t½, h

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

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

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C max, mg/L

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

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

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

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

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

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

Clearance, L/week	13.3 (9.17, 22.8)

Volume, L	4.58 (4.14, 4.99)

First‐phase t1/2, h	38.2 (23.2–56.7)

Terminal t1/2, h	12200 (3990–50200)

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

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

Clearance, L/week	14.0 (12.7–14.6)

Terminal t1/2, h	38.2 (36.5–41.9)

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

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

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

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

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

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AUCinf, μg. day/mL

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

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

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Pharmacokinetic data

      0
      1

      0
      0
      1

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

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

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

      4
      Citrate mass removal (%)
      83 ± 5

      5
      Citrate half-life (min)
      60 ± 29

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

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

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

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

Pharmacokinetic data

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Min (C 12 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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t½ (hour)

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

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

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CL (L/h/kg)

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

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Differences in mean individual predicted PK parameters for toxicity endpoints, assessed by calculation of geometric mean ratios (GMR) and 90% CI (n = 606).

aDid not have the event/had the event.CI, confidence interval; AUC0‐24, area under the concentration‐time curve over 24‐hour interval; Cmax, maximum concentration; C24, trough concentration, 24 hours postdose; C12, concentration 12 hours postdose representing the mid‐dose interval.

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Vmax (pmol/mg protein/min)

Results of the curve fitting analysis.

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

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AUC24h/MIC for bactericidal effect

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      Parameters
      Units
      Values

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      Emax
      Log CFU/mL
      2.71 ± 0.37

      2
      E0
      Log CFU/mL
      −4.61 ± 0.69

      3
      Emax−E0
      Log CFU/mL
      7.32 ± 1.06

      4
      EC50
      h
      30.07 ± 6.94

      5
      N (slope)
      /
      4.62 ± 0.72

      6
      AUC24h/MIC for bacteriostatic effect
      h
      26.72 ± 6.28

      7
      AUC24h/MIC for bactericidal effect
      h
      39.54 ± 7.31

      8
      AUC24h/MIC for eradication effect
      h
      50.69 ± 9.16

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

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Tmax (median, range),b hrs

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

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<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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Main pharmacokinetic parameters of oral tryptanthrin in KM mice.

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PK parameters	Unit	Value

AIC	–	−49.79

SBC	–	−47.36

V1_F	mL	343.89

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

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

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

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

AUC0–<italic>t</italic>	h μg/mL	9.38

AUC0–∞	h μg/mL	9.57

Alpha	1/h	1.19

Beta	1/h	0.30

Alpha_HL	h	0.57

Beta_HL	h	2.27

A	μg/mL	−208.93

B	μg/ml	2.60

CL_F	mL/h	204.58

<italic>T</italic>max	h	1.50

<italic>C</italic>max	μg/mL	3.13

MRT	h	3.06

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

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Tmax (hr)

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

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

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

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

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

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

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

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AUC0‐48 hr

Plasma pharmacokinetic parameters for canagliflozin and DPTQ in bile‐duct cannulated and intact dog

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Parameters	 	Canagliflozin	DPTQ	DPTQ‐O‐glucuronide

BDC	Intact	BDC	Intact<xref ref-type="fn" rid="prp2502-note-0004">
b
</xref>
	Intact

AUC0‐48 hr
	µmol/L*hr	15.7 ± 5.4	20.7 ± 3.7	5.89 ± 3.3	7.94 ± 2.5	2.61 ± 1.5

AUCinf
	µmol/L*hr	16.4 ± 5.9	21.2 ± 3.9	5.89 ± 3.3	NA	2.6 ± 1.7

<italic>t</italic>
1/2
	hr	10.9 ± 1.8	8.05 ± 0.62	2.50 ± 2.3	NA

<italic>V</italic>
dss
	L/kg	0.87 ± 0.28	0.72 ± 0.13	0.33 ± 0.07<xref ref-type="fn" rid="prp2502-note-0003">
a
</xref>
	1.48 ± 0.25

CL	mL/min/kg	1.32 ± 0.50	0.93 ± 0.18	4.43 ± 3.1	2.73 ± 1.2

NoteDogs were given canagliflozin and DPTQ at 0.5 mg/kg by IV bolus. Values were derived from plots shown in Figure 2. Results shown represent mean ± SD from four animals.a P < 0.01 compared to the parameters in intact animals.bThe elimination phase was flat and AUCinf was not extrapolated, the CL and V dss was CL0‐48 h and V dss 0‐48 hr

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Clearance

Final parameters for the population analysis of levetiracetam concentrations with LEV‐XR administered alone, with phenobarbital, or with zonisamide. Administration of LEV‐XR was repeated every 12 hours to achieve steady‐state conditions before sampling

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LEV‐XR alone	LEV‐XR + phenobarbital	LEV‐XR + Zonisamide	Overall (all groups)

Parameter	Units	Value	Ω2
	CV%	Value	Ω2
	CV%	Value	Ω2
	CV%	Value	Ω2
	CV%

AUC	hours∙μg/mL	352.95	—	—	134.86	—	—	452.76	—	—	388.72	—	—

Clearance	L/kg/hr	0.08	—	—	0.17	—	—	0.07	—	—	0.08	—	—

<italic>C</italic>
MAX
	mg/L	33.01	—	—	13.38	—	—	34.13	—	—	32.99	—	—

<italic>k</italic>
01 half‐life	hr	4.45	—	—	3.72	—	—	5.60	—	—	5.01	—	—

<italic>k</italic>
10 half‐life	hr	1.31	—	—	1.57	—	—	1.57	—	—	1.37	—	—

<italic>T</italic>
MAX
	hr	3.28	—	—	3.38	—	—	4.01	—	—	3.53	—	—

θ<italic>k</italic>
01
	1/hr	0.16	0.030	17.304	0.19	0.020	14.228	0.12	0.0004	2.117	0.138	0.058	24.39

θ<italic>k</italic>
10
	1/hr	0.53	0.0013	3.5870	0.44	0.0009	2.9850	0.44	0.0002	1.322	0.505	0.001	3.32

θ<italic>V</italic>
	L/kg	0.15	0.505	80.946	0.39	0.589	89.405	0.15	0.029	17.264	0.151	0.221	49.66

Abbreviations: LEV‐XR, extended‐release levetiracetam; CV, coefficient of variation; Ω2, variance of the random source error; AUC, area‐under‐the‐curve for the plasma‐concentration versus time profile; C MAX, peak concentration; θk 01, theta (typical value) for absorption rate and associated half‐life; θk 10, theta for elimination rate and associated half‐life; θV, theta for volume of distribution; T MAX, time to peak concentration. Clearance (CL) and V as shown in the table represent V/F and CL/F because they are calculated as per fraction absorbed for an oral dose. Values for Ω2 and CV% are not available for secondary parameters (shown by “—”) because random effects are only measured for primary parameters.

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AUC0‐∞, ng·h/mL

Bioequivalence Evaluation of OLZ for Comparison of ALKS 3831 Versus B‐OLZ and OLZ Versus B‐OLZ

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ALKS 3831	OLZ	B‐OLZ

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

AUC0‐∞, ng·h/mL

Geometric mean	627.9	607.0	610.4

Geometric mean ratio	1.0	0.994	—

90%CI	(0.995–1.063)	(0.962–1.028)	—

AUC0‐t, ng·h/mL

Geometric mean	594.4	578.9	578.9

Geometric mean ratio	1.0	1.0	—

90%CI	(0.993–1.062)	(0.967–1.034)	—

Cmax, ng/mL

Geometric mean	16.3	16.3	16.4

Geometric mean ratio	0.994	0.995	—

90%CI	(0.954–1.036)	(0.955–1.037)	—

AUC0‐∞, area under the plasma concentration‐time curve from zero to infinity; AUC0‐t, area under the plasma concentration‐time curve from zero to the time of the last quantifiable concentration; B‐OLZ, brand olanzapine; Cmax, maximal plasma concentration; OLZ, olanzapine; PK, pharmacokinetics.

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t 1/2u (h)

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

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Parameters	Mean ± SD

Cmax(mg/L)	1.37 ± 0.23

<italic>t</italic>max (h)	0.85 ± 0.12

t 1/2u (h)	0.35 ± 0.05

CL/F (LIb/kg)	0.17 ± 0.03

Ka(l/h)	3.47 ± 0.58

AUC(0-t) (mg·h/L)	3.46 ± 0.61

AUC(0-∞) (mg·h/L)	3.56 ± 0.64

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QP2 (L/hr)

Population parameter estimates for the final model

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

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

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

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

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

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

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

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

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

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

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

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

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

Residual variability (%)

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

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

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

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

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

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ka

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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a


AUC 0-t /dose (h·kg·L -1 )

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

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

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ηV/F

Final population model estimates of pantoprazole

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

η

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θCL/F, AF

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Css (µM)

Corresponding Dosimetry and Assay Information for Chemicals with OEDs < 1 µg/kg/day

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Chemical	<italic>C</italic>ss (µM)	Assay Endpoint	AC50 (µM)	Oral Equivalent (mg/kg/day)	<italic>C</italic>ss > 200 (µM)	AC50 < 0.5 (µM)

Heptadecafluorooctanesulfonic acid potassium salt	217.01	Inhibition of human CYP2C9 enzymatic activity	1.30E-02	5.99E-05	Yes	Yes

Mirex	70.82	Increased expression of prostaglandin E2 in human peripheral blood mononuclear cells	1.14E-02	1.61E-04	—	Yes

Diethylstilbestrol	0.46	Binding to human estrogen receptor	7.43E-05	1.61E-04	—	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor response element in transfected HepG2 cells	1.01E-04	2.19E-04	—	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor signaling pathway in transfected HEK293 cells	1.27E-04	2.76E-04	—	Yes

Potassium perfluorohexanesulfonate	266.56	Inhibition of human CYP2C9 enzymatic activity	8.25E-02	3.09E-04	Yes	Yes

Potassium perfluorohexanesulfonate	266.56	Inhibition of human CYP4F12 enzymatic activity	8.60E-02	3.23E-04	Yes	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor alpha signaling pathway in transfected HepG2 cells	1.80E-04	3.92E-04	—	Yes

Tannic acid	0.34	Inhibition of human GSK3b enzymatic activity	2.00E-04	5.83E-04	—	Yes

Dinoseb	485.94	Decreased mitochondrial membrane potential in HepG2 cells	3.50E-01	7.20E-04	Yes	Yes

Pentadecafluorooctanoic acid ammonium salt	269.96	Inhibition of human CYP2C9 enzymatic activity	2.02E-01	7.48E-04	Yes	Yes

Triphenyl phosphate	0.79	Binding to human peroxisome proliferator-activated receptor-gamma	6.09E-04	7.66E-04	—	Yes

Diethylstilbestrol	0.46	Activation of estrogen receptor signaling pathway in transfected HEK293 cells	4.02E-04	8.73E-04	—	Yes

Gentian violet	10.01	Decreased expression of interleukin-8 in human peripheral blood mononuclear cells	1.00E-02	9.99E-04	—	Yes

Gentian violet	10.01	Decreased expression of E-selectin adhesion protein in human endothelial cells	1.00E-02	9.99E-04	—	Yes

Gentian violet	10.01	Decrease expression of interleukin 1 alpha in human peripheral blood mononuclear cells	1.00E-02	9.99E-04	—	Yes

Endrin	238.20	Activation of estrogen receptor response element in transfected HepG2 cells	2.72E-01	1.14E-03	Yes	Yes

Dinoseb	485.94	Decreased expression of transforming growth factor-beta in human primary bronchial epithelial cells	6.28E-01	1.29E-03	Yes	—

2-Methyl-4,6-dinitrophenol	589.15	Decrease mitochondrial membrane potential in HepG2 cells	8.74E-01	1.48E-03	Yes	—

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Cmin (ng/mL)

Summary of Exposure Normalizeda Tacrolimus PK Parameters—mITT Analysis Set

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Kidneys

ODs and ED for (+)-[18F]flubatine based on mice data

ODs calculated for the adult male model (73.7 kg, implemented in OLINDA) based on mouse biodistribution and organ geometry data that were scaled to human circumstances OD organ dose, ED effective dose (ICRP 103), SD standard deviation mean over three animals

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AUC

Ortho-fluoro and ortho-methyl (3-chloro-4,5-dialkoxybenzamido)benzoic acids.

<!DOCTYPE html>

Potency and Selectivity
	PK

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

mouse	human	AUC	Cl	F%

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

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

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

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

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

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

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

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

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

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

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F

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.

F


VC/F (L)

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

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

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AUCinf (ng h/mL)a

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

<!DOCTYPE html>

Parameter	Study

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

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

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

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

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

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

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

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

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

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

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

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a


AUC (ng·h/mL)

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

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F

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

F


AUC0–32 (ng.h/ml)

Individual and mean pharmacokinetic parameters of daidzein following a single dose of orally administered soy beverage (B) and soy extract capsules (C).

1Pharmacokinetic parameters adjusted for oral administered dose. ND = statistical analysis was not performed due to differences in oral administered doses between both preparations, *Statistical significance (p < 0.05) compared to corresponding values of soy extract capsules.

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Cmax (ng/ml)

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

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

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

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

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

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

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

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

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koff (h−1)

      0
      1
      2

      0
      Parameter
      Values used in human D2RO Simulations
      Source

      1
      CL/F (l/h)
      19.5 (58)a
      (25)

      2
      V/F (l)
      1,150 (75)a
      (25)

      3
      Ka (h−1)
      0.600 (32)a
      (25)

      4
      koff (h−1)
      2.34
      (37)

      5
      Kd (nM)
      5.10b
      (38)

      6
      fraction unbound in plasma
      0.0700
      (22)

      7
      fraction unbound in brain
      0.034
      (19)

      8
      Human cerebral blood flow (l/h)
      36.0
      (24)

      9
      Human brain extravascular volume (l)
      1.4
      (23)

      10
      Human brain vascular volume (l)
      0.150
      (23)

      11
      CLbev (l/h)
      11.3
      –c

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

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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CLPM

      0
      1
      2
      3
      4

      0
      Parameter
      Clopidogrel
      H3
      H4 (active)
      CLPM

      1
      Dose: clopidogrel 75 mg
      (n = 41)
      (n = 30)
      (n = 30)
      (n = 45)

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

      3
      t max [h; mean ± SD]
      1.40 ± 1.07
      1.08 ± 0.62
      1.04 ± 0.53
      1.37 ± 0.74

      4
      t ½ [h; mean ± SD]
      1.71 ± 1.28
      0.78 ± 0.78
      0.90 ± 0.86
      7.14 ± 3.32

      5
      AUCt [ng·h/mL; mean ± SD]
      5.07 ± 3.80
      7.37 ± 6.71
      11.30 ± 9.58
      11,077 ± 7,768

      6
      AUC∞ [ng·h/mL; mean ± SD]
      6.29 ± 4.11
      7.96 ± 6.85
      11.97 ± 9.75
      12,383 ± 8,552

      7
      CL/F [×103 L/h; mean ± SD]
      18.96 ± 15.89
      –
      –
      –

      8
      V d/F [×103 L; mean ± SD]
      39.24 ± 33.52
      –
      –
      –

      9
      Dose: clopidogrel 300 mg
      (n = 3)
      (n = 3)
      (n = 3)
      (n = 17)

      10
      C max [ng/mL; mean ± SD]
      4.51 ± 3.42
      8.47 ± 1.69
      17.92 ± 20.38
      8,464 ± 3,772

      11
      t max [h; mean ± SD]
      1.17 ± 0.76
      0.83 ± 0.29
      0.83 ± 0.29
      1.61 ± 1.21

      12
      t ½ [h; mean ± SD]
      1.99 ± 0.44
      0.72 ± 0.18
      0.84 ± 0.20
      7.11 ± 3.50

      13
      AUCt [ng·h/mL; mean ± SD]
      20.82 ± 13.35
      11.24 ± 8.31
      25.04 ± 27.41
      32,979 ± 12,321

      14
      AUC∞ [ng·h/mL; mean ± SD]
      21.76 ± 13.34
      11.70 ± 8.33
      25.69 ± 27.54
      37,249 ± 13,861

      15
      CL/F [×103 L/h; mean ± SD]
      16.98 ± 10.41
      –
      –
      –

      16
      V d/F [×103 L; mean ± SD]
      45.50 ± 19.22
      –
      –
      –

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

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

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M


θCL/F, CYP3A4 inducer

θ

C

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Y

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AUC24h/MIC for eradication effect

      0
      1
      2

      0
      Parameters
      Units
      Values

      1
      Emax
      Log CFU/mL
      2.71 ± 0.37

      2
      E0
      Log CFU/mL
      −4.61 ± 0.69

      3
      Emax−E0
      Log CFU/mL
      7.32 ± 1.06

      4
      EC50
      h
      30.07 ± 6.94

      5
      N (slope)
      /
      4.62 ± 0.72

      6
      AUC24h/MIC for bacteriostatic effect
      h
      26.72 ± 6.28

      7
      AUC24h/MIC for bactericidal effect
      h
      39.54 ± 7.31

      8
      AUC24h/MIC for eradication effect
      h
      50.69 ± 9.16

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

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Diastolic BP Emax

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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CL (L/h/m2)

Pharmacokinetic parameters of eribulin (cycle 1, day 1)

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

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Diastolic Blood Pressure (mmHg)

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

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

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Systolic blood pressure (mmHg)

      0
      1
      2
      3

      0
      Vital signs
      Treatment Arm A
      Treatment Arm B
      Combination

      1
      Unnamed: 0_level_1
      LDX alone
      VXR alone
      LDX + VXRb

      2
      Pulse rate (beats/min)
      −0.78c to 12.76
      −3.73 to 8.73
      4.66–20.85

      3
      Systolic blood pressure (mmHg)
      −0.77c to 6.56
      −0.52 to 4.32
      4.44c to 13.78

      4
      Diastolic blood pressure (mmHg)
      0.57c to 5.74
      1.18–5.39
      7.05–12.46

CAPTION: Range (1–2 h post-dose) of mean change from time-matched baselinea in vital signs over 1–12 h post-dose
FOOTER: LDX lisdexamfetamine dimesylate, VXR venlafaxine extended-releaseaBaseline was defined as the time-matched measurement at day −1 for each treatment periodbIncludes subjects who received LDX + VXR in Treatment Arm A as well as those who received VXR + LDX in Treatment Arm BcValue occurred at first post-dose measurement (1 h post-dose)

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Cmax(mg/L)

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

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tmaxa (h)

Summary of glycopyrronium pharmacokinetic parameters (mITT population)

aMedian (Min, Max); bn = 11; cn = 10; dn = 12; en = 19; fn = 16.AUCx-y = area under the concentration-time curve from time x to time y; CL/F = apparent oral clearance; Cmax = maximum plasma concentration; CV% = coefficient of variation; GP MDI = glycopyrronium metered-dose inhaler; t1/2 = apparent terminal elimination half-life; tmax = time to maximum concentration; Vz/F = apparent volume of distribution; mITT=modified intention to treat.

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m

a

x

a

h


Potency and Selectivity

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y

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MAT (min)

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

<!DOCTYPE html>

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

<inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
				\usepackage{wasysym}
				\usepackage{amsfonts}
				\usepackage{amssymb}
				\usepackage{amsbsy}
				\usepackage{mathrsfs}
				\usepackage{upgreek}
				\setlength{\oddsidemargin}{-69pt}
				\begin{document}$$ \overline{x} $$\end{document}</tex-math><mml:math id="M10" display="inline"><mml:mover accent="false"><mml:mi>x</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="12906_2017_1809_Article_IEq5.gif"/></alternatives></inline-formula> ± SD	CV (%)
<inline-formula id="IEq6"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
				\usepackage{wasysym}
				\usepackage{amsfonts}
				\usepackage{amssymb}
				\usepackage{amsbsy}
				\usepackage{mathrsfs}
				\usepackage{upgreek}
				\setlength{\oddsidemargin}{-69pt}
				\begin{document}$$ \overline{x} $$\end{document}</tex-math><mml:math id="M12" display="inline"><mml:mover accent="false"><mml:mi>x</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="12906_2017_1809_Article_IEq6.gif"/></alternatives></inline-formula> ± SD	CV (%)

λ (min−1)	0.0039 ± 0.0010	25.17	0.0025 ± 0.0014	53.87	0.053a

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

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

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

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

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

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

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

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

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

MAT (min)	64.21	56.07

F (%)	36.73	41.52

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

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AUC0–24 (ng • h/ml)

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

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Cmax DHA (ng/mL)

AL dosing and pharmacokinetic parameters in patients weighing 5 to < 10 kg or 10 to < 15 kg

<!DOCTYPE html>

Body weight

5 to < 10 kg	10 to < 15 kg

<bold>Artemether & dihydroartemisinin (DHA)</bold>

Dispersible tablet	N = 171	N = 352

Total dose artemether (mg/kg)	14.8 ± 2.57	10.0 ± 1.30

Cmax artemether (ng/mL)	372 ± 251	110 ± 97.7

Cmax DHA (ng/mL)	107 ± 76.6	38.2 ± 42.4

Crushed tablet	N = 183	N = 37

Total dose artemether (mg/kg)	14.7 ± 1.94	10.0 ± 1.28

Cmax artemether (ng/mL)	295 ± 214	137 ± 111

Cmax DHA (ng/mL)	89.9 ± 83.5	36.6 ± 28.7

<bold>Lumefantrine</bold>

Dispersible tablet	N = 24	N = 78

Total dose lumefantrine (mg/kg)	90.4 ± 9.46	60.4 ± 7.37

Cmax (μg/mL)	6.55	5.55

AUC0-last (μg·h/mL)	550	393

Crushed tablet	N = 26	N = 75

Total dose lumefantrine (mg/kg)	88.6 ± 13.1	59.5 ± 6.87

Cmax (μg/mL)	5.50	6.29

AUC0-last (μg·h/mL)	578	558

Data are mean ± SD;1 N = 18 for DHA;2 N = 34 for DHA;3 N = 19 for DHA

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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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Heart rate AUEC0-1.5h

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Lanabecestat Cmax (ng/mL)

PK Parameters for Each Treatment Group

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

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Absorption rate constant

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

<!DOCTYPE html>

Parameter (unit)	Definition of parameter	Bootstrap

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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t ½ (h)

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

t

½

h


θCL/F, PGP

Parameter estimates in the final population pharmacokinetic model

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

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Typical value (RSE, %)b

      0
      1
      2

      0
      Parametera
      Typical value (RSE, %)b
      IIV, CV% (RSE, %)

      1
      IL‐18 model
      IL‐18 model
      IL‐18 model

      2
      R in (pg/mL/day)
      23.0 (12)
      —

      3
      k out (day−1)
      0.106 (13)
      47 (8.7)

      4
      Pool0 (pg/mL)
      499 (18)
      78 (18)

      5
      Slope (mL/μg)
      0.168 (26)
      80 (26)

      6
      k e0 (day−1)
      4.36·10−3 (25)
      —

      7
      Residual error (%)
      22.3 (2.5)
      —

      8
      ITAC model
      ITAC model
      ITAC model

      9
      R in (pg/mL/day)
      3.07 (24)
      48 (10)

      10
      k out (day−1)
      7.91·10−3 (23)
      —

      11
      Pool0 (pg/mL)
      271 (20)
      115 (15)

      12
      Slope (mL/μg)
      0.0599 (35)
      —

      13
      Proportional residual error (%)
      28.3 (3.9)
      —

      14
      Additive residual error (pg/mL)
      51.8 (15)
      —

      15
      TGI model
      TGI model
      TGI model

      16
      SLD0 (cm)
      4.75 (11)
      62 (8.3)

      17
      R Growth (cm/week)
      0.0169 (17)
      93 (17)

      18
      K Shr,Drug (l/mg/day/week)
      2.75·10−6 (23)
      124 (21)

      19
      λDrug (week−1)
      0.0609 (8.7)
      —

      20
      K Shr,IL‐18 (1/(% week))
      0.00282 (14.1)
      181 (24)

      21
      θ Rgrowth‐LiverMets
      8.48 (8.5)
      —

      22
      θ SLD0‐Mets
      0.927 (27)
      —

      23
      θ KShr,Drug‐Non‐Smoking
      0 fixed
      —

      24
      Residual error (%)
      13.4 (2.1)
      —

      25
      Dropout model
      Dropout model
      Dropout model

      26
      h 0 (week−1)
      0.0306 (1.8)
      nan

      27
      Β
      1.56 (8.8)
      nan

CAPTION: Final parameter estimates and relative standard errors for the interleukin 18 (IL‐18), interferon‐inducible T‐cell alpha chemoattractant (ITAC), dropout and tumor growth inhibition (TGI) models
FOOTER: CV%, coefficient of variation; IIV, interindividual variability; IL‐18, interleukin‐18; ITAC, interferon‐inducible T‐cell alpha chemoattractant; RSE, relative standard error; SLD, sum of the longest diameter; TGI, tumor growth inhibition.a R in, zero‐order input rate; k out, first‐order fractional turn‐over rate; Pool0, baseline concentration in the pool compartment; Slope, linear drug effect; k e, first‐order effect compartment rate constant; SLD0, baseline sum of longest diameters; R Growth, zero‐order tumor growth rate; K Shr,Drug, rate constant for tumor shrinkage related to drug area under the curve (AUC) in former or current smokers; λDrug, rate constant for reduced effect of AUC on tumor shrinkage; K Shr,IL‐18, rate constant for tumor shrinkage related to IL‐18; θ Rgrowth‐LiverMets, describes the fractional change in R Growth (1 + θ) for patients with liver metastases at baseline; θ SLD0‐Mets., describes the fractional change in SLD0 (1 + θ) for patients with more than two metastases at baseline; θ KShr,Drug‐Non‐Smoking describes the rate constant for tumor shrinkage related to drug AUC in nonsmokers; h 0, baseline hazard; β, parameter relating the tumor size to dropout. bThe RSEs related to the PK model were computed based on the NONMEM variance covariance matrix (sandwich matrix). For the biomarker, TGI and dropout models, the RSEs were computed based on the NONMEM variance covariance matrix (S matrix).

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b


Cmax, 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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CLd (L/h)

Model Parameters for the Final Integrated Model

<!DOCTYPE html>

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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AUCinf

Plasma pharmacokinetic parameters for canagliflozin and DPTQ in bile‐duct cannulated and intact dog

<!DOCTYPE html>
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Parameters	 	Canagliflozin	DPTQ	DPTQ‐O‐glucuronide

BDC	Intact	BDC	Intact<xref ref-type="fn" rid="prp2502-note-0004">
b
</xref>
	Intact

AUC0‐48 hr
	µmol/L*hr	15.7 ± 5.4	20.7 ± 3.7	5.89 ± 3.3	7.94 ± 2.5	2.61 ± 1.5

AUCinf
	µmol/L*hr	16.4 ± 5.9	21.2 ± 3.9	5.89 ± 3.3	NA	2.6 ± 1.7

<italic>t</italic>
1/2
	hr	10.9 ± 1.8	8.05 ± 0.62	2.50 ± 2.3	NA

<italic>V</italic>
dss
	L/kg	0.87 ± 0.28	0.72 ± 0.13	0.33 ± 0.07<xref ref-type="fn" rid="prp2502-note-0003">
a
</xref>
	1.48 ± 0.25

CL	mL/min/kg	1.32 ± 0.50	0.93 ± 0.18	4.43 ± 3.1	2.73 ± 1.2

NoteDogs were given canagliflozin and DPTQ at 0.5 mg/kg by IV bolus. Values were derived from plots shown in Figure 2. Results shown represent mean ± SD from four animals.a P < 0.01 compared to the parameters in intact animals.bThe elimination phase was flat and AUCinf was not extrapolated, the CL and V dss was CL0‐48 h and V dss 0‐48 hr

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t1/2 (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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h


VM3G (L)

Population parameter estimates for the final model

<!DOCTYPE html>
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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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MRTINF (h)

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, d

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B (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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Final population model estimates of pantoprazole

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

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Cmin (mg/L)

Observed meropenem concentrations in serum and cerebrospinal fluid

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

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Geometric mean AUC(0–tlast) (se) (pg × h/ml)

Pharmacokinetic parameters of plasma exenatide concentrations following a single subcutaneous exenatide dose (10 μg) by anti-emetic treatment [population: ITT subjects evaluable for pharmacokinetic analysis (n = 116)]

<!DOCTYPE html>

Group by anti-emetic treatment

Non-premedicated (<italic>n</italic> = 60)	Premedicated (<italic>n</italic> = 56)	<italic>P</italic>-value

Geometric mean AUC(0–tlast) (<sc>se</sc>) (pg × h/ml)	863.53 (30.540)	818.38 (38.065)	0.36

Minimum, maximum	556.6, 1763.3	191.1, 1511.1

Geometric mean Cmax(0–tlast) (<sc>se</sc>) (pg/ml)	242.74 (12.404)	227.36 (15.361)	0.44

Minimum, maximum	109.1, 705.4	92.6, 906.9

Geometric mean = exp{mean[log(X)]}; se of geometric mean = geometric mean × se of mean[log(X)].AUC(0–tlast), area under the concentration-time curve calculated using the linear trapezoidal method from time zero to tlast; Cmax(0–tlast), maximum concentration observed during the blood sampling period from time zero to time tlast; ITT, intent to treat; tlast, time of last quantifiable sample during the 8-h post-dose collection period. SE, standard error.

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AUC24h/MIC for bacteriostatic effect

PK-PD modeling of ex vivo cyadox after oral administration at a dose of 30 mg/kg.

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Cmax (μg/mL)

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

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

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CL/F (liters/h)

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

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

Parameter (unit)	Basic model
	Final model

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

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

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

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

IIV CL/F (%)	33.5	26.9	33.2	27.4

IOV CL/F (%)	34.9	23.3	31.8	24.2

Covariates

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

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

Residual error

    Proportional (%)	13.1	17.0	13.1	17.0

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

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AUCM3G,0‐∞ (µM*hr)b

Individual parameter and exposure estimates stratified by disease status

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

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Baseline (Day −1) (−24 to 0 Hours)

      0
      1
      2
      3
      4

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

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

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

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

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

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

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

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

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

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Vss (liters)

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

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

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AUC0-inf (mean, SD) h × ng/mL

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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AUC (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.

A

U

C

μ

g

h

m

L


Vp/F (L)

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.

V

p

F

L


λ (h-1)

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

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

λ

h