CREA, umol/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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o

l

L


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

<!DOCTYPE html>

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.

K

a

h


Plasma AUC0–24

In vivo activity of SCY-078 versus C. albicans MY1055 and target exposures measured after dose 13 on treatment day 7 in a C′5-deficient DBA/2N murine model of disseminated candidiasis

<!DOCTYPE html>
<colgroup span="1"><col align="left" span="1"/><col align="left" span="1"/><col align="left" span="1"/><col align="left" span="1"/><col align="left" span="1"/><col align="left" span="1"/></colgroup>

Study and SCY-078 treatment (mg/kg)<xref ref-type="table-fn" rid="T1F1"><italic>a</italic></xref>	Plasma AUC0–24
	Kidney tissue burden (log10 CFU/g of tissue)	% animals sterilized<xref ref-type="table-fn" rid="T1F2"><italic>b</italic></xref>	Reduction from sham treatment (log10 CFU/g of tissue)

μg·h/ml	μM·h

Study A

    12.5	19.7	27.0	2.23	80	4.24

    Efficacious	12.9	17.7	2.51	60	4

    6.25	6.19	8.48	2.78	40	3.69

Study B

    12.5	16.2	22.2	2.2	100	4.67

    Efficacious	9.71a	13.3	2.86	50	4.01

    6.25	3.27	4.48	3.52	0	3.35

Study C

    6.25	11.0	15.1	2.61	60	4.35

Efficacy (mean)	15.4

aSCY-078 was administered orally twice daily. Efficacious, projected efficacious exposure assuming linearity regarding both efficacy and plasma exposure. Data are from 3 independent studies.bFive animals per group.

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s

m

a

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Tmax (h)

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

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

T

m

a

x

h


KIN, Plac (min−1)

Parameter estimates of the PK/PD models for quinpirole effect on ACTH, GH, prolactin and TSH with plasma and brainECF as target site

In bold the parameters of the selected models. DPlac, the extent of the placebo effect; ECF, extracellular fluid; EC50, concentration at half maximal drug effect; EMAX, maximal drug effect; kDEC, dose‐independent hormone decay; kDEG, hormone elimination rate; kREL, hormone release reate; RUV, residual unexplained variability; S0, EMAX/EC50.

K

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N

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a

c

m

i

n


CLR

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

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

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

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

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

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

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

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

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

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

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AUCa, μg*h mL−1

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

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

A

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a

μ

g

h

m

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RARαrel EC50a

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

R

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a


Cl

<!DOCTYPE html>

Potency and Selectivity
	PK

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

mouse	human	AUC	Cl	F%

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

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

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

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

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

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

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

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

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

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

C

l


C max (ng/mL)a

Summary of amenamevir pharmacokinetic parameters after administration of a single 400-mg dose of amenamevir alone and with ketoconazole at a dosage of 400 mg once daily or rifampicin at a dosage of 600 mg once daily

<!DOCTYPE html>

Parameter	Study

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

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

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

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

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

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

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

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

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

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

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

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T max, d

Summary of pharmacokinetic parameters of durvalumaba

AUC0‐t, area under the concentration‐time curve from time zero to t; C max, maximum plasma concentration; CV, coefficient of variation; max, maximum; min, minimum; q2w, every 2 weeks; q3w, every 3 weeks; q4w, every 4 weeks; T max, time to C max.aPharmacokinetics analysis set.bAUC0‐14 for 1, 3 and 10 mg/kg, AUC0‐21 for 15 mg/kg, and AUC0‐28 for 20 mg/kg.

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Tmax [h]

Comparison of population median plasma profile and experimental plasma profile pharmacokinetics

<!DOCTYPE html>

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

AUC_tEnd [μmol*min/l]	1296.06	1504.96	13.88

Cmax μmol/l	9.86	11.6	15

Tmax [h]	1.5	1.56	3.846

Half life [h]	29.21	Infinity	__

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km (1/h)

Final population PK model parameter estimates

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<col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/><col style="border-bottom:solid 1px #000000border-right:solid 1px #000000" width="80pt" span="1"/>

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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m

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Cmax (μg/L)

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

<!DOCTYPE html>

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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CL/f, L/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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h


First‐phase t1/2, h

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

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

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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eGFR, mL/min/1.73 m2

      0
      1
      2
      3
      4

      0
      Unnamed: 0_level_0
      Unnamed: 1_level_0
      Insulin plus ipragliflozin
      Insulin plus ipragliflozin
      Insulin plus ipragliflozin

      1
      Unnamed: 0_level_1
      Insulin plus placebo (n = 10)
      25 mg(n = 9)
      50 mg(n = 12)
      100 mg(n = 10)

      2
      Sex
      Sex
      Sex
      Sex
      nan

      3
      Male
      3 (30.0)
      3 (33.3)
      2 (16.7)
      4 (40.0)

      4
      Female
      7 (70.0)
      6 (66.7)
      10 (83.3)
      6 (60.0)

      5
      Age, years
      Age, years
      Age, years
      Age, years
      nan

      6
      nan
      44.8 ± 13.2
      47.2 ± 15.7
      43.4 ± 12.3
      41.7 ± 14.0

      7
      Body weight, kg
      Body weight, kg
      Body weight, kg
      Body weight, kg
      nan

      8
      nan
      63.09 ± 7.63
      67.27 ± 10.20
      64.88 ± 10.32
      66.53 ± 6.82

      9
      BMI, kg/m2
      BMI, kg/m2
      BMI, kg/m2
      BMI, kg/m2
      nan

      10
      nan
      23.93 ± 2.72
      26.56 ± 5.60
      24.54 ± 3.77
      24.25 ± 2.64

      11
      Duration of type 1 diabetes, months
      Duration of type 1 diabetes, months
      Duration of type 1 diabetes, months
      Duration of type 1 diabetes, months
      nan

      12
      nan
      213.9 ± 99.1
      230.6 ± 182.0
      180.0 ± 114.2
      130.2 ± 62.5

      13
      HbA1c
      HbA1c
      HbA1c
      HbA1c
      nan

      14
      %
      8.66 ± 0.74
      8.51 ± 0.79
      8.45 ± 0.76
      8.85 ± 0.72

      15
      mmol/Mol
      71.1 ± 7.9
      69.4 ± 8.7
      68.9 ± 8.3
      73.1 ± 8.2

      16
      Fasting plasma glucose level
      Fasting plasma glucose level
      Fasting plasma glucose level
      Fasting plasma glucose level
      nan

      17
      mg/dL
      150.9 ± 72.4
      152.2 ± 68.1
      128.3 ± 32.9
      198.2 ± 75.4

      18
      mmol/L
      8.38 ± 4.02
      8.43 ± 3.79
      7.11 ± 1.82
      11.00 ± 4.21

      19
      Postprandial plasma glucose level, mg/dL
      Postprandial plasma glucose level, mg/dL
      Postprandial plasma glucose level, mg/dL
      Postprandial plasma glucose level, mg/dL
      Postprandial plasma glucose level, mg/dL

      20
      1 h after breakfast
      265.2 ± 100.3
      230.0 ± 67.8
      228.2 ± 61.9
      275.4 ± 50.4

      21
      2 h after breakfast
      302.7 ± 96.0
      239.1 ± 76.5
      234.0 ± 66.7
      293.5 ± 61.1

      22
      3 h after breakfast
      271.2 ± 90.5
      232.1 ± 101.9
      228.8 ± 51.4
      275.4 ± 73.4

      23
      Postprandial plasma glucose level, mmol/L
      Postprandial plasma glucose level, mmol/L
      Postprandial plasma glucose level, mmol/L
      Postprandial plasma glucose level, mmol/L
      Postprandial plasma glucose level, mmol/L

      24
      1 h after breakfast
      14.73 ± 5.58
      12.78 ± 3.77
      12.66 ± 3.44
      15.28 ± 2.80

      25
      2 h after breakfast
      16.79 ± 5.34
      13.26 ± 4.25
      13.00 ± 3.71
      16.30 ± 3.39

      26
      3 h after breakfast
      15.06 ± 5.02
      12.90 ± 5.65
      12.71 ± 2.85
      15.28 ± 4.06

      27
      Plasma glucose AUC0‐24h
      Plasma glucose AUC0‐24h
      Plasma glucose AUC0‐24h
      Plasma glucose AUC0‐24h
      Plasma glucose AUC0‐24h

      28
      h·mg/dL
      5048 ± 1301
      4498 ± 842
      4230 ± 1075
      4464 ± 657

      29
      h·mmol/L
      280.2 ± 72.2
      249.6 ± 46.6
      234.7 ± 59.8
      247.8 ± 36.5

      30
      Urinary glucose excretion
      Urinary glucose excretion
      Urinary glucose excretion
      Urinary glucose excretion
      nan

      31
      g/24 h
      24.8 ± 20.4
      7.9 ± 9.0
      8.6 ± 9.5
      11.1 ± 7.0

      32
      mmol/24 h
      137.44 ± 113.36
      44.01 ± 49.77
      47.85 ± 52.79
      61.77 ± 38.87

      33
      Renal glucose clearance0‐24h, mL/min
      Renal glucose clearance0‐24h, mL/min
      Renal glucose clearance0‐24h, mL/min
      Renal glucose clearance0‐24h, mL/min
      Renal glucose clearance0‐24h, mL/min

      34
      nan
      7.13 ± 5.13
      2.77 ± 2.85
      2.94 ± 3.09
      3.98 ± 2.38

      35
      Fasting C‐peptide
      Fasting C‐peptide
      Fasting C‐peptide
      Fasting C‐peptide
      nan

      36
      ng/mL
      0.05 ± 0.13
      0.12 ± 0.16
      0.09 ± 0.14
      0.04 ± 0.07

      37
      nmol/L
      0.01 ± 0.03
      0.03 ± 0.05
      0.03 ± 0.05
      0.01 ± 0.03

      38
      Glycoalbumin, %
      Glycoalbumin, %
      Glycoalbumin, %
      Glycoalbumin, %
      Glycoalbumin, %

      39
      nan
      26.05 ± 3.73
      25.46 ± 4.25
      25.48 ± 2.76
      24.59 ± 4.63

      40
      Insulin daily dose, IU
      Insulin daily dose, IU
      Insulin daily dose, IU
      Insulin daily dose, IU
      nan

      41
      Basal
      16.70 ± 7.24
      17.10 ± 8.02
      16.72 ± 7.00
      18.60 ± 4.88

      42
      Bolus
      27.30 ± 11.69
      29.64 ± 12.89
      22.08 ± 6.42
      33.80 ± 10.46

      43
      Total
      44.00 ± 17.83
      46.74 ± 19.71
      38.80 ± 12.27
      52.40 ± 11.05

      44
      eGFR, mL/min/1.73 m2
      eGFR, mL/min/1.73 m2
      eGFR, mL/min/1.73 m2
      eGFR, mL/min/1.73 m2
      eGFR, mL/min/1.73 m2

      45
      nan
      105.98 ± 31.10
      90.60 ± 27.07
      93.74 ± 22.48
      100.62 ± 17.20

      46
      Total serum ketones, μmol/La
      Total serum ketones, μmol/La
      nan
      nan
      nan

      47
      nan
      373.74 ± 322.59
      148.09 ± 162.80
      197.44 ± 139.87
      338.79 ± 298.77

CAPTION: Demographic and baseline characteristics (PDAS)
FOOTER: Values are presented as n (%) or mean ± standard deviation.aSafety analysis set data (placebo n = 11, ipragliflozin 25 mg n = 10, 50 mg n = 12, and 100 mg n = 10).Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; PDAS, pharmacodynamic analysis set.

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Peak value (μmol/L)

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

<!DOCTYPE html>

Basal Diurnal Variation (DV)	Powdered Supplement	Tablet Supplement

<bold>Iron</bold>

 AUC (μmol·h/L)	104.5 ± 34.1

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

 Peak value (μmol/L)	14.6	3.0	8.9

Time to peak value (hrs)	3	4

<bold>Folate</bold>

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

 Peak value (nmol/L)	NA	54.4	53.1

Time to peak value (hrs)	NA	4	3

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

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CLtot (ml min−1 kg−1)

Pharmacokinetic parameters

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

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Albumin-bound doxorubicin

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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AUC0‐24 (ng•h/mL)

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

<!DOCTYPE html>
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<bold>Study Population</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>CF</bold>

<bold>HV</bold>

<bold>HV</bold>

<bold>Dosing Day</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>15</bold>

<bold>14</bold>

<bold>14</bold>

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

<bold>50</bold>

<bold>50</bold>

<bold>100</bold>

<bold>100</bold>

<bold>150</bold>

<bold>200</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

<bold>Mean</bold>

<bold>SD</bold>

<bold>N</bold>

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

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

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

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

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

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

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

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

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

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

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

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

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ΔOBJ

      0
      1
      2
      3
      4

      0
      Hypothesis test
      OBJ
      ΔOBJ
      P-value
      Comments

      1
      Basic model
      2206.300000
      nan
      nan
      nan

      2
      If Gender affect CL ?
      2205.000000
      -1.300000
      >0.05
      NO

      3
      If Age affect CL ?
      2097.600000
      -108.700000
      <0.01
      YES

      4
      If Weight affect CL ?
      2094.000000
      -112.300000
      <0.01
      YES

      5
      If Body surface area affect CL ?
      2095.400000
      -110.900000
      <0.01
      YES

      6
      If ALT affect CL ?
      2204.800000
      -1.500000
      >0.05
      NO

      7
      If AST affect CL ?
      2204.800000
      -1.500000
      >0.05
      NO

      8
      If CRE affect CL ?
      2197.500000
      -8.800000
      <0.01
      YES

      9
      If BUN affect CL ?
      2205.600000
      -0.700000
      >0.05
      NO

      10
      If GFR affect CL ?
      2140.600000
      -65.700000
      <0.01
      YES

CAPTION: Hypothesis test results of covariates affecting on vancomycin clearance (CL)
FOOTER: []

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β/αratio b

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Covariate 3: ADA on CL

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

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

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Tmax (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–τ (mg/L × hour)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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AUCinf (ng h mL−1)

Bioavailability of esaxerenone and effects of food on esaxerenone pharmacokinetics

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Bioavailability	Geometric least squares mean	Ratio	90% CI

Oral administration	IV administration	Oral/IVa

AUCinf (ng h mL−1)

 Fasting	1224.33	1374.99	89.0	86.7, 91.5

 Postprandial	1247.86	–	90.8	88.3, 93.2

AUC area under the curve; Cmax peak plasma concentration; CI confidence interval; IV intravenousaPresented as ratio ( ×100)%

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C (n = 3)

      0
      1
      2
      3
      4
      5
      6
      7

      0
      Single‐dose period
      Single‐dose period
      Single‐dose period
      Single‐dose period
      Single‐dose period
      Single‐dose period
      Single‐dose period
      Single‐dose period

      1
      Step
      Summary statistics
      t1/2 (h)
      t max (h)
      C max (ng/mL)
      AUC0‐48 (ng·h/mL)
      AUC0‐inf (ng·h/mL)
      Ae (%)

      2
      1 (n = 5)
      Mean (SD) or median (min–max)
      8.61 (4.20)
      2.00 (0.50–2.00)
      839 (383)
      2729 (901)
      2759 (936)
      24.98 (3.81)

      3
      1 (n = 5)
      CV (%)
      48.7
      nan
      45.6
      33.0
      33.9
      15.3

      4
      2 (n = 5)
      Mean (SD) or median (min–max)
      7.70 (3.16)
      2.00 (1.00–2.00)
      1847 (996)
      5946 (2967)
      5962 (2967)
      26.53 (3.84)

      5
      2 (n = 5)
      CV (%)
      41.1
      nan
      53.9
      49.9
      49.8
      14.5

      6
      3 (n = 5)
      Mean (SD) or median (min–max)
      7.05 (4.07)
      2.00 (1.00–2.00)
      3202 (1493)
      9401 (3493)
      9446 (3646)
      31.89 (9.40)

      7
      3 (n = 5)
      CV (%)
      57.8
      nan
      46.6
      37.2
      38.6
      29.5

      8
      Repeated‐dose period
      Repeated‐dose period
      Repeated‐dose period
      Repeated‐dose period
      Repeated‐dose period
      Repeated‐dose period
      Repeated‐dose period
      Repeated‐dose period

      9
      nan
      nan
      Day 1
      Day 1
      Day 7
      Day 7
      Day 4
      Day 7

      10
      Step
      Summary statistics
      t max, day 1 (h)
      C max, day 1 (ng/mL)
      t max, day 7 (h)
      C max, day 7 (ng/mL)
      Cpre, day 4 (ng/mL)
      Cpre, day 7 (ng/mL)

      11
      A (n = 5)
      Mean (SD) or median (min–max)
      2.00 (1.00–2.00)
      1004 (656)
      2.00 (2.00–2.00)
      891 (297)
      42.9 (19.9)
      41.1 (14.2)

      12
      A (n = 5)
      CV (%)
      nan
      65.3
      nan
      33.3
      46.3
      34.6

      13
      B (n = 5)
      Mean (SD) or median (min–max)
      2.00 (1.00–2.00)
      1894 (691)
      2.00 (1.00–2.00)
      2322 (776)
      68.94 (41.0)
      70.9 (36.0)

      14
      B (n = 5)
      CV (%)
      nan
      36.5
      nan
      33.4
      59.6
      50.7

      15
      C (n = 3)
      Mean (SD) or median (min–max)
      2.00 (2.00–4.00)
      2635 (2813)
      2.00 (0.50–2.00)
      4660 (3671)
      75.9 (34.7)
      98.7 (55.7)

      16
      C (n = 3)
      CV (%)
      nan
      106.8
      nan
      78.8
      45.8
      56.5

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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n


CL (L/h/kg)

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

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Parameter	Triptolide	Triptolide + puerarin

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

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

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

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

CL (L/h/kg)	4.92 ± 0.35	3.75 ± 0.19*

*p < 0.05 indicates significant differences from the control.

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CL (L/day)

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Vz/F (L)

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.

V

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F

L


t1/2 (h)

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

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

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

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

t

h


Human studies reporting pharmacokinetic (PK) parameters for cannabidiol (CBD).

<!DOCTYPE html>

<bold>References</bold>	<bold>Total n, sex</bold>	<bold>Administration</bold>	<bold>Source</bold>	<bold>CBD dose</bold>	<bold>Plasma</bold><xref ref-type="table-fn" rid="TN1"><bold>a</bold></xref><bold>PK details</bold>	<bold>Other</bold>

<bold>Tmax (median, range),<xref ref-type="table-fn" rid="TN1">b</xref> hrs</bold>	<bold>Cmax (mean, SD)<xref ref-type="table-fn" rid="TN1">b</xref> ng/mL</bold>	<bold>AUC0-t (mean, SD)<xref ref-type="table-fn" rid="TN1">b</xref> h × ng/mL</bold>	<bold>AUC0-inf (mean, SD) h × ng/mL</bold>	<bold>Kel (mean, SD) 1/h</bold>	<bold>t1/2 (mean, SD)<xref ref-type="table-fn" rid="TN1">b</xref> h</bold>	<bold>CL/F (mean, SD) L/h</bold>	<bold>Mean (SD)</bold>

Ohlsson et al., <xref rid="B46" ref-type="bibr">1986</xref>	5, M, infrequent to frequent cannabis smokers	i.v.	In lab	20 mg	686 (239)	ng/ml min × 10−3 = 16.67 (3.23)	24 (6)	74.4 (14.4)	Distribution volume: 32.7 (8.6) l/kg.

<bold>‘'</bold>	Smoking	In lab	19.2 ± 0.3mg	110 (55)	ng/ml min × 10−3 = 4.85 (1.72)	31 (4)	Estimated systemic availability (%) from smoking: 31 (13)

Consroe et al., <xref rid="B8" ref-type="bibr">1991</xref>	15, M/F	Oral capsules	NIDA	10 mg/kg/day daily for 6 weeks	2–5 days

Guy and Robson, <xref rid="B25" ref-type="bibr">2004b</xref>	12, M/F	Oromucosal spray sublingual (CBD and THC)	GW	10 mg	1.63 (SD 0.68)	2.5 (1.83)	6.81 (4.33)	7.12 (4.31)	1.44 (0.79)

Oromucosal spray buccal (CBD and THC)	GW	10 mg	2.79 (SD 1.31)	3.02 (3.15)	6.4 (4.62)	6.8 (4.46)	1.81 (2.05)

Oromucosal spray oro-pharyngeal (CBD and THC)	GW	10 mg	2.04 (SD 1.13)	2.61 (1.91)	7.81 (5.13)	8.28 (5.32)	1.76 (0.8)

CBME oral capsule (CBD and THC)	GW	10 mg	1.27 (SD 0.84)	2.47 (2.23)	5.76 (4.94)	6.03 (4.97)	1.09 (0.46)

Guy and Robson, <xref rid="B24" ref-type="bibr">2004a</xref>	24, M	Oromucosal spray sublingual (CBD and THC)	GW	10 mg	4.22	3.33	11.34	11.97	1.81

Guy and Flint, <xref rid="B23" ref-type="bibr">2004</xref>	6 M/F	Nebuliser (CBD and THC)	GW	20 mg	0.6 (0.08–1)	9.49 (8.01)	9.41 (10.8)	12.11 (10.83)	0.98 (0.58)	1.1 (0.97)

Aerosol (with THC)	GW	20 mg	2.35 (0.75–6)	2.6 (1.38)	5.43 (5.88)	13.53 (3.64)	0.43 (0.26)	2.4 (2.02)

Sublingual drops (CBD)	GW	20 mg	2.17 (1–4)	2.05 (0.92)	2.60 (3.45)

Sublingual drops (CBD and THC)	GW	20 mg	1.67 (1–3)	2.58 (0.68)	3.49 (2.65)	9.65 (4.02)	0.37 (0.114)	1.97 (0.62)

Nadulski et al., <xref rid="B40" ref-type="bibr">2005a</xref>	24, M/F	Oral capsule (CBD and THC)	Scherer GmbH & Co. KG, Eberbach,Germany	5.4mg once a week for 3 weeks	Mean 0.99 (0.5–2)	0.93 (range 0–2.6)	Mean 4.35, range (2.7–5.6)

12, M/F	Oral capsule (CBD and THC) and breakfast consumed 1 hour after	Scherer GmbH & Co. KG, Eberbach,Germany	5.4mg once a week for 3 weeks	Mean 1.07 (0.5–2)	1.13 (range 0.39–1.9)	Mean 4.4 (range 2.5–5.3)

Nadulski et al., <xref rid="B41" ref-type="bibr">2005b</xref>	24, M/F	Cannabis extract	Sigma	5.4 mg	Mean 1.0 (0.5–2.0)	0.95 (range 0.3–2.57)

Karschner et al., <xref rid="B33" ref-type="bibr">2011</xref>	9, M/F cannabis smokers	Oromucosal spray (Sativex: CBD and THC)	GW	5 mg	3.6 (1.0–5.5)	Mean (SE): 1.6 (0.4)	4.5 (SE 0.6)

15 mg	4.6 (1.2–5.6)	Mean (SE): 6.7 (2.0)	18.1 (SE 3.6)

Schwope et al., <xref rid="B47" ref-type="bibr">2011</xref>	10, M/F, usual infrequent cannabis smokers	Cannabis cigarette	NIDA	2 mg	0.25 (0.25–0.50 h) whole blood/plasma	Median (range): plasma 2 (< LOQ−3.4)

Eichler et al., <xref rid="B15" ref-type="bibr">2012</xref>	9, M	Oral capsules (CBD and THC)	Cannapharm AG	Heated CBD (27.8 mg CBD: 0.8 mg CBDA)	0.83 (SD 0.17)	pmol/mL: 0.94 (0.22)	pmol h/moL 3.68 (1.34)

Unheated 14.8 mg CBD:10.8 mg CBDA)	1.17 (SD 0.39)	3.95 (0.92) pmoL/mL	pmol h/mol 7.67 (2.06)

Lee et al., <xref rid="B34" ref-type="bibr">2012</xref>	10, M/F, cannabis smokers	Cannabis cigarette	NIDA	2 mg	Median 0.25 (oral fluid)	0.03 (oral fluid)

Sellers et al., <xref rid="B48" ref-type="bibr">2013</xref>	60, M/F	Oromucosal spray (CBD and THC)	GW	20 mg, 5 days	1.4 (0, 8.45)	1.5 (0.78)	6.1 (5.76)	14.8 (7.87)

51, M/F	90 mg – 60 mg, 5 days	1.5 (0–6.45)	4.8 (3.4)	38.9 (33.75)	60.3 (37.71)

Stott et al., <xref rid="B51" ref-type="bibr">2013b</xref>	12, M	Oromucosal spray (CBD and THC)	GW	10 mg (fed state)	4.00 (3.02–9.02);	3.66 (2.28)	23.13 (9.29)	20.21 (8.43)	0.155 (0.089)	5.49 (2.17)	533 (318)

Stott et al., <xref rid="B50" ref-type="bibr">2013a</xref>	24, M	Oromucosal spray (CBD and THC)	GW	5 mg single dose	Mean 1.00 (0.75–1.50)	0.39 (0.08)	0.82 (0.33)	1.66 (0.51)	0.173 (0.084)	5.28 (3.28)	3,252 (1,002)

10 mg single dose	Mean 1.39 (0.75–2.25)	1.15 (0.74)	4.53 (3.53)	5.64 (4.09)	0.148 (0.079)	6.39 (4.48)	2,546 (1,333)

20 mg single dose	Mean 1.00 (0.75–1.75)	2.17 (1.23)	9.94 (9.02)	13.28 (12.86)	0.123 (0.097)	9.36 (6.81)	3,783 (4,299)

5 mg, 9 days	Mean 1.64 (1.00–4.02)	0.49 (0.21)	2.52 (0.73)

10 mg, 9 days	Mean 1.27 (0.75–2.52)	1.14 (0.86)	6.66 (3.10)

20 mg 9 days	Mean 2.00 (1.02–6.00)	3.22 (1.90)	20.34 (7.29)

Stott et al., <xref rid="B49" ref-type="bibr">2013c</xref>	36, M	Oromucosal spray (CBD and THC)	GW	10 mg (3 groups)	1.00 (0.50–4.00); 1.38 (0.75–6.00); 1.15 (0.50–3.02)	1.03 (0.81); 0.66 (0.37); 0.63 (0.43)	3.23 (2.13); 1.82 (1.03); 1.83 (1.19)	5.10 (3.06); 3.54 (0.80); 3.00 (1.43)	0.148(0.108); 0.122 (0.111); 0.224 (0.158)	10.86(12.71); 7.81 (3.00); 5.22 (4.51)	2817 (1913); 2998 (896); 4,741 (3,835)	Varea/F (L): 28312 (19355); 31994 (12794); 26298 (14532)

15 mg	4.5 (1.2–5.6)	Mean (SE): 6.7 (2.0)

Newmeyer et al., <xref rid="B44" ref-type="bibr">2014</xref>	24, M/F, frequent or occasional cannabis smokers	Cannabis cigarette (frequent smokers)	NIDA	2 ± 0.6 mg	0.5 (0.5–1)	Median (range): 14.8 (1.4–162)	Median (range): 29 (4.7–211)

Cannabis cigarette (occasional smokers)	2 ± 0.6 mg	1 (0.5–2)	Median (range): 7 (1.9–111)	Median (range): 11.6 (4.1–185)

Desrosiers et al., <xref rid="B11" ref-type="bibr">2014</xref>	21, M/F frequent and occasional smokers	Cannabis cigarette (frequent smokers)	NIDA	2 mg	0.5 (0.0–1.1)	1.1 (0.0–1.6)

Cannabis cigarette (occasional smokers)	2 mg	0 (0–500)	0 (0–1300)

Manini et al., <xref rid="B37" ref-type="bibr">2015</xref>	17, M/F	Oral capsules Co-administered with i.v. fentanyl	GW	400 mg	3 and 1.5 (plasma) and 6 and 2 (urine)	Plasma: 181.2 (39.8) and 114.2 (9.5); Urine: 4600 and 2900	704 (283) and 482 (314) mcg*hr/dL

800 mg	3 and 4 (plasma) and 4 and 6 (urine)	Plasma: 221 (35.6) and 157.1 (49.0); Urine: 3700 and 2800	867 (304) and 722 (443) mcg*hr/dL

Haney et al., <xref rid="B28" ref-type="bibr">2016</xref>	8, M/F cannabis smokers	Oral capsules	STI pharmaceuticals	800 mg	Mean 3 (2–6)	77.9 (range 1.6–271.9)

Cherniakov et al., <xref rid="B6" ref-type="bibr">2017a</xref>	9, M	Oral capsules with piperine pro-nanolipospeheres (CBD and THC)	STI pharmaceuticals	10 mg	1 (0.5–1.5)	2.1 (0.4)	6.9 (1.3)

Oromucosal spray (CBD and THC; Sativex®)	10 mg	3 (1–5)	0.5 (0.1)	3.1 (0.4)

Swortwood et al., <xref rid="B53" ref-type="bibr">2017</xref>	20, M/F Cannabis smokers	Cannabis cigarettes – frequent smokers	NIDA	1.5 mg	Mean 0.29 (0.17–1.5) (oral fluid)	93.3 (range 0.65–350) (oral fluid)

Cannabis cigarettes – occasional smokers	NIDA	1.5 mg	Mean 0.17 (oral fluid)	55.9 (range 2.5–291) (oral fluid)

Cannabis containing brownie – frequent smokers	NIDA	1.5 mg	Mean 0.53 (0.17–1.5) (oral fluid)	8.0 (range 0.48–26.3) (oral fluid)

Cannabis containing brownie – occasional smokers	NIDA	1.5 mg	Mean 0.47 (0.17–1.5) (oral fluid)	5.9 (range 2.1–11.4) (oral fluid)

Vaporization – frequent smokers	Volcano® Medic, Storz & Bickel, Tuttlingen, Germany	1.5 mg	Mean 0.29 (0.17–1.5) (oral fluid)	76.3 (range 2.3–339) (oral fluid)

Vaporization – occasional smokers	Volcano® Medic, Storz & Bickel, Tuttlingen, Germany	1.5 mg	Mean 0.17 (oral fluid)	28.2 (range 0.23–167) (oral fluid)

Atsmon et al., <xref rid="B3" ref-type="bibr">2017b</xref>	15, M	CBD extract >93% in a PTL101 formulation (oral gelatin matrix pellet technology)Sublingual/buccal	AiFame-AiLab GmbH (CBD), Gelpell AG (capsules)	10 mg	3.0 (2.0–4.0)	3.22 (1.28)	9.64 (3.99)	10.31 (4.14)	2.95 (2.58)

100 mg	3.5 (1.5–5.0)	47.44 (20.14)	149.54 (34.34)	153.04 (34.7)	3.59 (0.26)

Oromucosal spray (CBD and THC)	GW	10 mg	3.5 (1.0–5.0)	2.05 (1.1)	7.3 (2.86)	7.81 (2.81)	0.33 (0.09)	2.31 (0.72)

Atsmon et al., <xref rid="B2" ref-type="bibr">2017a</xref>	15, M	CBD and THC in a PTL401 capsule (self-emulsifying oral drug delivery system)	STI pharmaceuticals	10 mg	1.25 (0.5–4.0)	2.94 (0.73)	9.85 (4.47)	10.52 (4.53)	0.29 (0.17)	3.21 (1.62)

Devinsky et al., <xref rid="B14" ref-type="bibr">2018b</xref>	34, children	Oral solution	GW	2.5 mg	70.23 (mean from 3 groups)

5 mg/kg/day	241

10 mg/kg/day	722

20 mg/kg/day	963

a, bUnless otherwise stated. PK, pharmacokinetics; CBD, cannabidiol; THC, Tetrahydrocannabinol; M, male; F, female; AUC, area under the curve; Conc., concentration; GW, GW pharmaceuticals; NIDA, US national institute on drug abuse; LOQ, limit of quantification; IV, intravenous; CBME, cannabis based medicine extract; Min(s), min(s).

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AUCinf (μg*hr/mL)

Summary of Key IV and SC PK Parameters for PF-06645849 in Rats and Monkeys.

Cmax, maximum observed concentration; Tmax, time to Cmax; AUCinf, area under the concentration-time curve from time zero extrapolated to infinity; Cl, systemic clearance; Vss, volume of distribution at steady state; t1/2, terminal half-life; F (%), SC bioavailability. All values are expressed as (Means ± SD) with n = 3 for rats and n = 2 for monkeys.

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IOV MTT (CV%)

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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AUC0-0.5h [ng*hr/L]

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

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

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Cminss

Predicted Exposures With Nivolumab 240 mg Q2W in Chinese Patients and 10 mg/kg Q2W in the Global Population

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

Chinese Patients 240 mg Q2W (n = 314)<xref ref-type="fn" rid="jcph1432-tbl4-note-0002">a</xref>
	Global Population 10 mg/kg Q2W (n = 148)<xref ref-type="fn" rid="jcph1432-tbl4-note-0003">b</xref>

Predicted Exposure (µg/mL)	Geometric Mean	CV (%)	Geometric Mean	CV (%)	Difference in Geometric Means (%)

Cmin1
	20.7	24.1	53.6	27.5	−61.0

Cmax1
	71.2	18.9	178.0	25.2	−60.0

Cavg1
	32.4	18.3	85.7	22.0	−62.0

Cminss
	78.3	71.8	206.0	64.0	−62.0

Cmaxss
	152.0	44.7	393.0	39.6	−61.0

Cavgss
	101.0	58.1	268.0	52.3	−62.0

Cavg1 indicates postdose 1 time‐averaged serum concentration; Cavgss, time‐averaged serum concentration at steady‐state; Cmax1, postdose 1 peak serum concentration; Cmaxss, peak serum concentration at steady state; Cmin1, postdose 1 trough serum concentration; Cminss, trough serum concentration at steady state; CV, coefficient of variation; Q2W, every 2 weeks.aPredicted data for all Chinese patients in CheckMate 077 and 078 receiving nivolumab 3‐mg/kg (n = 294) or 240‐mg Q2W (n = 20) doses.bPredicted data for global patients receiving 10 mg/kg Q2W from global studies MDX‐1106‐01 and CA209‐003.

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AUC0–24h (ng · h/mL)

Summary of Exposure Normalizeda Tacrolimus PK Parameters—mITT Analysis Set

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Day 1a<xref ref-type="fn" rid="cpdd657-tbl4-note-0002">b</xref> (Adjustment Factor 1 + 0.95)	Day 7 (Adjustment Factor 1 – 0.015)	Day 14 (Adjustment Factor 1 – 0.105)

Geometric Mean (%CV), Arithmetic Mean ± SD	Geometric Mean (%CV), Arithmetic Mean ± SD	Geometric Mean (%CV), Arithmetic Mean ± SD

PK Parameter	LCPT (n = 29)	IR‐Tac (n = 28)
<italic>P</italic>‐Value<xref ref-type="fn" rid="cpdd657-tbl4-note-0003">c</xref>
	LCPT (n = 23)	IR‐Tac (n = 26)
<italic>P</italic>‐Value<xref ref-type="fn" rid="cpdd657-tbl4-note-0003">c</xref>
	LCPT (n = 21)	IR‐Tac (n = 23)
<italic>P</italic>‐Value<xref ref-type="fn" rid="cpdd657-tbl4-note-0003">c</xref>

Total daily dose (mg)	12.64 ± 2.48	8.29 ± 2.55	9.64 ± 4.1	9.33 ± 3.77	8.44 ± 3.73	9.65 ± 4.14

AUC0–24h (ng · h/mL)
<list list-type="simple" id="cpdd657-list-0017"><list-item>
116.16 (54.86)
</list-item><list-item>
132.95 ± 72.94
</list-item></list>

<list list-type="simple" id="cpdd657-list-0018"><list-item>
116.17 (54.51)
</list-item><list-item>
135.62 ± 73.92
</list-item></list>
	.999
<list list-type="simple" id="cpdd657-list-0019"><list-item>
228.46 (40.83)
</list-item><list-item>
247.52 ± 101.01
</list-item></list>

<list list-type="simple" id="cpdd657-list-0020"><list-item>
226.87 (41.56)
</list-item><list-item>
245.47 ± 102.03
</list-item></list>
	.95
<list list-type="simple" id="cpdd657-list-0021"><list-item>
227.55 (50.02)
</list-item><list-item>
250.23 ± 125.17
</list-item></list>

<list list-type="simple" id="cpdd657-list-0022"><list-item>
229.55 (33.12)
</list-item><list-item>
241.22 ± 79.90
</list-item></list>
	.94

Cmax (ng/mL)
<list list-type="simple" id="cpdd657-list-0023"><list-item>
9.86 (58.15)
</list-item><list-item>
11.6 ± 6.75
</list-item></list>

<list list-type="simple" id="cpdd657-list-0024"><list-item>
11.13 (49.48)
</list-item><list-item>
12.7 ± 6.29
</list-item></list>
	.44
<list list-type="simple" id="cpdd657-list-0025"><list-item>
15.18 (46.04)
</list-item><list-item>
16.89 ± 7.78
</list-item></list>

<list list-type="simple" id="cpdd657-list-0026"><list-item>
19.24 (42.52)
</list-item><list-item>
21.10 ± 8.97
</list-item></list>
	.083
<list list-type="simple" id="cpdd657-list-0027"><list-item>
16.96 (46.64)
</list-item><list-item>
19.06 ± 8.89
</list-item></list>

<list list-type="simple" id="cpdd657-list-0028"><list-item>
19.61 (63.47)
</list-item><list-item>
22.95 ± 14.57
</list-item></list>
	.38

Cmin (ng/mL)
<list list-type="simple" id="cpdd657-list-0029"><list-item>
4.97 (74.27)
</list-item><list-item>
6.27± 4.66
</list-item></list>

<list list-type="simple" id="cpdd657-list-0030"><list-item>
3.62 (63.97)
</list-item><list-item>
4.42 ± 2.83
</list-item></list>
	.082
<list list-type="simple" id="cpdd657-list-0031"><list-item>
6.75 (48.32)
</list-item><list-item>
7.22 ± 3.49
</list-item></list>

<list list-type="simple" id="cpdd657-list-0032"><list-item>
6.83 (53.29)
</list-item><list-item>
7.61 ± 4.06
</list-item></list>
	.77
<list list-type="simple" id="cpdd657-list-0033"><list-item>
5.97 (56.27)
</list-item><list-item>
6.64 ± 3.73
</list-item></list>

<list list-type="simple" id="cpdd657-list-0034"><list-item>
7.17 (34.95)
</list-item><list-item>
7.56 ± 2.64
</list-item></list>
	.13

AUC0–24h, area under the concentration‐time curve, 0 to 24 hours; Cmax, maximum concentration; Cmin, minimum concentration; CV, coefficient of variation; IR‐Tac, twice‐daily immediate‐release tacrolimus capsules; LCPT, once‐daily extended‐release tablet formulation of tacrolimus; mITT, modified intent‐to‐treat; PK, pharmacokinetics; SD, standard deviation.aExposure normalization is an adjustment by which the AUC of LCPT and IR‐Tac are made equal, and all other PK parameters mathematically adjusted, to allow direct comparisons of PK parameters under assumption of equivalent exposure.bDay 1 refers to level drawn 24 hours after drug initiation.c P‐value determined by analysis of variance.

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kfeces

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/F (L/h)

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

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

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

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

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

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

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

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

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

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

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

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

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Dose-normalized b  AUC0–∞ (μg/mL 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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AUC0–12 h (hour·ng/mL)

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Cl/F (mL/min/kg)

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

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

<inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
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				\begin{document}$$ \overline{x} $$\end{document}</tex-math><mml:math id="M10" display="inline"><mml:mover accent="false"><mml:mi>x</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="12906_2017_1809_Article_IEq5.gif"/></alternatives></inline-formula> ± SD	CV (%)
<inline-formula id="IEq6"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
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				\begin{document}$$ \overline{x} $$\end{document}</tex-math><mml:math id="M12" display="inline"><mml:mover accent="false"><mml:mi>x</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="12906_2017_1809_Article_IEq6.gif"/></alternatives></inline-formula> ± SD	CV (%)

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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k off (min−1)

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

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

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Tmax (h)

Effect of food and parasite infection on the oral absorption of N-251 in mice

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Conditions	Pharmacokinetic parameters

<italic>C</italic>max (ng/mL)	<italic>T</italic>max (h)	AUCpo (ng/mL·h)
<italic>F</italic>
	MRTpo (h)

Normal-fasted (control)	1677.33 ± 811.23	2	3768.25	0.2277	2.46

Infected-fasted	1767.17 ± 1649.75	2	3273.35	0.1978	2.45

Normal-fed	952.50 ± 332.49	1.5	2282.17	0.1379	3.01

The Cmax with SD and Tmax were the observed values. AUC and MRT were calculated from 0 to infinity using the trapezoidal rule. F was calculated utilizing the AUC value of 2433.64 ng/mL·h after the intravenous administration of 10 mg/kg

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Vz/F (L)

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

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Parameter	Geometric mean/%CV	Range

Primary pharmacokinetic parameters

AUC∞ (μg·h/L)	354.4/30.3	209.7–458.0

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

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

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

MRT (h)	10.68/14.8	8.823–13.34

Secondary pharmacokinetic parameters

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

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

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

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

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

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CLM,R (L/hr)

Population parameter estimates for the final model

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Description	Parameter	Population estimate (RSE, %)	IIV, %CV (RSE, %)

Nonrenal clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	CLM,NR (L/hr)	44.1 (9)	31.6 (80)

Central volume of distribution of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	VM (L)	9.41 (13)	42.3 (55)

1st Peripheral volume of distribution of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	VP1 (L)	108 (37)	—

1st Intercompartmental clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	QP1 (L/hr)	67.1 (17)	—

2nd Peripheral volume of distribution of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	VP2 (L)	50.7 (21)	—

2nd Intercompartmental clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	QP2 (L/hr)	83.4 (15)	—

Renal clearance of morphine<xref ref-type="fn" rid="psp412185-note-0004">a</xref>
	CLM,R (L/hr)	6.32 (11)	—

Total clearance of M3G	CLM3G (L/hr)	7.32 (10)	34.5 (38)

Central volume of distribution of M3G	VM3G (L)	9.51 (15)	56.6 (36)

Liver transit rate constant	ktrans (hr−1)	14.4 (14)	—

NASF effect on clearance of M3G<xref ref-type="fn" rid="psp412185-note-0005">b</xref>
	NASF on CLM3G
	−0.628 (26)	—

Correlation between IIV CLM3G and IIV VM3G
	Corr(CLM3G‐VM3G)	—	0.751 (20)

Residual variability (%)

Proportional residual error of morphine in serum<xref ref-type="fn" rid="psp412185-note-0007">c</xref>
	σ2
M
	27.2 (6)	—

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

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

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

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

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c.430 C > T p.R144C

Genetic variants distribution in different profiles of propofol metabolism rate.

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Vss (mL/kg)

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

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

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t1/2 (h)

Pharmacokinetic profile of NAT after intravenous administration in NZ rabbit.

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Parameters	Estimates

<italic>C</italic>0 (ng/mL)	537±322

AUC0−<italic>∞</italic> (h*ng/mL)	162±55

<italic>t</italic>1/2 (h)	1.4±0.4

<italic>V</italic><italic>d</italic> (L/kg)	8.3±2.8

Cl (L/h/kg)	6.6±1.9

Abbreviation: C0: concentration at time zero, AUC: area under the curve from 0 to ∞, Vd: volume of distribution, Cl: clearance, t1/2: terminal half-life, n=3.

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VP1/F (L)

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

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

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AUC0‐inf,norm, IU*h/mL*

Pharmacokinetic endpoints

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

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t ½, h

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

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

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CL (mL/min)

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

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

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t max, h

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tmax (min)

Mean PK parameters (SD) of ST zolpidem

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t1/2 (hr)

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

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

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Cmax (µg/ml)

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

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

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

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

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

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

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

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C max at steady‐state dosing 210 mg Q2W+1 (µg/mL)

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

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Pharmacokinetic parameter	Mean	Median	CV%

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

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

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

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

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

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tmax, h

Pharmacokinetic profile across study groups

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

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t1/2 (h)

Pharmacokinetic parameters – Cycle 1

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

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If Gender affect CL ?

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

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<bold>Hypothesis test</bold>

<bold>OBJ</bold>

<bold>ΔOBJ</bold>

<bold>P-value</bold>

<bold>Comments</bold>

Basic model	2206.3

If Gender affect CL ?	2205.0	-1.3	>0.05	NO

If Age affect CL ?	2097.6	-108.7	<0.01	YES

If Weight affect CL ?	2094.0	-112.3	<0.01	YES

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

If ALT affect CL ?	2204.8	-1.5	>0.05	NO

If AST affect CL ?	2204.8	-1.5	>0.05	NO

If CRE affect CL ?	2197.5	-8.8	<0.01	YES

If BUN affect CL ?	2205.6	-0.7	>0.05	NO

If GFR affect CL ?	2140.6	-65.7	<0.01	YES

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C max (μM/L)

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

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Administered compound	Regorafenib	M‐2	M‐5

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

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

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

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

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

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

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

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Cmax (ng/mL)

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

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

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

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

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

Cl/F	224.84 ± 59.89

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

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CL (mL/h/kg)

Mean (±standard deviation) non-compartmental pharmacokinetic parameters of telavancin and the excipient hydroxypropylbetadex in subjects with varying degrees of renal function (see Table 1 for definitions CLcr (ml/min) from study A and eGFR (ml/min/1.73 m2) from study B)

The CL reported for ESRD is the CL for the subjects (i.e., includes residual clearance and any dialysis clearance) AUC area under concentration-time curve, ESRD end-stage renal disease, C max maximum plasma concentration, CL clearance, CL cr creatinine clearance, t ½ terminal elimination half-life, V ss apparent volume of distribution at steady state aStudy A only

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CLss/F (L/h)

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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Cpre, day 4 (ng/mL)

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

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

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TPGS/CCM

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      Free CCM
      TPGS/CCM

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      Cmax (ng/ml)
      311.42 ± 15.51
      794.97 ± 43.94

      2
      Tmax (h)
      0
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      3
      T1/2 (h)
      0.35 ± 0.07
      3.16 ± 0.78

      4
      Ke (h−1)
      0.133
      0.133

      5
      AUC0–24 (ng • h/ml)
      529.49 ± 22.32
      3,461.48 ± 102.47

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

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Citrate plasma water clearance (ml/min)

Pharmacokinetic data

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

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

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

Citrate mass removal (%)	83 ± 5

Citrate half-life (min)	60 ± 29

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

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

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

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

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TC50 (days)

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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