Fraction to ramiprilat

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      1
      2
      3
      4
      5

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      Subject
      Clint_L (l/min)
      Clint_K (l/min)
      Fraction to ramiprilat
      IV Ramipril Ave. Error
      Oral Ramipril Ave. Error

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      1
      4.8
      1.2
      0.1
      0.2
      0.23

      2
      3
      1
      1.5
      0.32
      0.17
      0.25

      3
      4
      3.6
      0.9
      0.4
      0.23
      0.27

      4
      5
      2
      2
      0.0
      0.17
      Poor fit

      5
      6
      3
      1
      0.25
      0.23
      0.28

      6
      7
      4
      1
      0.2
      0.14
      0.14

      7
      8
      5.5
      0
      0.4
      0.13
      0.22

      8
      9
      3.48
      0.52
      0.2
      0.12
      0.38

      9
      10
      3.5
      1.5
      0.4
      0.30
      0.34

      10
      11
      2.8
      1.2
      0.3
      0.23
      0.14

      11
      12
      6.16
      0.84
      0.2
      0.13
      0.2

      12
      nan
      nan
      nan
      nan
      nan
      nan

      13
      Ave (SD)
      3.62 (1.5)
      1.06 (0.53)
      0.25 (0.13)
      0.19 (0.057)
      0.24 (0.077)

CAPTION: Ramipril adjustable PBPK parameters: 1) intrinsic liver clearance (Clint_L); 2) intrinsic kidney clearance (Clint_K; 3) the fraction of the liver ramipril clearance that is converted to systemic ramiprilat. The "average weighted residual error'' of the PBPK model plasma ramiprilat following either IV or oral ramipril is listed in the last two columns.
FOOTER: []

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Cmax/dose (μg/ml/[mg/kg])

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

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

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

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

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

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

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

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

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

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

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

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

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

AUC0–∞ (h · μg/ml)	61.4 (33.0–231)

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

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

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

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DPlac (pg·mL−1)

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

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

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tmax (hours)a

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

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

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fAUC0-24 h/MIC for 2 log10 kill

      0
      1

      0
      Parameter
      Mean ±SD

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      E0 (log10CFU/lung)
      4.16 ± 0.43

      2
      Imax (log10CFU/lung)
      8.66 ± 1.10

      3
      IC50
      21.57 ± 8.38

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

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

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

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

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Mean E2/T ratio §

Summary of steady‐state pharmacokinetic parameters by treatment

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

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23.4%CVa , b

      0
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      2
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      4

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

      1
      Parameter
      Typical value
      %RSE
      Magnitude
      %RSE

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

      3
      CL: Allometric exponent for weight (−)c
      1.05
      4.33
      nan
      nan

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

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

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

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

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

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

      10
      F1: Bioavailability
      0.658
      FIXED
      NE
      nan

      11
      ALAG1: Lag time (d)
      0.0803
      FIXED
      NE
      nan

      12
      Residual variability iv
      0.0467
      32.6
      nan
      nan

      13
      Residual variability SC proportional componentg
      0.0531
      4.03
      nan
      nan

      14
      Residual variability SC additive componentg
      0.204
      25.6
      nan
      nan

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

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

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Curcumin

Pharmacokinetic parameters of the seven components of Shengjiang decoction

aP < 0.05 vs CG + SJD. ALEM: Aloe-emodin; CHRY: Chrysophanol; DEME: Demethoxycurcumin; BISD: Bisdemethoxycurcumin; Cmax: Maximum concentration; Tmax: Time of maximum concentration; MRT: Mean residence time.

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AUC (hr × ng/ mL/mg dose)

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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ΔΔHMM b

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

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

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Diastolic BP AUEC0-tlast [mm Hg*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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AUC0-∞ (ng/mL*h)

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

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

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Capsule on Kab

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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C1 (μg/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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Peak value (nmol/L)

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

<!DOCTYPE html>

Basal Diurnal Variation (DV)	Powdered Supplement	Tablet Supplement

<bold>Iron</bold>

 AUC (μmol·h/L)	104.5 ± 34.1

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

 Peak value (μmol/L)	14.6	3.0	8.9

Time to peak value (hrs)	3	4

<bold>Folate</bold>

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

 Peak value (nmol/L)	NA	54.4	53.1

Time to peak value (hrs)	NA	4	3

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

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CL/F (mean, SD) L/h

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

<!DOCTYPE html>

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

5 mg/kg/day	241

10 mg/kg/day	722

20 mg/kg/day	963

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

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AUCINF (h·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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tmax (h) a

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

<!DOCTYPE html>
<colgroup><col width="1*"/><col width="1*"/><col width="1*"/><col width="1*"/></colgroup>

PK parameter	LCDP polymeric micelles	LCDP oral suspension	Statistical test

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

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

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

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

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

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

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CL, L/hr or CL/F

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

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

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θCL/F, Weak CYP3A4 inhibitor

Parameter estimates in the final population pharmacokinetic model

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

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

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

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

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

θV/F, weight
	Power	0.216	17.4	0.143	0.278

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

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

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

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

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

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

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

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

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

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

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

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

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

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

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AUC_tEnd [μmol*min/l]

Comparison of population median plasma profile and experimental plasma profile pharmacokinetics

<!DOCTYPE html>

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

AUC_tEnd [μmol*min/l]	1296.06	1504.96	13.88

Cmax μmol/l	9.86	11.6	15

Tmax [h]	1.5	1.56	3.846

Half life [h]	29.21	Infinity	__

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

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

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

Cmin1
	20.7	24.1	53.6	27.5	−61.0

Cmax1
	71.2	18.9	178.0	25.2	−60.0

Cavg1
	32.4	18.3	85.7	22.0	−62.0

Cminss
	78.3	71.8	206.0	64.0	−62.0

Cmaxss
	152.0	44.7	393.0	39.6	−61.0

Cavgss
	101.0	58.1	268.0	52.3	−62.0

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

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Clearance, L/week

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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AUC0-last/dose (ng·h/mL/mg/kg)

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

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

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V/F (l)‡

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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Cl_obs (L/h/kg)

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MRTlast

Comparison of pharmacokinetic and pharmacodynamic parameters of epinephrine for inhalative administration (B: 4 mg, C: 8 mg) relative to i.m. administration (A: 0.3 mg) or to placebo inhalation (D) (point estimates and 90 % confidence intervals)

AUC area under the concentration vs. time profile (indices apply for the postdose time interval); AUEC area under the effect curve; Cmax maximal concentration; Emax maximal effect; MRTlast mean residence time calculated from concentrations up to the last point of observation; BP blood pressure; *blood pressure did not show consistent differences between treatments, fractional AUECs are presented in the Supplementary Material

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Baseline, ng/mL

PD Response Summary of IGF-I to a Single Dose Administration of VRS-317 in the PK/PD Population (n = 48)

Stability refers to the time during which daily rhGH treatment was given. Baseline refers to day 1, before the dose of VRS-317 or placebo. The IGF-I AUC was calculated using the linear trapezoid rule. Average IGF-I was calculated by dividing AUC by the observation interval of 29 days. The dose proportionality correlation coefficients (log:log) were 0.76 for baseline corrected Cmax and 0.76 for baseline corrected AUC0–t.Abbreviations: AUC0–t, area under the curve from time zero to the last measurable time point; Cmax, maximum concentration; ND, not determined; Tmax, time to maximum concentration.

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CRPC on CL/Fb

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AUC0-inf (ng*h/ml)

Mean PK parameters (SD) of ST zolpidem

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CLm (L/h)

Model Parameters for the Final Integrated Model

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

ADC

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

 Km (nmol/L)	0.959 (1.68)	––

 Vc (L)	0.0996 (2.6)	0.0118 (36.9)

 CLd (L/h)	0.00197 (1.9)	–

 Vp (L)	0.183 (8.7)	0.230 (25.4)

 λ [Weibull scale parameter]	1.51 (0.9)	–

 κ [Weibull shape parameter]	1.10 (0.6)	–

 Fmp	0.783 (2.2)	–

 Fmd	0.0242 (30.9)	1.78 (34.2)

MMAE

 CLm (L/h)	2.27 (8.3)	0.333 (20.2)

 Vm (L)	1.00 (0.3)	–

 CLmd (L/h)	23.0 (0.7)	–

 Vmp (L)	88.4 (4.8)	0.0670 (31.9)

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

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

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

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

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Heart rate AUEC0-tlast

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Covariate effect

      0
      1
      2
      3
      4
      5
      6
      7
      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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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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IIV−CL/F

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

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Description	Estimate	RSE*	Bootstrap

Mean	95% CI

Ka (h–1)	2.85	8.7%	2.24	1.21 to 3.87

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

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

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

Vp/F (L)	168.	11.7%	175.9	135 to 239

ALAG1	0.877	4.7%	0.800	0.672 to 0.928

DRUG0 ON Ka	1.89	22.0%	2.00	1.23 to 2.88

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

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

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

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

WT ON Vc	0.579	25.7%	0.590	0.191 to 1.06

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

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

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

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

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

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

Prop-Error	0.216	5.0%	0.200	0.189 to 0.232

Add-Error	0.303	14.5%	0.300	0.215 to 0.382

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

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α (1/h)

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ktrans (hr−1)

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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Heart rate AUEC0-tlast [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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Clearance †  [mL/kg/days]

Pharmacokinetic parameters for IGSC 20% and IGIV 10% treatments

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

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AUC0-∞ (μg · h/mL)

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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A (n = 5)

      0
      1
      2
      3
      4
      5
      6
      7

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

Q


IIV in t½, abs-1

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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Trough LTB4 inhibition (%)

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

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

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T max (h)

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

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

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CSF t1/2 (h)

Estimation of QC target inhibition in the CSF using plasma AUC

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

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t 1/2, hr

Descriptive statistics for secondary PK parameters

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

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Tmax (h)

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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Relative bioavailability (%)

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

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

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      GT solids and PE pharmacokinetic studies in humans
      Predicted and actual C max in the plasma (μg/mL)
      Predicted and actual C max in the plasma (μg/mL)
      Predicted and actual C max in the plasma (μg/mL)
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

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      GT solids and PE pharmacokinetic studies in humans
      EGCG
      EGC
      EC
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

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      Lee et al. (2002); 20 mg/kg GT solids
      0.06a (0.08)b
      0.07 (0.22)c
      0.04 (0.12)c
      0.200000
      6.060000

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      Chow et al. (2005); 400 mg PE
      0.11 (0.14)
      0.01 (0.02)
      0.01 (0.00)
      0.130000
      8.420000

      4
      Chow et al. (2001); 600 mg PE
      0.21 (0.17)
      0.02 (0.01)
      0.01 (0.01)
      0.210000
      12.460000

      5
      Chow et al. (2005); 800 mg PE
      0.21 (0.29)
      0.02 (0.03)
      0.01 (0.00)
      0.250000
      15.710000

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      Chow et al. (2005); 1200 mg PE
      0.35 (0.92)c
      0.04 (0.04)
      0.02 (0.01)
      0.420000
      26.700000

CAPTION: Using C max as a dose surrogate to predict plasma dosimetry of TCM in humans
FOOTER: aValues without brackets are predicted C max of unchanged TCs based on PBPK modeling.bBracketed values are C max from the literature. These C max usually are determined from free tea catechin concentrations except those of Lee et al. (2002) study, which are determined from total tea catechin concentrations (free plus conjugated forms).cCmax is under‐predicted when compare with the observed value.dTotal TCM concentrations are expressed as μg EGCg equivalents/mL plasma; they are calculated using predicted C max and the concentration/dose additivity model (ATSDR, 2004).eAdministered dose metrics are expressed as mg EGCg equivalents/kg BW; they are calculated using the concentrations of individual TCs in PE and the additivity model (ATSDR, 2004).

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AUC0–t (ng h/mL)

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

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

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ke (h−1)**

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Correlation CL.V1

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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t1/2, h

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

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

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F:M Ratiob

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

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t ½β (h)

Plasma pharmacokinetic parameters of fexinidazole (single-dose studies)

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

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Median Tmax (h) [range]

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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Bioavailability

Bioavailability of esaxerenone and effects of food on esaxerenone pharmacokinetics

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Bioavailability	Geometric least squares mean	Ratio	90% CI

Oral administration	IV administration	Oral/IVa

AUCinf (ng h mL−1)

 Fasting	1224.33	1374.99	89.0	86.7, 91.5

 Postprandial	1247.86	–	90.8	88.3, 93.2

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

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

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Ae (%)

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

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F1 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)

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

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

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

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

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

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      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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C 0 (nmol/L)

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

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Parameters	Units	i.v	i.m

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

AUC	μg∗h/ml	7.94 ± 1.11	6.79 ± 0.45

<italic>T</italic>max	h	–	0.25 ± 0.06

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

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

CLb	L/h	0.46 ± 0.08	0.43 ± 0.07

MRTlast	h	8.06 ± 1.6	22.85 ± 2.96

<italic>F</italic>	%	85.5 ± 7.11

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

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ΔΔTSvib d

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

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

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1st Intercompartmental 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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Tmax (hr)

Primary PK parameters for CLR457 at cycle 1 day 1 by treatment groups

AUC(0-24h), Area Under The Curve during 24 h; Cmax, maximum plasma concentration; Tmax, time to reach maximum (peak) plasma concentration following drug administration

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K D § (nM)

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

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

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Imax (log10CFU/lung)

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      Parameter
      Mean ±SD

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      E0 (log10CFU/lung)
      4.16 ± 0.43

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      Imax (log10CFU/lung)
      8.66 ± 1.10

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      IC50
      21.57 ± 8.38

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      fAUC0-24 h/MIC for bacteriostatic action
      19.93 h

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

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

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

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Weight (kg)

Study participant baseline characteristics

n, number of study participants with characteristic; N, total number of study participants; PK, pharmacokinetic; VWD, von Willebrand disease. Among other bleedings, one study participant experienced ulorrhagia after each meal, that is, 2–3 times per day; such bleedings also occurred during the study, but were not reported as they were considered too minor.aBody weight measured at month 12 (start of prophylactic treatment for arm 3 study participants).

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Duration of absorption for the zero-order absorption process (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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WT ON Vc

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

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

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AUC_%Extrap_obs (%)

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

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Free YM155 (2 h)a (1 mg/kg)

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      3

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      Unnamed: 0
      Free YM155 (2 h)a (1 mg/kg)
      YM155 liposomes (1 mg/kg)
      GD2-YM155 liposomes (1 mg/kg)

      1
      t1/2 (h)
      0.400000
      5.300000
      6.800000

      2
      AUC0-∞ (ng/mL*h)
      136.000000
      71473.000000
      37787.000000

      3
      CL (mL/h)
      7337.000000
      12.000000
      26.000000

      4
      Vz (mL/kg)
      4653.000000
      90.000000
      258.000000

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      Vss (mL/kg)
      2466.000000
      75.000000
      98.000000

      6
      MRT0-∞ (h)
      0.340000
      6.400000
      3.700000

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

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Km (nmol/L)

Model Parameters for the Final Integrated Model

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

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C2min (ng/mL)

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

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

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2nd Peripheral volume of distribution of morphinea

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Kel (h-1)

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

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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V/F

Parameter estimates in the final population pharmacokinetic model

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

ka
	1/h	0.821	2.36	0.780	0.860

CL/F	L/h	6.58	2.33	6.29	6.86

V/F	L	62.5	2.04	59.6	64.4

Fmin
	Proportion	0.590	5.99	0.51	0.653

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

D50
	mg	14.4	14.8	10.7	19.7

θCL/F, CrCL
	Power	0.406	6.03	0.351	0.453

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

θV/F, weight
	Power	0.216	17.4	0.143	0.278

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

θV/F, Sex
	Proportion	0.889	1.46	0.867	0.914

θCL/F, PGP
	Proportion	0.966	1.73	0.933	1.00

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

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

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

θCL/F, CYP3A4 inducer
	Proportion	1.30	6.30	1.16	1.48

θCL/F, AF
	Proportion	0.849	3.48	0.793	0.900

θCL/F, ACS
	Proportion	1.14	1.93	1.10	1.18

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

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

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

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

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

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

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

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

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V/F (l)

Population Pharmacokinetic Parameters, Passive Membrane Permeability, Physiological Parameters and In Vitro Binding Values Used for the Simulations

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Parameter	Values used in human D2RO Simulations	Source

CL/F (l/h)	19.5 (58)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

V/F (l)	1,150 (75)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

Ka (h−1)	0.600 (32)a	(<xref ref-type="bibr" rid="CR25">25</xref>)

koff (h−1)	2.34	(<xref ref-type="bibr" rid="CR37">37</xref>)

Kd (nM)	5.10b	(<xref ref-type="bibr" rid="CR38">38</xref>)

fraction unbound in plasma	0.0700	(<xref ref-type="bibr" rid="CR22">22</xref>)

fraction unbound in brain	0.034	(<xref ref-type="bibr" rid="CR19">19</xref>)

Human cerebral blood flow (l/h)	36.0	(<xref ref-type="bibr" rid="CR24">24</xref>)

Human brain extravascular volume (l)	1.4	(<xref ref-type="bibr" rid="CR23">23</xref>)

Human brain vascular volume (l)	0.150	(<xref ref-type="bibr" rid="CR23">23</xref>)

CLbev (l/h)	11.3	–c

CL/F clearance; Ka absorption rate constant; V/F central volume of distributionaPopulation mean (inter-individual variability as %CV)bIn vitro Ki value assumed as KdcCalculated as Papp* human brain endothelial surface area

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Tmax (h)

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

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Vss (liters/kg)

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

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

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

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

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

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

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

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

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

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

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

3.6	1	43.3	10.0	100

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

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

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

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

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F2 dihydrotestosterone (ng/mL)

Pharmacokinetic parameters for total testosterone, free testosterone, and dihydrotestosterone after F1 and F2 administration

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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Age on Vc/Fc

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Systolic BP AUEC0-tlast [mm Hg*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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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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Race (Asian) on Vc/Fb

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IIV Ka (CV%)

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

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Parameter (unit)	Definition of parameter	Bootstrap

Median	95% CI<xref rid="tfn1" ref-type="table-fn">
a
</xref>

<bold>𝜽−<italic>Estimates</italic></bold>

<italic>CL / F</italic> (<italic>l / h</italic>)	Apparent clearance	62.8	(54.4–71.2)

<italic>Vc / F</italic> (<italic>l</italic>)
	Apparent central volume of distribution	254	(226–281)

<italic>Vp / F</italic> (<italic>l</italic>)	Apparent peripheral volume of distribution	388	(344–456)

<italic>Q</italic> (<italic>l / h</italic>)	Intercompartmental clearance between central and peripheral compartment	23.6	(19.3–29.5)

<italic>Ka</italic>(<italic>h</italic>-1)	Absorption rate constant	12.4	(6.57–33.9)

<italic>MTT</italic> (<italic>h</italic>)	Mean transit time	0.812	(0.797–0.831)

<italic>N</italic>	Number of transit compartment	20.2	(16.6–25.6)

<bold>𝝎2−<italic>Estimates</italic></bold>

<italic>IIV CL</italic> (<italic>CV%</italic>)	Interindividual variability on clearance	12.6	(3.69–20.4)

<italic>IIV Ka</italic> (<italic>CV%</italic>)	Interindividual variability on absorption rate	155	(55.9–628)

<italic>IIV Q</italic> (<italic>CV%</italic>)	Interindividual variability on distributional clearance	25.7	(7.74–42.0)

<italic>IIV N</italic> (<italic>CV%</italic>)	Interindividual variability on number of transit compartments	20.2	(7.57–38.2)

<italic>IOV MTT</italic> (<italic>CV%</italic>)	Inter-occasional variability on mean transit time	4.39	(2.31–6.18)

<italic>IOV N</italic> (<italic>CV%</italic>)	Inter-occasional variability on number of transit compartments	17.6	(9.32–25.2)

<bold>𝝈2−<italic>Estimates</italic></bold>

<italic>PRV</italic> (<italic>CV%</italic>)	Proportional residual variability	19.4	(16.0–22.9)

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

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CRPC on Vc/Fb

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AUC(0–1,590) (ng*h/mL)

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

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

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

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

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

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

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

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AUC

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

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

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First VGB dose (eight patients*)

      0
      1
      2
      3

      0
      Unnamed: 0
      Cmax (μmol l−1)
      Tmax (h)
      AUC0–t (h μmol l−1)

      1
      Plasma
      nan
      nan
      nan

      2
      First VGB dose (eight patients*)
      31.7 (26.9–42.6)
      3.0 (2.0–4.0)
      249.1 (205.4–317.3)

      3
      Brain microdialysates
      nan
      nan
      nan

      4
      First VGB dose (nine patients, total 11 catheters)
      2.41 (2.03–5.94)
      5.1 (4.3–7.4)
      23.2 (17.0–41.0)

      5
      Third VGB dose (eight patients†, total 10 catheters)
      5.22 (4.24–7.14)
      4.7 (4.0–5.6)
      43.8 (36.4–58.8)

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