t 1/2 a (h)

Noncompartmental pharmacokinetic parameters of prexasertib

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

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Between‐subject variability Tmax ω (SD)

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

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

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AUC, hr ng/ml

Pharmacokinetic parameters of prasugrel active metabolite

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

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

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

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

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

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

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VP2 (L)

Population parameter estimates for the final model

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

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

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

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

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

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

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

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

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

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

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

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

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

Residual variability (%)

Proportional residual error of morphine in serum<xref ref-type="fn" rid="psp412185-note-0007">c</xref>
	σ2
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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increase in t½, abs-2 with BMI ≥25 kg/m2 (%)

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

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Parameter	Mean	Bootstrap, median (95% CI)

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

Structural model parameters

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

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

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

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

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

Variable model parameters (shrinkage%)

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

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

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

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

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

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

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

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

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Cmax (mg/L)

Observed meropenem concentrations in serum and cerebrospinal fluid

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

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Absorption lag time

Final population PK model parameter estimates

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Population parameters	Interindividual variation (std. dev.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sex on km
	Covariate effect	0.15	0.05	31	0.001

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

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

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

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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Renal clearance of morphinea

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CLM3G (L/hr)

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t ½ (h)

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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AUCINF_obs (μg × h/mL)

Pharmacokinetic parameter values estimated from non-compartmental analysis after an intravenous bolus of stable-labeled TPM.

LOW = 10 mg/kg dose; HIGH = 20 mg/kg dose; t1/2, elimination half-life; C1, first measured concentration; AUCINF_obs, observed area under the curve from time 0 to infinity; V_obs, observed volume of distribution; Cl_obs, observed clearance.

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ARCtrough

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

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Dose	Day 1	Day 7

1%	3%	1%	3%

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

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

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

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

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

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

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

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

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ηCL/F

Final population model estimates of pantoprazole

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

η

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Absorption rate constant

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AUC0–d98 (μg ⋅ h/ml)

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

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

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Summary of Urine PD Parameters at Baseline and Following Single or Combination Treatment With Verinurad (VERU) and Febuxostat (FBX) (Arithmetic Mean [95%CI])

Baseline was calculated for each treatment group based on the subjects who received the treatment.AeUR, amount of drug excreted unchanged in urine; CLUR, renal clearance of uric acid; FEUA, fractional excretion of uric acid.

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Total serum ketones, μmol/La

      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)

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      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

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      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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FBX 80 mg

      0
      1
      2
      3
      4

      0
      Treatment
      n
      Baseline (Day −1) (−24 to 0 Hours)
      Day 7 of Treatment (0 to 24 Hours)
      % Change From baseline

      1
      AeUR, mg
      AeUR, mg
      AeUR, mg
      AeUR, mg
      AeUR, mg

      2
      VERU 10 mg
      10
      673 (552 to 795)
      569 (421 to 717)
      −17.0 (−33.2 to −0.739)

      3
      VERU 10 mg + FBX 40 mg
      9
      699 (578 to 821)
      361 (302 to 420)
      −47.6 (−54.5 to −40.6)

      4
      FBX 40 mg
      10
      695 (588 to 802)
      246 (204 to 288)
      −64.1 (−69.7 to −58.6)

      5
      VERU 2.5 mg
      10
      808 (696 to 920)
      620 (485 to 755)
      −21.0 (−34.1 to −7.93)

      6
      VERU 2.5 mg + FBX 80 mg
      9
      808 (680 to 936)
      244 (197 to 292)
      −69.4 (−74.7 to −64.0)

      7
      FBX 80 mg
      10
      818 (704 to 932)
      221 (179 to 264)
      −72.4 (−77.2 to −67.7)

CAPTION: Summary of Urine PD Parameters at Baseline and Following Single or Combination Treatment With Verinurad (VERU) and Febuxostat (FBX) (Arithmetic Mean [95%CI])
FOOTER: Baseline was calculated for each treatment group based on the subjects who received the treatment.AeUR, amount of drug excreted unchanged in urine; CLUR, renal clearance of uric acid; FEUA, fractional excretion of uric acid.

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AUC0‐∞ a

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

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

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CL/F (l h–1)†

Parameter estimates of final dolutegravir population PK model

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

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Tk0 (h)

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

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

Mean	95 % CI	Mean	95 % CI

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

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

F	Bioavailability	0.22	0.15–0.30	0.15	0.15–0.15

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

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

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

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Cl (mL/min/kg)

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

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

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

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

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AUC(0–t) (ng·h/mL)

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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<colgroup><col width="1*"/><col width="1*"/><col width="1*"/></colgroup>

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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t ½ (hours)

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

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

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

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

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

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

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

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

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

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

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

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CL/F, L/day

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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Tmax (h)

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

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

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h


Cmax

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

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AUC(0-inf) (ng⋅h/mL)

Pharmacokinetic parameters of eribulin (cycle 1, day 1)

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

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Cmax (μg ml−1)

Statistical comparison of primary pharmacokinetic endpoints between MSB11022 and reference products

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

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Nonrenal clearance of morphinea

Population parameter estimates for the final model

%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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Cmax (ng/mL)

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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AUC0-last(ng mL-1⋅h-1)

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

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Main pharmacokinetic parameters of oral tryptanthrin in KM mice.

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PK parameters	Unit	Value

AIC	–	−49.79

SBC	–	−47.36

V1_F	mL	343.89

<italic>K</italic>01	1/h	1.17

<italic>K</italic>10	1/h	0.59

<italic>K</italic>12	1/h	0.29

<italic>K</italic>21	1/h	0.61

AUC0–<italic>t</italic>	h μg/mL	9.38

AUC0–∞	h μg/mL	9.57

Alpha	1/h	1.19

Beta	1/h	0.30

Alpha_HL	h	0.57

Beta_HL	h	2.27

A	μg/mL	−208.93

B	μg/ml	2.60

CL_F	mL/h	204.58

<italic>T</italic>max	h	1.50

<italic>C</italic>max	μg/mL	3.13

MRT	h	3.06

AIC, Akaike Information Criterion ; Alpha_HL, alpha half life ; AUC0–t, plasma concentration–time curve from time zero to the last time point; Beta_HL, terminal half-life; CL_F, systemic clearance rate; Cmax, maximal plasma concentration; KM, Kunming; MRT, mean retention time ; SBC, Schwarz Bayesian Criterion ; Tmax, highest temperature; V1_F, apparent volume of distribution.

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AUCτ,SS (pmol h/L)

Pharmacokinetic end‐points for insulin degludec at steady state in Japanese patients with type 1 diabetes

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End‐point	Japanese patients Mean (CV%)

AUCτ,SS (pmol h/L)	81,270 (28)

AUC0–12h,SS/AUCτ,SS (%)	53 (5.8)

Geometric mean presented. AUCτ,SS, area under the serum insulin concentration curve during one dosing interval (0–24 h as ‘τ’) at steady state; CV%, coefficient of variation in percent.

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AUC0‐∞, μg·h/mL

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

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

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AUC0-24h/Dose (ng*h/mL/mg/kg)

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

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C48h (ng/mL)

Model-predicted variation in panobinostat exposure across covariates

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Cmax

Ninety percent confidence intervals for the ratios of computed pharmacokinetic parameters of metoprolol and alpha-hydroxymetoprolol obtained following metoprolol administration with PA or without PA

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Parameter by drug	<italic>n</italic>	With PA/without PA ratio	Lower limit	Upper limit

Metoprolol

    <italic>C</italic>max	22	147.93	130.52	167.66

    AUC0-t	22	125.60	115.78	136.25

    AUC0–∞	22	123.32	114.38	132.96

Alpha-hydroxymetoprolol

    <italic>C</italic>max	22	96.76	88.57	105.70

    AUC0-t	22	87.46	79.53	96.17

    AUC0–∞	19	93.87	85.43	103.15

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AUC0–48 (μg·h/dL)

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

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

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

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

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

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

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Heart rate AUEC0-1h [bpm*hr]

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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CL/F (L/h)

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

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Parameter	Study

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

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

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

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

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

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

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

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

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

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

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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Q/F (L/h)

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

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

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Cmax (μmol l−1)

Pharmacokinetic results [median (interquartile range)] for vigabatrin in blood plasma and brain microdialysates

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<italic>C</italic>max (μmol l−1)	<italic>T</italic>max (h)	AUC0–<italic>t</italic> (h μmol l−1)

<bold>Plasma</bold>

<bold> First VGB dose (eight patients</bold><xref ref-type="table-fn" rid="tf1-1">*</xref>)	31.7 (26.9–42.6)	3.0 (2.0–4.0)	249.1 (205.4–317.3)

<bold>Brain microdialysates</bold>

<bold> First VGB dose (nine patients, total 11 catheters)</bold>	2.41 (2.03–5.94)	5.1 (4.3–7.4)	23.2 (17.0–41.0)

<bold> Third VGB dose (eight patients</bold><xref ref-type="table-fn" rid="tf1-2">†</xref><bold>, total 10 catheters)</bold>	5.22 (4.24–7.14)	4.7 (4.0–5.6)	43.8 (36.4–58.8)

Abbreviations are as follows: AUC, area under curve; Cmax, maximum concentration; Tmax, time of maximum concentration; VGB, vigabatrin. The VGB patients received 0.5 g VGB every 12 h.*One of the patients did not have blood samples taken (Patient 9).†Brain microdialysates of one of the VGB patients (Patient 3) were not monitored up to the third VGB dose.See Supporting Information Tables S2 and S3 for VGB data for individual patients. The Cmax values for brain microdialysates include a contribution from an unknown species with the same high-performance liquid chromatography retention time as VGB, which was equivalent to a median (interquartile range) of 1.19 (0.61–1.93) μmol l−1 VGB (Cav,pre), quantified from the pre-first dose period for the VGB patients. Control patients did not receive VGB and had no blood samples taken. The unknown species was present in microdialysates from control patients (seven patients, eight catheters) and had AUC0–t values of 9.43 (7.0–18.2) and 14.9 (11.0–17.9) h μmol l−1 for the first and third 12 h monitoring periods, respectively.

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T1/2z (h) [% CV]

Mean pharmacokinetic parameters of S 47445 (0.3 mg/kg) and donepezil (1.0 mg/kg), given alone or combined in middle-aged mice

Three groups (n = 4 subjects for S 47445 and n = 4 per sampling time for donepezil) were used for the pharmacokinetic (PK) study

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

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k21 (1/h)

Final population PK model parameter estimates

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AUC0–8 hour (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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Tmax (h)

Summary statistics: oxycodone PK parameters

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

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Lanabecestat CL/F (L/h)

PK Parameters for Each Treatment Group

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

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AUC0−∞ (h*ng/mL)

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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Clearance

Median prediction error (MPE) for predicted concentrations vs. observed concentrations, and individual predicted clearance vs. population‐predicted clearance

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Study	MPE (%)<xref ref-type="fn" rid="bcp13459-note-0002">a</xref>

Plasma concentrations	Clearance

<bold>Model building</bold>
	Vet <italic>et al</italic>. <xref rid="bcp13459-bib-0006" ref-type="ref">6</xref>
	−13.7	5.27

<bold>New data for external validation</bold>
	De Wildt <italic>et al</italic>. <xref rid="bcp13459-bib-0013" ref-type="ref">13</xref>
	−14.1	25.4

Valkenburg <italic>et al</italic>. <xref rid="bcp13459-bib-0014" ref-type="ref">14</xref>
	3.1	22.0

<bold>New data for extrapolation</bold>
	De Wildt <italic>et al</italic>. <xref rid="bcp13459-bib-0015" ref-type="ref">15</xref>
	−63.5	1746

Jacqz‐Aigrain <italic>et al</italic>. <xref rid="bcp13459-bib-0016" ref-type="ref">16</xref>
	−68.3	186

van Gerven <italic>et al</italic>. <xref rid="bcp13459-bib-0017" ref-type="ref">17</xref>
	−35.6	1.48

Swart <italic>et al</italic>. <xref rid="bcp13459-bib-0018" ref-type="ref">18</xref>
	−40.6	−1.67

aThe MPE is the median of the prediction error, which reflects for plasma concentrations the difference in observed and predicted concentrations (see Methods, Eq. (3)). For clearance, the difference in individual predicted and population‐predicted clearance is calculated

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Cmax μmol/l

Comparison of population median plasma profile and experimental plasma profile pharmacokinetics

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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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Cmax (ng/ml)

Pharmacokinetic parameters (summary statistics) in single-dose study

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Cohort (dosage level)	n	AUClast (ng·h/ml)
	Cmax (ng/ml)

Mean ± SD

S1 (5 mg)	4	1110 ± 360	236 ± 89

S2 (10 mg)	4	2550 ± 110	589 ± 88

S3 (20 mg)	4	5460 ± 680	999 ± 135

AUC last, area under the curve from time 0 to last time point with quantifiable concentration before the next hemodialysis; S, single-dose.

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MVOF

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

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

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TMAX (hr)

A comparison of the artemether pharmacokinetic properties to literature values

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

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Kab (h-1)

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

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	<bold>Dox-a</bold>
	<bold>Dox-pol|</bold>
	<bold>Dox-β</bold>

 	<bold>Mean ± SD</bold>	<bold>Mean ± SD</bold>	<bold>Mean ± SD</bold>

AUC (μg · h/mL)
	3.1 <bold>±</bold> 0.2 a
	17.0 ± 2.2b
	1.5 ± 0.1 c

AUMC (μg · h2/mL)
	35.2 <bold>±</bold> 1.2 a
	208.3 ± 31.1b
	12.3 ± 0.1 c

AUC0<bold>-</bold>∞ (μg · h/mL)
	3.0 ± 0.2 a
	16.1 ± 4.8 b
	1.5 ± 0.9 c

AUMC0 <bold>-</bold>∞ (μg · h2/mL)
	31.2 ± 2.3 a
	171.3 ± 5.8 b
	12.3 ± 0.5 c

MRT (h)
	11.3 ± 4.4 a
	12.2 ± 4.2a
	8.1 ± 2.1 a

MRT0 <bold>-</bold>∞ (h)
	10.2 ± 2.6 a
	10.7 ± 2.1 a
	8.1 ± 1.2 a

T½β (h)
	2.8 ± 0.9a
	4.9 ± 1.0b
	4.2 ± 0.9b

T½ab(h)
	1.2 ± 0.2 a
	3.5 ±1.2 b
	1.4 ± 0.1 a

Kel (h-1)
	0.2 ± 0.0 a
	0.1 ± 0.1 a
	0.2 ± 0.1 a

Kab (h-1)
	1.6 ± 0.2 a
	0.2 ± 0.2 b
	0.5 ± 0.3 c

α (h-1)
	1.2 ± 0.0
	-
	-

β (h-1)
	9.2 ± 0.0
	-
	-

Cmax (μg/mL)
	0.3 ± 0.1 a
	1.3 ± 0.7 b
	0.2 ± 0.0 c

Tmax (h)
	2.2 ± 0.4 a
	5.9 ± 1.7 b
	3.4 ± 0.6 c

Frel (%)*	-	548% a	48% b

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

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Cavg, ng/mL

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

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

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

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

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

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

Clearance, L/week	13.3 (9.17, 22.8)

Volume, L	4.58 (4.14, 4.99)

First‐phase t1/2, h	38.2 (23.2–56.7)

Terminal t1/2, h	12200 (3990–50200)

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

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

Clearance, L/week	14.0 (12.7–14.6)

Terminal t1/2, h	38.2 (36.5–41.9)

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

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

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

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

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

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Plasma glucose AUC0‐24h

Demographic and baseline characteristics (PDAS)

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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t max (h)b

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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Tmax

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

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

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AUC 0-t c (μg/ml × h or μg/g × h)

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

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

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Half‐life (h)

Mean (range) half‐life of N8‐GP in adults (≥18 y) according to blood type

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Adults (≥18 y)

Blood type	Number of patients	Half‐life (h)

A	11	23.7 (11.5‐52.3)

AB	1	31.7 (31.7‐31.7)

O	7	15.6 (9.8‐21.5)

Missing	1	24.4 (22.5‐26.3)

NoteOnly patients who contributed to the primary PK analysis were included.Abbreviations: PK, pharmacokinetic.

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AUC (μg·min/mL)

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

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				\setlength{\oddsidemargin}{-69pt}
				\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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F2 total testosterone (ng/mL)

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

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

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

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

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

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

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

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

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Fmax

Parameter estimates in the final population pharmacokinetic model

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

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      8

      0
      Unnamed: 0_level_0
      Unnamed: 1_level_0
      Population parameters
      Population parameters
      Population parameters
      Population parameters
      Interindividual variation (std. dev.)
      Interindividual variation (std. dev.)
      Interindividual variation (std. dev.)

      1
      Parameter
      Description
      Estimate
      Std. error
      Rel. std. error (%)
      P‐value
      Estimate
      Std. error
      Rel. std. error (%)

      2
      tlag (h)
      Absorption lag time
      0.67
      ‐
      ‐
      nan
      1.920000
      0.200000
      10.000000

      3
      ka (1/h)
      Absorption rate constant
      0.71
      0.04
      5
      nan
      0.390000
      0.050000
      12.000000

      4
      Vp/F (L)
      Apparent volume of distribution, central compartment selexipag
      12.90
      2.00
      16
      nan
      0.310000
      0.120000
      38.000000

      5
      Body weight on Vp/F
      Covariate effect
      1.20
      0.30
      25
      <0.001
      nan
      nan
      nan

      6
      CL/F (L/h)
      Apparent selexipag clearance
      19.10
      1.60
      8
      nan
      0.730000
      0.030000
      4.000000

      7
      Body weight on CL/F
      Covariate effect
      0.61
      0.15
      25
      <0.001
      nan
      nan
      nan

      8
      Total bilirubin on CL/F
      Covariate effect
      −0.40
      0.07
      18
      <0.001
      nan
      nan
      nan

      9
      k12 (1/h)
      Transfer rate constant central to peripheral compartment selexipag
      0.09
      0.02
      18
      nan
      0.250000
      0.180000
      73.000000

      10
      k21 (1/h)
      Transfer rate constant peripheral to central compartment selexipag
      0.06
      0.01
      17
      nan
      1.060000
      0.130000
      12.000000

      11
      Vm/F (L)
      Apparent volume of distribution, central compartment ACT‐333679
      4.65
      0.80
      17
      nan
      0.100000
      0.250000
      241.000000

      12
      Body weight on Vm/F
      Covariate effect
      0.88
      0.18
      21
      <0.001
      nan
      nan
      nan

      13
      kmet (1/h)
      Metabolism rate constant selexipag to ACT‐333679
      0.67
      0.12
      18
      nan
      0.050000
      0.420000
      788.000000

      14
      k34 (1/h)
      Transfer rate constant central to peripheral compartment ACT‐333679
      1.04
      0.23
      22
      nan
      0.470000
      0.180000
      39.000000

      15
      k43 (1/h)
      Transfer rate constant peripheral to central compartment ACT‐333679
      0.18
      0.03
      14
      nan
      0.890000
      0.140000
      16.000000

      16
      km (1/h)
      Elimination rate constant ACT‐333679
      0.49
      0.08
      16
      nan
      0.270000
      0.060000
      20.000000

      17
      Sex on km
      Covariate effect
      0.15
      0.05
      31
      0.001
      nan
      nan
      nan

      18
      PAH comedication on km (ERA)
      Covariate effect
      0.15
      0.06
      38
      0.008
      nan
      nan
      nan

      19
      PAH comedication on km (PDE5 inh.)
      Covariate effect
      0.07
      0.05
      77
      0.190
      nan
      nan
      nan

      20
      PAH comedication on km (ERA and PDE5 inh.)
      Covariate effect
      0.37
      0.05
      14
      <0.001
      nan
      nan
      nan

      21
      Residual error terms
      Residual error terms
      Residual error terms
      Residual error terms
      Residual error terms
      Residual error terms
      nan
      nan
      nan

      22
      b_1
      Proportional error selexipag
      0.75
      0.01
      2
      nan
      nan
      nan
      nan

      23
      b_2
      Proportional error ACT‐333679
      0.49
      0.01
      2
      nan
      nan
      nan
      nan

CAPTION: Final population PK model parameter estimates
FOOTER: []

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T > MIC (%).1

Time (min) above possible MICs ranging from 0.25 to 8 mg/L corresponding to total serum concentration ranging from 0.39 to 12.5 mg/L for the quantiles (Q) 90 and 95% and corresponding value of the T > MIC in % of 24 h.

Q90%: quantile 90%; Q95%: quantile 95%; for a MIC of 2 mg/L corresponding to a total serum concentration of 3.12 mg/L, 90% of the simulated curves were equal or above a free plasma concentration for 821 min, i.e., for 57% of the considered dosing interval.

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C 0 variability

Parameter estimates from final model for fluticasone furoate AUC and serum cortisol

AUC 50 the FF area under the concentration–time curve over 24 h (AUC24) producing 50 % of maximum effect, C 0 the weighted mean 24 at zero FF AUC24, CI confidence interval, DPI dry powder inhaler, FF fluticasone furoate, FOIH formulation/inhaled, GAM slope for single dose and repeat dose, k coefficient on the number of days of dosing, RD repeat dose, RSE relative standard error, SD single dose

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IOV CL/F (%)

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

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Parameter (unit)	Basic model
	Final model

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

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

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

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

IIV CL/F (%)	33.5	26.9	33.2	27.4

IOV CL/F (%)	34.9	23.3	31.8	24.2

Covariates

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

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

Residual error

    Proportional (%)	13.1	17.0	13.1	17.0

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

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AUC0-∞, ng · h/mL

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

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

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CL/F

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

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

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

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

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

θV/F, weight
	Power	0.216	17.4	0.143	0.278

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

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

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

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

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

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

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

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

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

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

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

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

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

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Tmax (h)

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

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

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C max at week 1 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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Ka(l/h)

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

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Parameters	Mean ± SD

Cmax(mg/L)	1.37 ± 0.23

<italic>t</italic>max (h)	0.85 ± 0.12

t 1/2u (h)	0.35 ± 0.05

CL/F (LIb/kg)	0.17 ± 0.03

Ka(l/h)	3.47 ± 0.58

AUC(0-t) (mg·h/L)	3.46 ± 0.61

AUC(0-∞) (mg·h/L)	3.56 ± 0.64

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Cpre, day 7 (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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MRT0-t (h)

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

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F (%)

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

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

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tlag (h)

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Population parameters	Interindividual variation (std. dev.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sex on km
	Covariate effect	0.15	0.05	31	0.001

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

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

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

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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t1/2 (h)

Summary statistics of midazolam plasma PK parameter values

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

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Relative bioavailability

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

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Parameter	Commercial capsule	Rectal hydrogel (F8)

Dose (mg/kg)	50	50

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

tmax (h)	1	4

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

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

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

MRT (h)	3.923 ± 0.24	9.512 ± 0.233

Relative bioavailability	–	357.93%

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Additive (µg/L)

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      Unnamed: 0
      Base model
      Final model
      Bootstrap (977/1000 successful)

      1
      Parameters
      Population mean (%RSE)
      Population mean (%RSE)
      Median (2.5 to 97.5 percentile)

      2
      Elimination rate (1/hour)
      0.0317 (13%)
      0.0408 (15%)
      0.0411 (0.0318 to 0.0558)

      3
      Volume (L)
      216 (22%)
      233 (17%)
      228 (167 to 312)

      4
      Absorption rate (1/hour)
      3.43 (fixed)
      3.43 (fixed)
      3.43 (fixed)

      5
      Volume: age exponent
      –
      0.775 (13%)
      0.780 (0.601 to 1.01)

      6
      Elimination rate: creatinine clearance exponent
      –
      0.850 (24%)
      0.842 (0.470 to 1.25)

      7
      Fluconazole elimination rate (1/hour)
      –
      0.0268 (5%)
      0.0267 (0.0234 to 0.0321)

      8
      Between-subject variability
      nan
      nan
      nan

      9
      ωke2
      0.219 (51%)
      0.262 (40%)
      0.256 (0.0858 to 0.590)

      10
      ωV2
      0.991 (27%)
      0.329 (35%)
      0.291 (0.0637 to 0.518)

      11
      Residual error
      SD (%RSE)
      SD (%RSE)
      nan

      12
      Additive (µg/L)
      4.24 (14%)
      3.69 (13%)
      3.65 (3.16 to 4.14)

Population pharmacokinetic parameter estimates

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Cl (hr/kg)

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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AUC0−12, ng·h/mL

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

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

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Tmax

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

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

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AUC0-4 (ng•h/mL)

Mean (SD) pharmacokinetic parameters for hydrocodone by treatment

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

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Calcium loss per 4 h of HD, mmol (mg)

Pharmacokinetic data

      0
      1

      0
      0
      1

      1
      Plasma water flow rate (ml/min)
      118 ± 11

      2
      Citrate plasma water clearance (ml/min)
      98 ± 10

      3
      Net citrate dose per 4 h of HD (mmol)
      17 ± 7

      4
      Citrate mass removal (%)
      83 ± 5

      5
      Citrate half-life (min)
      60 ± 29

      6
      Citrate distribution volume, litres (% of body weight)
      41 ± 22 (54 ± 18)

      7
      Calcium removal rate, mmol/min (mg/min)
      0.18 ± 0.02 (7.2 ± 0.8)

      8
      Calcium loss per 4 h of HD, mmol (mg)
      43 ± 4 (1720 ± 160)

      9
      Calcium substitution per 4 h of HD, mmol (mg)
      48 ± 1 (1920 ± 40)

Pharmacokinetic data

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Volume (L)

<!DOCTYPE html>

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

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

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

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

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

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

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

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

Between-subject variability

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

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

Residual error	SD (%RSE)

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

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tmax (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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      0
      1
      2

      0
      Parameters
      Units
      Values

      1
      Emax
      Log CFU/mL
      2.71 ± 0.37

      2
      E0
      Log CFU/mL
      −4.61 ± 0.69

      3
      Emax−E0
      Log CFU/mL
      7.32 ± 1.06

      4
      EC50
      h
      30.07 ± 6.94

      5
      N (slope)
      /
      4.62 ± 0.72

      6
      AUC24h/MIC for bacteriostatic effect
      h
      26.72 ± 6.28

      7
      AUC24h/MIC for bactericidal effect
      h
      39.54 ± 7.31

      8
      AUC24h/MIC for eradication effect
      h
      50.69 ± 9.16

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

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Ka (1/h)

Population pharmacokinetic parameters of baclofen.

<!DOCTYPE html>

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

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

CL/F (L/h)	11.6	3	10.8–12.3

Vd/F (L)	72.8	5	66.5–80.4

Ka (1/h)	1.64	10	1.34–2.00

<bold>BETWEEN SUBJECT VARIABILITY</bold>

ω(CL/F)	0.21	14	0.16–0.27

ω(Vd/F)	0.22	31	0.11–0.36

ω(Ka)	0.44	24	0.19–0.65

<bold>RESIDUAL VARIABILITY</bold>

σ exponential	0.24	5	0.21–0.26

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

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AUCt (μg·h/L)

Point Estimates of Anagrelide

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

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Km (μM)

Results of the curve fitting analysis.

Parameter estimates are expressed as mean value (standard deviation). For each interaction, 4 different mycotoxin concentrations were used in combination with 6 different substrate concentrations. Each incubation was performed in triplicate. ZEA, zearalenone; T-2, T-2 toxin; FB1, fumonisin B1; TB, tolbutamide; CM, coumarin; MDZ, midazolam; DXM, dextromethorphan; Km, Michaelis-Menten constant; Ki, inhibitory constant; α, affinity constant modulator for enzyme-inhibitor complex; β, catalytic constant of the enzyme-substrate-inhibitor complex; NA, not available. ∗Residual activity at the highest concentration of substrate and inhibitor. The full dataset can be found in Supplementary Data Sheet 2.

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Ki (μM)

Results of the curve fitting analysis.

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T max a (h)

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

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

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Vp / F (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.

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AUC, 0–48 h (ng·h/mL)

Model-predicted variation in panobinostat exposure across covariates

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C max, mg/L

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

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

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AUC0–last (h · ng/ml)

Bioequivalence analysis of artesunate, dihydroartemisinin, pyronaridine, primaquine, and carboxyprimaquine after pyronaridine-artesunate and primaquine were administered as single oral doses alone or in combination

<!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>

Parameter<xref ref-type="table-fn" rid="T4F1"><italic>a</italic></xref>	Geometric mean ratio (% [90% confidence interval]) for:

Artesunate (<italic>n</italic> = 15)	Dihydroartemisinin (<italic>n</italic> = 15)	Pyronaridine (<italic>n</italic> = 15)	Primaquine (<italic>n</italic> = 15)	Carboxyprimaquine (<italic>n</italic> = 15)

<italic>C</italic>max (ng/ml)	120 (76.8–188)	109 (87.3–137)	101 (91.4–112)	130 (117–146)	109 (104–115)

AUC0–last (h · ng/ml)	101 (89.3–114)	110 (104–116)	101 (95.9–106)	115 (107–125)	104 (98.6–111)

AUC0–∞ (h · ng/ml)	101 (89.5–114)	110 (104–116)	99.3 (93.9–105)	115 (106–124)	98.1 (93.0–104)

aCmax, maximum observed plasma or whole-blood concentration after oral administration; AUC0–last, observed area under the plasma or whole-blood concentration-time curve from zero time to last observed concentration; AUC0–∞, predicted area under the plasma or whole-blood concentration-time curve after the last dose from zero time to infinity.

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MRT (h)

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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IIV Q (CV%)

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C max

Levodopa bioequivalence results LCIG‐HV vs LCIG‐LV Commercial (Test vs Reference)

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

PK parameter	Geometric mean ratio

Point estimate	90% CI

<italic>C</italic>
max
	1.036	0.894‐1.201

AUCt
	0.999	0.892‐1.117

AUCinf
	0.995	0.891‐1.111

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C max, 0–48 h (ng/mL)

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Overall P-Value (time)

Change in Cardiovascular Variables in Response to Inhaler Condition and IV l-Methamphetamine as Measured by Impedance Cardiography.

Data presented as mean (SD).IV-l-meth-IV l-methamphetamine; p-value (time)-compared to baseline vs. 15 minutes and 2 hours post-dose

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B (µg/L)

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

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

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