CL/F (L/h)

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

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Parameter	Geometric mean/%CV	Range

Primary pharmacokinetic parameters

AUC∞ (μg·h/L)	354.4/30.3	209.7–458.0

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

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

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

MRT (h)	10.68/14.8	8.823–13.34

Secondary pharmacokinetic parameters

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

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

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

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

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

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h


AUC (mg/L*h)

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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Time (h)

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

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AUCinf (hour·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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AUC0−∞ (µg.h/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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µ

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l


IIV in V

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

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

Parameter	Mean	Bootstrap, median (95% CI)

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

Structural model parameters

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

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

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

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

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

Variable model parameters (shrinkage%)

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

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

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

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

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

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

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

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

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AUC(0‐24) (ng h/mL)

Noncompartmental pharmacokinetic parameters of prexasertib

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

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Vc/F (L)

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 (pg/mL)

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

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

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tmax (hour) b

Summary of the Pharmacokinetic Parameters for SMT C1100 Following Single Oral Doses and Multiple Doses. Geometric Mean (Coefficient of Variation) Are Presented Unless Otherwise Stated

AUC0‐∞ = area under the plasma concentration‐time curve from time zero to infinity (percentage of AUC that is due to extrapolation from tz to infinity was <10% in all cases); AUC0− τ = area under the plasma concentration‐time curve over a dosing interval; Cmax = maximum observed plasma concentration; tmax = time of maximum observed plasma concentration; t½ = apparent plasma terminal elimination half‐life (for Day 10 of multiple‐dose study this is post drug induction); CL/F = apparent total plasma clearance; VZ/F = apparent volume of distribution during the terminal phase; RAobs = observed accumulation ratio based on AUC0‐ τ.aArithmetic mean (CV%).bMedian (min–max).cn = 5.dn = 3.

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Anemia <30 % at screening

      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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WBC, 10∧9/L

      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

Pharmacokinetic parameters of prasugrel active metabolite

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

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

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

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

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

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

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Cmax, µg/mL

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

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

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Lanabecestat AUC0–t (ng·h/mL)

PK Parameters for Each Treatment Group

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

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AUCτ

Statistical Analysis of Lopinavir and Ritonavir Pharmacokinetic Parameters in Part 2

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Geometric Least‐Squares Mean Ratio, % (90%CI)

Parameter	Lopinavir	Ritonavir

AUCτ
	73 (56, 96)	69 (48, 98)

Cmax
	77 (62, 95)	67 (46, 98)

AUCτ, area under the plasma concentration‐time curve following last dose on day 13 (12 hours); Cmax, maximum plasma concentration; CI, confidence interval.

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AUC0-∞, ng/mL*h

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

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

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AUC0-inf (day • nM)

Non-compartmental PK parameters of TAC TAb and ac-dmDNA31 following a single IV administration of TAC in mice infected with S. aureus.

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 	TAC Total Antibody
	Antibody-conjugated dmDNA31

PK Parameters	25 mg/kg	50 mg/kg	25 mg/kg	50 mg/kg

Cmax (nM)	3850	7640	5060	13100

AUC0-inf (day • nM)	29560	53720	12630	24390

Clearance (mL/day/kg)	5.78	6.37	26.6	27.5

Vss (mL/kg)	115	123	114	110

t1/2λz (day)	14.0	13.8	3.81	3.73

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CL/F (L/h)*

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F (%)

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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Vz_obs (L/kg)

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

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Tmax (h)

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

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<bold>Study Population</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>HV</bold>

<bold>Dosing Day</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>14</bold>

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

<bold>50</bold>

<bold>50</bold>

<bold>100</bold>

<bold>100</bold>

<bold>150</bold>

<bold>200</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

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

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

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

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

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

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

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

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

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

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

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

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

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C max (ng/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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Cmax (mg/L)

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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Vss (l kg−1)

Pharmacokinetic parameters

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

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Between‐subject variability V2 ω (CV%)

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

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

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AUC ratio (%)b

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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GB on Vc/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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MCH, pg

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Cmin [g/L]

Pharmacokinetic parameters for IGSC 20% and IGIV 10% treatments

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

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Tmax

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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Cmax, 0–48 h (ng/mL)

Model-predicted variation in panobinostat exposure across covariates

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AUC(0,∞) (μg ml−1 h)

Statistical comparison of primary pharmacokinetic endpoints between MSB11022 and reference products

AUC(0,∞), area under the concentration–time curve from time 0 extrapolated to infinity; AUC(0,t last), AUC from time 0 to the last quantifiable concentration; CI, confidence interval; C max, maximum observed concentration; EU‐RMP, Europe‐approved reference medicinal product; LS, least‐squares; US‐RP, US‐licensed reference product.

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t max, day 1 (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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ω(Vd/F)

Population pharmacokinetic parameters of baclofen.

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

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

CL/F (L/h)	11.6	3	10.8–12.3

Vd/F (L)	72.8	5	66.5–80.4

Ka (1/h)	1.64	10	1.34–2.00

<bold>BETWEEN SUBJECT VARIABILITY</bold>

ω(CL/F)	0.21	14	0.16–0.27

ω(Vd/F)	0.22	31	0.11–0.36

ω(Ka)	0.44	24	0.19–0.65

<bold>RESIDUAL VARIABILITY</bold>

σ exponential	0.24	5	0.21–0.26

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

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MRT (min)

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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k10 t1/2 (h)

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

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

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

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

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

Cl/F	224.84 ± 59.89

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

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AUC0−t [ng/(h mL)]

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

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

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

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

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

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

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

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

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t1/2 (h)

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

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PK parameter	LCDP polymeric micelles	LCDP oral suspension	Statistical test

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

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

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

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

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

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

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Pharmacokinetic endpoints

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

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Cmax, ng/mL

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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AUCτ (ng·h/mL)

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

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

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k34 (1/h)

Final population PK model parameter estimates

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Population parameters	Interindividual variation (std. dev.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sex on km
	Covariate effect	0.15	0.05	31	0.001

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

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

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

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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Cmax (μg/mL) a

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Tmax

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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Cavg, mg/L

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

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

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

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

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

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

Clearance, L/week	13.3 (9.17, 22.8)

Volume, L	4.58 (4.14, 4.99)

First‐phase t1/2, h	38.2 (23.2–56.7)

Terminal t1/2, h	12200 (3990–50200)

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

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

Clearance, L/week	14.0 (12.7–14.6)

Terminal t1/2, h	38.2 (36.5–41.9)

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

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

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

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

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

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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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Fever >(38.0 degree celsius)

Demographic and baseline clinical characteristics

AM + PQP: FDC of arterolane maleate and PQP

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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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Cmax

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C max, day 7 (ng/mL)

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Cmax (pg/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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CSF/AUC (%)

Estimation of QC target inhibition in the CSF using plasma AUC

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

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t1/2β (h)

Pharmacokinetic parameters

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

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F (%)

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

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

<inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
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<inline-formula id="IEq6"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
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λ (min−1)	0.0039 ± 0.0010	25.17	0.0025 ± 0.0014	53.87	0.053a

AUC (μg·min/mL)	1164.9 ± 262.1	22.50	1496.9 ± 438.9	29.32	0.160a

Cmax (μg/mL)	3.39 ± 0.290	8.53	3.12 ± 0.197	6.32	0.087a

tmax (min)c
	110.0 ± 15.49	14.08	120.0 ± 0.00	-	0.138b

Cl/F (mL/min/kg)	26.83 ± 5.81	21.67	21.65 ± 6.88	31.76	0.160a

Va/F (mL/kg)	7070.8 ± 884.9	12.52	9317.5 ± 1803.8	19.36	0.022a

Vss/F (mL/kg)	3891.2 ± 731.8	18.81	3080.4 ± 908.7	29.50	0.101a

t1/2λ (min)	189.6 ± 44.7	17.48	336.2 ± 152.6	45.40	0.052a

AUMC (μg·min2/mL)	380,326.9 ± 158,923.7	41.79	827,234.6 ± 560,290.1	67.73	0.093a

MRT (min)	145.9 ± 6.37	4.36	143.1 ± 4.07	2.84	0.409a

MAT (min)	64.21	56.07

F (%)	36.73	41.52

at Test bMann-Whitney Test csignificant differences with the value obtained when metformin was administered alone (Mann-Whitney Test)

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Ke (1/h)

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

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Interindividual variability on distributional clearance

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ER intact

      0
      1
      2
      3

      0
      Unnamed: 0_level_0
      Hydrocodone 45 mg
      Unnamed: 2_level_0
      Unnamed: 3_level_0

      1
      Variable
      IR
      ER crushed
      ER intact

      2
      Variable
      (n = 39)
      (n = 41)
      mg (n = 40)

      3
      Cmax (ng/mL)
      91.5 (16.8)
      40.8 (10.2)
      28.8 (6.1)

      4
      tmax (h)*
      0.8 (0.3, 4.1)
      4.0 (1.8, 7.0)
      7.1 (6.1, 12.0)

      5
      AUC0-∞ (ng•h/mL)
      625 (137)
      586 (139)
      584 (125)

      6
      AUC0-0.75 (ng•h/mL)
      29 (14)
      3 (2)
      1 (0)

      7
      AUC0-4 (ng•h/mL)
      246 (43)
      103 (25)
      34 (9)

      8
      AUC0-7 (ng•h/mL)
      377 (60)
      212 (47)
      104 (23)

      9
      AUC0-t (ng•h/mL)
      623 (136)
      584 (139)
      581 (125)

      10
      Extrapolation (%)†
      0.3 (0.1)
      0.4 (0.2)
      0.6 (0.5)

      11
      λz (1/h)
      0.1384 (0.0218)
      0.0933 (0.0252)
      0.0929 (0.0267)

      12
      t1/2 (h)
      5.1 (0.8)
      8.0 (2.1)
      8.0 (2.2)

      13
      Abuse quotient (ng/mL/h)‡
      108.6 (58.8)
      11.0 (4.0)
      3.9 (1.1)

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

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AUC0–24, μg × hr/ml

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

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

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Mean AUClast ng · h/mL (CV%)

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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V d/F [×103 L; mean ± SD]

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

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Parameter	Clopidogrel	H3	H4 (active)	CLPM

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

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

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

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

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

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

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

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

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

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

 <italic>t</italic>
max [h; mean ± SD]	1.17 ± 0.76	0.83 ± 0.29	0.83 ± 0.29	1.61 ± 1.21

 <italic>t</italic>
½ [h; mean ± SD]	1.99 ± 0.44	0.72 ± 0.18	0.84 ± 0.20	7.11 ± 3.50

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

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

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

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

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

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Cmax

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

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

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DRUG0 ON Ka

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

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Description	Estimate	RSE*	Bootstrap

Mean	95% CI

Ka (h–1)	2.85	8.7%	2.24	1.21 to 3.87

CL/F (L h–1)	25.4	3.6%	25.4	23.7 to 27.4

Vc/F (L)	2390.	12.6%	2377.8	1479 to 3690

Q/F (L h-1)	8.41	13.3%	9.80	6.54 to 16.20

Vp/F (L)	168.	11.7%	175.9	135 to 239

ALAG1	0.877	4.7%	0.800	0.672 to 0.928

DRUG0 ON Ka	1.89	22.0%	2.00	1.23 to 2.88

DRUG0 ON Vc/F	0.216	13.1%	0.220	0.138 to 0.359

DRUG1 ON Vc/F	0.207	12.8%	0.210	0.128 to 0.328

DRUG0 ON CL/F	0.610	6.6%	0.610	0.537 to 0.696

DRUG1 ON CL/F	0.610	5.9%	0.610	0.545 to 0.695

WT ON Vc	0.579	25.7%	0.590	0.191 to 1.06

<inline-formula><mml:math id="inf1"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Ka	88.2%	24.0%	73.1%	37.7% to 115%

<inline-formula><mml:math id="inf2"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>CL/F	49.1%	7.4%	46.7%	39.8% to 53.4%

<inline-formula><mml:math id="inf3"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi>ω</mml:mi></mml:mrow></mml:mrow></mml:mstyle></mml:math></inline-formula>covCL/F-Vc/F	0.174	–	0.174	0.0832 to 0.259

<inline-formula><mml:math id="inf4"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Vc/F	40.8%	16.1%	39.7%	22.9% to 51.4%

<inline-formula><mml:math id="inf5"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Q/F	0 FIXED	–	–	–

<inline-formula><mml:math id="inf6"><mml:mstyle displaystyle="true" scriptlevel="0"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">I</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">V</mml:mi></mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:mstyle></mml:math></inline-formula>Vp/F	52.4%	29.3%	50.1%	11.5% to 90.1%

Prop-Error	0.216	5.0%	0.200	0.189 to 0.232

Add-Error	0.303	14.5%	0.300	0.215 to 0.382

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

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Cmax (mg/L)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Vm/F (L)

Final population PK model parameter estimates

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Ka (day−1)

Summary of the results obtained from the final model and the bootstrap analysis

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Parameter<xref ref-type="table-fn" rid="T2F1"><italic>a</italic></xref>	Median value for<xref ref-type="table-fn" rid="T2F2"><italic>b</italic></xref>:

Estimate	%RSE	%CV	Bootstrap estimate (95% CI)

CL/<italic>F</italic> (liters/day)	377	6.58	371.7	(302–435)

<italic>V</italic>2/<italic>F</italic> (liters)	2,230	6.59	2,212	(1,930–2,580)

<italic>V</italic>3/<italic>F</italic> (liters)	3,230	15.0	3,298	(2,360–4,710)

<italic>Q</italic>/<italic>F</italic> (liters/day)	804	11.2	831	(651–1,130)

<italic>Ka</italic> (day−1)	17.9	11.7	17.7	(14.1–22.5)

θ6 age on <italic>V</italic>3/<italic>F</italic>	0.624	38.6	0.629	(0.224–1.05)

θ7 formulation on <italic>Ka</italic>	1.63	37.8	1.86	(0.517–4.11)

IIV

    CL/<italic>F</italic>	0.166	26.7	40.7	0.160	(0.055–0.318)

    <italic>V</italic>2/<italic>F</italic>	0.993	8.76	99.6	0.994	(0.805–1.170)

    <italic>V</italic>3/<italic>F</italic>	0.256	48.4	50.6	0.265	(0.033–0.593)

    <italic>Q</italic>/<italic>F</italic>

    <italic>Ka</italic>	0.433	26.6	65.8	0.413	(0.194–0.669)

RV (additive error)	0.195	12.1	0.195	(0.15–0.244)

aFor both of the derived parameters distribution half-life (T1/2α) and elimination half-life (T1/2β) for pediatric malaria patients, the mean value ± standard deviation was 0.9 ± 0.6. F, oral bioavailability; CL, clearance; V2, central volume of distribution; V3, peripheral volume of distribution; Q, intercompartmental clearance; Ka, first-order absorption rate constant; IIV, interindividual variability; RV, residual variability.b%RSE, relative standard error [(SE/mean) × 100%]; %CV, percent coefficient of variation [(SD/estimate) × 100%].

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Cl/F

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

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

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Incremental AUC (nmol·h/L)

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

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Basal Diurnal Variation (DV)	Powdered Supplement	Tablet Supplement

<bold>Iron</bold>

 AUC (μmol·h/L)	104.5 ± 34.1

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

 Peak value (μmol/L)	14.6	3.0	8.9

Time to peak value (hrs)	3	4

<bold>Folate</bold>

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

 Peak value (nmol/L)	NA	54.4	53.1

Time to peak value (hrs)	NA	4	3

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

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

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CL/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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AUC0–∞ (hr ng/mL)

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

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

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35.1%CVa , b , f

      0
      1
      2
      3
      4

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      Parameter
      Final parameter estimate
      Final parameter estimate
      Between‐subject variability
      Between‐subject variability

      1
      Parameter
      Typical value
      %RSE
      Magnitude
      %RSE

      2
      CL: Central clearance (L/d)
      0.0902
      1.50
      23.4%CVa , b
      4.60

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      CL: Allometric exponent for weight (−)c
      1.05
      4.33
      nan
      nan

      4
      Vc,iv: Central volume of distribution IV (L)d
      2.98
      FIXED
      NE
      nan

      5
      Vc,SC: Central volume of distribution SC (L)e
      1.88
      3.38
      35.1%CVa , b , f
      19.9

      6
      Vc: Allometric exponent for weight (−)d , e
      1.53
      10.3
      nan
      nan

      7
      ka: Absorption rate constant (/d)
      0.180
      12.2
      59.0%CVa , b , f
      15.8

      8
      Q: Intercompartmental clearance (L/d)
      0.262
      FIXED
      NE
      nan

      9
      Vp: Peripheral volume of distribution (L)
      1.72
      FIXED
      NE
      nan

      10
      F1: Bioavailability
      0.658
      FIXED
      NE
      nan

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      ALAG1: Lag time (d)
      0.0803
      FIXED
      NE
      nan

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      Residual variability iv
      0.0467
      32.6
      nan
      nan

      13
      Residual variability SC proportional componentg
      0.0531
      4.03
      nan
      nan

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      Residual variability SC additive componentg
      0.204
      25.6
      nan
      nan

      15
      Minimum value of the objective function = 73303.561
      Minimum value of the objective function = 73303.561
      Minimum value of the objective function = 73303.561
      Minimum value of the objective function = 73303.561
      Minimum value of the objective function = 73303.561

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

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Cmax (ng/mL)

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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AUCinf (h.ng ml−1)

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

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

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IIV CL (CV%)

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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V z/F, L

Descriptive statistics for secondary PK parameters

CL/F, apparent systemic clearance after extravascular dosing; CV, coefficient of variation; EU Humira, adalimumab EU Humira; LS, least squares; M923, adalimumab biosimilar M923; PK, pharmacokinetics; t 1/2, terminal half‐life; t max, time to maximum concentration (median and range only); US Humira, adalimumab US Humira; V z/F, apparent volume of distribution.aTwenty‐seven of the 315 subjects in the PK analysis set had individual parameters that were excluded from the PK analysis set due to protocol deviations or failure to meet acceptability criteria. Half‐life and related PK parameters could not be calculated in 6 subjects due to lack of defined terminal elimination phase.

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Cmax (ng/mL)

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

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

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CL/F (mL/min/kg)

Summary of the Pharmacokinetic Parameters for SMT C1100 Following Single Oral Doses and Multiple Doses. Geometric Mean (Coefficient of Variation) Are Presented Unless Otherwise Stated

AUC0‐∞ = area under the plasma concentration‐time curve from time zero to infinity (percentage of AUC that is due to extrapolation from tz to infinity was <10% in all cases); AUC0− τ = area under the plasma concentration‐time curve over a dosing interval; Cmax = maximum observed plasma concentration; tmax = time of maximum observed plasma concentration; t½ = apparent plasma terminal elimination half‐life (for Day 10 of multiple‐dose study this is post drug induction); CL/F = apparent total plasma clearance; VZ/F = apparent volume of distribution during the terminal phase; RAobs = observed accumulation ratio based on AUC0‐ τ.aArithmetic mean (CV%).bMedian (min–max).cn = 5.dn = 3.

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Q/F, L/h

Final population model estimates of pantoprazole

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

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CLNPC,h(irinotecan)

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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Cl_obs (mL/min kg)

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

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AUC24 h

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

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Parameters	Units	i.v	i.m

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

AUC	μg∗h/ml	7.94 ± 1.11	6.79 ± 0.45

<italic>T</italic>max	h	–	0.25 ± 0.06

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

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

CLb	L/h	0.46 ± 0.08	0.43 ± 0.07

MRTlast	h	8.06 ± 1.6	22.85 ± 2.96

<italic>F</italic>	%	85.5 ± 7.11

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

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Cmax (ng/mL)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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CL/F

Summary of the results obtained from the final model and the bootstrap analysis

aFor both of the derived parameters distribution half-life (T1/2α) and elimination half-life (T1/2β) for pediatric malaria patients, the mean value ± standard deviation was 0.9 ± 0.6. F, oral bioavailability; CL, clearance; V2, central volume of distribution; V3, peripheral volume of distribution; Q, intercompartmental clearance; Ka, first-order absorption rate constant; IIV, interindividual variability; RV, residual variability.b%RSE, relative standard error [(SE/mean) × 100%]; %CV, percent coefficient of variation [(SD/estimate) × 100%].

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Vp/F (L)

Final population PK model parameter estimates

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Mean Cmax ng/mL (CV%)

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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Interindividual variability on clearance

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Cmax, ng/mL

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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Systolic 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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AUCtau (ng•h/mL)

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

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<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"/>

Dose	Day 1	Day 7

1%	3%	1%	3%

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

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

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

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

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

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

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

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

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IIV−Ka

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

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

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Tmax

Bioequivalence evaluations of CUR-C-HLN and CUR after oral administration at the CUR dose of 15 mg/kg or intravenous injection at the CUR dose of 2.5 mg/kg

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Administration route	Parameter	90% confidence interval calculated	<italic>P</italic> value calculated	Bioequivalence standard	Bioequivalence

Oral administration	<italic>AUC</italic>	464.88%–633.13%	-	80%–125%	No

<italic>C</italic>max	189.19%–319.46%	-	70%–143%	No

<italic>T</italic>max	-	< 0.05	> 0.05	No

In all	-	-	-	No

Intravenous injection	<italic>AUC</italic>	565.32%–671.09%	-	80%–125%	No

<italic>C</italic>max	546.04%–636.78%	-	70%–143%	Yes

<italic>T</italic>max	-	< 0.05	> 0.05	No

In all	-	-	-	No

Note: Data presented as the mean ± standard deviation (n = 6).

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λ [Weibull scale parameter]

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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First order elimination rate order

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

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

Mean	95 % CI	Mean	95 % CI

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

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

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

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

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

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

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Cl (L/h/kg)

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

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

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AUC

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tmax, h

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

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

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