1.BUP/NAL + GZR: coadministration of BUP 8 mg / NAL 2 mg to 24/6 mg once daily with GZR 200 mg once daily on days 2–11.AUC0‐∞, area under the concentration–time curve from time 0 extrapolated to infinity; BUP, buprenorphine; CI, confidence interval; Cmax, maximum concentration; D, dose normalized; GM, geometric mean; GMR, geometric mean ratio; GZR, grazoprevir; NAL, naloxone; NorBUP, norbuprenorphine; Tmax, time to Cmax.aPseudo within‐participant %CV = 100 × sqrt[(σA 2 + σB 2 ‐2σAB)/2], where σA 2 and σB 2 are the estimated variance on the log scale for the two treatments, and σAB is the corresponding estimated covariance, each obtained from the linear mixed‐effects model.bBack‐transformed least‐squares mean and CI from the linear mixed‐effects model performed on natural log‐transformed values.cMedian (minimum, maximum) reported for Tmax.dGM and geometric CV reported for apparent terminal T½.eNo apparent terminal T½ could be calculated for two participants following administration of BUP/NAL alone and for one participant following coadministration of BUP/NAL with GZR, due to the lack of data in the terminal phase.fNo apparent terminal T½ could be calculated for seven participants following administration of BUP/NAL alone and for four participants following coadministration of BUP/NAL with GZR, due to the lack of data in the terminal phase.gNo apparent terminal T½ could be calculated for two participants following administration of BUP/NAL alone due to the lack of data in the terminal phase.

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CLmd (L/h)

Model Parameters for the Final Integrated Model

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

ADC

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

 Km (nmol/L)	0.959 (1.68)	––

 Vc (L)	0.0996 (2.6)	0.0118 (36.9)

 CLd (L/h)	0.00197 (1.9)	–

 Vp (L)	0.183 (8.7)	0.230 (25.4)

 λ [Weibull scale parameter]	1.51 (0.9)	–

 κ [Weibull shape parameter]	1.10 (0.6)	–

 Fmp	0.783 (2.2)	–

 Fmd	0.0242 (30.9)	1.78 (34.2)

MMAE

 CLm (L/h)	2.27 (8.3)	0.333 (20.2)

 Vm (L)	1.00 (0.3)	–

 CLmd (L/h)	23.0 (0.7)	–

 Vmp (L)	88.4 (4.8)	0.0670 (31.9)

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

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

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

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

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AUC0−∞ (h ng/mL)

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

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

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

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

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

Cl/F	224.84 ± 59.89

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

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Cmax (ng/mL)

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

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