θV/F, Age

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>

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	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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Vz (L)

Pharmacokinetic parameters – Cycle 1

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

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Amount of successful bootstraps out of 1000 replicates

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

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

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

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

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tmax, hr

Pharmacokinetic parameters of prasugrel active metabolite

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

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

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

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

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

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

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AUC0–12h,SS/AUCτ,SS (%)

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

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End‐point	Japanese patients Mean (CV%)

AUCτ,SS (pmol h/L)	81,270 (28)

AUC0–12h,SS/AUCτ,SS (%)	53 (5.8)

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

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AUCT

Bioequivalence metrics

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Parameter	Ratio of LS means	90% confidence interval

AUCT
	99.5%	93.8–105.6%

AUCinf
	98.1%	92.2–104.3%

Recovery (IU/dL per IU/kg)	100.6%	97.6–103.6%

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C48 h (ng/mL)

Model-predicted variation in panobinostat exposure across covariates

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Weight (kg)

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      3
      4
      5

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      a Final model 1
      a Final model 1
      a Final model 1
      a Final model 1
      a Final model 1
      a Final model 1

      1
      Body surface area (m2)
      Age (years)
      Race
      C max, 0–48 h (ng/mL)
      C48 h (ng/mL)
      AUC, 0–48 h (ng·h/mL)

      2
      1.9
      61
      Caucasian
      10.6
      0.574
      98.1

      3
      1.8
      61
      Caucasian
      11.3
      0.601
      104.1

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      2.1
      61
      Caucasian
      9.3
      0.526
      87.8

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      1.9
      51
      Caucasian
      11.2
      0.583
      102.3

      6
      1.9
      70
      Caucasian
      10.1
      0.566
      94.9

      7
      1.9
      61
      Asian
      8.0
      0.517
      79.6

      8
      1.9
      61
      Black
      9.0
      0.607
      90.9

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      1.9
      61
      Other
      10.4
      0.893
      116.3

      10
      b Final model 2
      b Final model 2
      b Final model 2
      b Final model 2
      b Final model 2
      b Final model 2

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      Weight (kg)
      Age (years)
      Race
      Cmax, 0–48 h (ng/mL)
      C48h (ng/mL)
      AUC,0-48h (ng∙h/mL)

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      76.4
      61
      Caucasian
      12.6
      0.552
      94.7

      13
      64.8
      61
      Caucasian
      14.4
      0.630
      108.3

      14
      88.5
      61
      Caucasian
      11.1
      0.491
      84.0

      15
      76.4
      51
      Caucasian
      13.0
      0.569
      98.9

      16
      76.4
      70
      Caucasian
      12.2
      0.538
      91.6

      17
      76.4
      61
      Asian
      10.1
      0.433
      82.3

      18
      76.4
      61
      Black
      11.1
      0.606
      98.0

      19
      76.4
      61
      Other
      14.3
      0.914
      123.3

CAPTION: Model-predicted variation in panobinostat exposure across covariates
FOOTER: []

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AUC0−∞ [ng/(h mL)]

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

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

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

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

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

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

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

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

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AUMC (µg h2/ml)**

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

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

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T1/2 (h)

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

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

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ω2 CL/F

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MRT (h)

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

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

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AUCinf

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

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

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

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

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

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

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

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

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

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

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

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

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CL/F [×103 L/h; mean ± SD]

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

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Parameter	Clopidogrel	H3	H4 (active)	CLPM

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Parameter estimates of final dolutegravir population PK model

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

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Emax

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      Emax
      Log CFU/mL
      2.71 ± 0.37

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      E0
      Log CFU/mL
      −4.61 ± 0.69

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      Emax−E0
      Log CFU/mL
      7.32 ± 1.06

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      EC50
      h
      30.07 ± 6.94

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      N (slope)
      /
      4.62 ± 0.72

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      AUC24h/MIC for bacteriostatic effect
      h
      26.72 ± 6.28

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      AUC24h/MIC for bactericidal effect
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      39.54 ± 7.31

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      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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VM (L)

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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AUC0–∞ (mg · h/liter)

Plazomicin plasma pharmacokinetic parameters by renal function groupa

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PK parameter	Normal renal <break/>function (<italic>n</italic> = 6)	Mild renal <break/>impairment (<italic>n</italic> = 6)	Moderate renal <break/>impairment (<italic>n</italic> = 6)	Severe renal <break/>impairment (<italic>n</italic> = 6)

Cmax (mg/liter)	37.9 ± 5.01	32.8 ± 4.30	39.2 ± 6.43	41.4 ± 7.83

AUC0–∞ (mg · h/liter)	136 ± 17.2	138 ± 23.7	281 ± 96.0	647 ± 259

Vss (liters)	36.0 ± 7.76	28.5 ± 2.17	25.8 ± 6.96	25.1 ± 7.89

CLT (liters/h)	4.64 ± 1.17	3.98 ± 0.481	2.25 ± 0.685	0.96 ± 0.379

aAll values are reported as mean ± SD. PK, pharmacokinetics; Cmax, maximum concentration of drug in plasma; AUC0–∞, area under the concentration-time curve from 0 h to infinity; Vss, volume of distribution at steady state; CLT, total clearance.

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Mean AUC0–168h—ng × h/dL (SD)

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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Cmax, norm (nmol/L)

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

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

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Ka (h−1)

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

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Parameter	Values used in human D2RO Simulations	Source

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

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

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

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

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

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

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

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

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

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

CLbev (l/h)	11.3	–c

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

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T MAX

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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fraction unbound in plasma

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t1/2 (h)

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

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

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V d (L)

Base model PK estimates with associated bootstrap (1000 replicates)

CL, clearance; K a, absorption rate constant; SE, standard error; V d, volume of distribution; ωCL, between subject variability on rivaroxaban clearance; ωVd, between subject variability on rivaroxaban volume of distribution.

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AUMC (μg · h2/mL)

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

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

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

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

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

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

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

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

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

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

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

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

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

α (h-1)
	1.2 ± 0.0
	-
	-

β (h-1)
	9.2 ± 0.0
	-
	-

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

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

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

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

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AUC

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

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

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Ke (h−1)

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

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

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

Metoprolol

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

    AUC0-t	22	125.60	115.78	136.25

    AUC0–∞	22	123.32	114.38	132.96

Alpha-hydroxymetoprolol

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

    AUC0-t	22	87.46	79.53	96.17

    AUC0–∞	19	93.87	85.43	103.15

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CL/F (L h–1)

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

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Description	Estimate	RSE*	Bootstrap

Mean	95% CI

Ka (h–1)	2.85	8.7%	2.24	1.21 to 3.87

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

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

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

Vp/F (L)	168.	11.7%	175.9	135 to 239

ALAG1	0.877	4.7%	0.800	0.672 to 0.928

DRUG0 ON Ka	1.89	22.0%	2.00	1.23 to 2.88

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

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

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

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

WT ON Vc	0.579	25.7%	0.590	0.191 to 1.06

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

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

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

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

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

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

Prop-Error	0.216	5.0%	0.200	0.189 to 0.232

Add-Error	0.303	14.5%	0.300	0.215 to 0.382

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

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k el (h−1·70 kg−1)

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

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Parameter	Mean	Bootstrap, median (95% CI)

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

Structural model parameters

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

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

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

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

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

Variable model parameters (shrinkage%)

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

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

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

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

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

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

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

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

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Mean Cavg0–168h—pg/mL (SD) ¶

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Tmax (h)

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

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

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intrinsic Clinte

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

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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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FOIH (DPI) on C 0

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

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

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Cmax (ng/ml)

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

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PK parameter	LCDP polymeric micelles	LCDP oral suspension	Statistical test

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

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

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

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

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

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

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Cmax (ng/mL)

Summary of plasma remogliflozin and GSK279782 PK parameters in healthy subjectsa

a. n = 8 unless otherwise specified.b. R = remogliflozin.c. The median percentage of AUC(0-∞) extrapolated for R was low ranging from 0.07% to 2.1% across all doses and for 279782 ranging from 0.29% to 4.51%.d. n = 5.

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θ7 formulation on Ka

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

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

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

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

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

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

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

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

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

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

IIV

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

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

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

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

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

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

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

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AUCinf, μg.h/ml

Pharmacokinetic parameters following single doses of RN317 or bococizumab in subjects with hypercholesterolemia receiving ongoing statin therapy

Data shown are geometric mean (coefficient of variation; %CV) for all parameters except for Tmax where median (min, max) is shown, and t1/2 where arithmetic mean ± SD is shown.*n is the number of subjects in the treatment group and contributing to the mean; N is the number of subjects with a well‐characterized terminal phase. AUCinf, area under the plasma concentration–time curve from time zero to infinity; Cmax, maximum concentration; NR, not reported where <3 subjects had reportable parameter values; SD, standard deviation; t1/2, terminal half‐life; Tmax, time to reach maximum concentration.

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t1/2α (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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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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Chow et al. (2001); 600 mg PE

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

      1
      GT solids and PE pharmacokinetic studies in humans
      EGCG
      EGC
      EC
      Total TCM concentration in the plasma (μg EGCg equivalents/mL)d
      Administered TCM dose metrics (mg EGCg equivalents/kg)e

      2
      Lee et al. (2002); 20 mg/kg GT solids
      0.06a (0.08)b
      0.07 (0.22)c
      0.04 (0.12)c
      0.200000
      6.060000

      3
      Chow et al. (2005); 400 mg PE
      0.11 (0.14)
      0.01 (0.02)
      0.01 (0.00)
      0.130000
      8.420000

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

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

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

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

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Cmax (ng/mL)

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

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Parameter	Triptolide	Triptolide + puerarin

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

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

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

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

CL (L/h/kg)	4.92 ± 0.35	3.75 ± 0.19*

*p < 0.05 indicates significant differences from the control.

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Tmax, hoursa

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

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

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Cmax coefficient (nasal/serum)

MEDI4893 nasal pharmacokinetic parameters for each dose determined by noncompartmental analysisa

aData are expressed as the mean ± standard deviation.

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ER crushed

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

      1
      Variable
      IR
      ER crushed
      ER intact

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

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

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

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

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

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

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

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

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

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

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

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

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

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Correlation V1.V2

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

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

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T1/2 (h)

Pharmacokinetic parameters of the seven components of Shengjiang decoction

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

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Weight on CL/Fc

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

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

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AUCinf (DN), μg. day/mL/mg

Comparison of the dose‐normalized pharmacokinetic parameters of bococizumab when administered alone or in co‐mixture with rHuPH20

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Comparison and Pharmacokinetic Parameters	Test<xref ref-type="fn" rid="hsr261-note-0008">a</xref>
	Reference<xref ref-type="fn" rid="hsr261-note-0008">a</xref>
	Test/Reference Ratio, % (90% Confidence Interval)

Test: Bococizumab 150 mg + rHuPH20<break/>
Reference: Bococizumab 300 mg

AUCinf (DN), μg. day/mL/mg	1.238	1.047	118.32 (97.93‐142.95)

AUClast (DN), μg. day/mL/mg	1.197	1.023	117.03 (96.59‐141.81)

<italic>C</italic>
max (DN), μg/mL/mg	0.07919	0.05691	139.14 (116.67‐165.95)

Test: bococizumab 300 mg + rHuPH20<break/>
Reference: bococizumab 300 mg

AUCinf (DN), μg. day/mL/mg	1.430	1.047	136.64 (112.81‐165.50)

AUClast (DN), μg. day/mL/mg	1.405	1.023	137.37 (113.09‐166.86)

<italic>C</italic>
max (DN), μg/mL/mg	0.07385	0.05691	129.76 (108.55‐155.11)

Test: bococizumab 450 mg + rHuPH20<break/>
Reference: bococizumab 300 mg

AUCinf (DN), μg. day/mL/mg	1.428	1.047	136.42 (112.92‐164.81)

AUClast (DN), μg. day/mL/mg	1.407	1.023	137.56 (113.54‐166.67)

<italic>C</italic>
max (DN), μg/mL/mg	0.07208	0.05691	126.64 (106.19‐151.03)

AUCinf, area under the plasma concentration‐time profile from time zero extrapolated to infinite time; AUClast, area under the plasma concentration‐time profile from time zero to the time of the last quantifiable concentration; C max, maximum plasma concentration; DN; dose‐normalized to a 300‐mg dose; rHuPH20, recombinant human hyaluronidase.aData are presented as natural log‐transformed, adjusted geometric means obtained from an ANCOVA model with body mass index as a covariate.

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C (cold coffee – 20 min)

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      0
      Unnamed: 0_level_0
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)
      Mean values ± SD (range)

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      Condition
      Cmax (μg/mL) a
      Dose-normalized b  Cmax (μg/mL)
      Tmax (min)
      AUC0–∞ (μg/mL min)
      Dose-normalized b  AUC0–∞ (μg/mL min)
      MRT (min)
      MAT (min)
      CL/F (mL/min/kg)
      Vd,ss/F (mL/kg) a
      t1/2 (min)

      2
      A (hot coffee – 20 min)
      3.74 ± 1.09 (1.96–5.95)
      1.69 ± 0.43 (1.07–2.40)
      59 ± 27 (20–120)
      2312 ± 1338
      1035 ± 541
      601 ± 263
      12 ± 11
      1.2 ± 0.6
      623 ± 129
      408 ± 178 (210–990)

      3
      B (cold coffee – 2 min)
      3.64 ± 1.36 (1.81–8.17)
      1.57 ± 0.59 (0.981–3.13)
      62 ± 32 (40–120)
      2447 ± 1781
      1047 ± 725
      607 ± 267
      14 ± 10
      1.3 ± 0.7
      626 ± 145
      411 ± 183 (187–966)

      4
      C (cold coffee – 20 min)
      3.56 ± 1.06 (1.69–5.77)
      1.60 ± 0.44 (0.917–2.79)
      64 ± 20 (40–90)
      2625 ± 2177
      1172 ± 882
      673 ± 362
      16 ± 6
      1.2 ± 0.6
      642 ± 151
      455 ± 249 (217–1386)

      5
      D (energy drink – 2 min)
      3.36 ± 1.20 (1.40–5.78)
      1.51 ± 0.48 (0.782–2.81)
      70 ± 44 (20–240)
      2473 ± 2302
      1059 ± 834
      665 ± 427
      15 ± 16
      1.4 ± 0.8
      712 ± 194
      450 ± 295 (154–1386)

      6
      E (energy drink – 20 min)
      3.14 ± 0.95 (1.87–5.25)
      1.41 ± 0.32 (0.940–1.96)
      82 ± 42 (40–240)
      2107 ± 1504
      925.1 ± 565
      593 ± 258
      17 ± 8
      1.5 ± 0.8
      708 ± 144
      399 ± 177 (187–990)

CAPTION: Pharmacokinetic parameters for caffeine in five studied conditions – means and ranges.
FOOTER: A: hot coffee 20 min; B: cold coffee 2 min; C: cold coffee 20 min; D: sugar-free energy drink 2 min; E: sugar-free energy drink 20 min.a -RM ANOVA p ≤ 0.05.b Values normalized by mg/kg dose of caffeine.

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Distribution volume (l/kg)

Overview of the pharmacokinetics of intravenous (iv) paracetamol in cohorts of women as retrieved in literature

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Author	Study characteristics	Clearance (l/h)	Distribution volume (l/kg)

Ochs et al. [<xref ref-type="bibr" rid="CR18">18</xref>]	single iv, 650 mg, young women, age matched study design

Controls (<italic>n</italic> = 10), 21–30 year, 54 (SE 2.1) kg	16.8 (SE 0.6)	0.98 (SE 0.08)

Oral contraceptives (<italic>n</italic> = 10), 62 (SE 2.5) kg	22.7 (SE 2.3)	0.98 (SE 0.06)

Sonne et al. [<xref ref-type="bibr" rid="CR19">19</xref>]	single iv, 1 000 mg, 2 episodes in each individual	16.6	1.01

3 women 54–56 kg, 29–33 years

Scaveno et al. [<xref ref-type="bibr" rid="CR14">14</xref>]	single iv, 650 mg, 30 post-menopausal women

controls (<italic>n</italic> = 18): 45 (SE 3.9) years, 64.9 (SE 3.3) kg	16.6 (SE 0.69)	0.85 (SE 0.04)

conjugated oestrogens (<italic>n</italic> = 12): 46 (3.4) years, 60.2 (1.7) kg	16.6 (SE 0.25)	0.82 (SE 0.05)

Abernethy et al. [<xref ref-type="bibr" rid="CR9">9</xref>]	single iv, 650 mg, 16 women

controls (<italic>n</italic> = 8): 23–32 years, 48–66 kg	13.7 (SD 1.26)	0.96 (SD 0.08)

oral contraceptives (<italic>n</italic> = 8): 21–36 years, 48–77 kg	20.0 (SD 1.68)	1.04 (SD 0.08)

Wynne et al.[<xref ref-type="bibr" rid="CR10">10</xref>]	single iv, 500 mg, 42 female/5 male volunteers, <italic>.</italic>all results pooled

healthy, young:	25 (SE 1) years, 59 (SE 2) kg	16.6 (SE 0.71)	1.00 (SE 0.04)

healthy, elderly:	73 (SE 1) years, 66 (SE 2) kg	14.6 (SE 0.79)	1.07 (SE 0.03)

frail, elderly:	82 (SE 2) years, 53 (SE 4) kg	7.9 (SE 0.32)	0.81 (SE 0.03)

Kulo et al. [<xref ref-type="bibr" rid="CR16">16</xref>]	single iv, 2 000 mg

28 cases, at delivery	31.5 (20–42) years, 79 (57–110) kg	20.3 (11.8–62.8)	0.72 (0.52–1.56)

SE standard error, SD standard deviation

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AUC0–24 (pg•h/mL)

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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AUCpo (ng/mL·h)

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

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Conditions	Pharmacokinetic parameters

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

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

Infected-fasted	1767.17 ± 1649.75	2	3273.35	0.1978	2.45

Normal-fed	952.50 ± 332.49	1.5	2282.17	0.1379	3.01

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

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AUC (0-t)( μg/L/h)

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Diastolic BP AUEC0-tlast*

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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      0
      1
      2
      3

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

      1
      Plasma
      nan
      nan
      nan

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

      3
      Brain microdialysates
      nan
      nan
      nan

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

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

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

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k out (day−1)

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

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Parameter<xref ref-type="fn" rid="cpt1198-note-0002">a</xref>
	Typical value (RSE, %)<xref ref-type="fn" rid="cpt1198-note-0002">b</xref>
	IIV, CV% (RSE, %)

IL‐18 model

<italic>R</italic>
in (pg/mL/day)	23.0 (12)	—

<italic>k</italic>
out (day−1)	0.106 (13)	47 (8.7)

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

Slope (mL/μg)	0.168 (26)	80 (26)

<italic>k</italic>
e0 (day−1)	4.36·10−3 (25)	—

Residual error (%)	22.3 (2.5)	—

ITAC model

<italic>R</italic>
in (pg/mL/day)	3.07 (24)	48 (10)

<italic>k</italic>
out (day−1)	7.91·10−3 (23)	—

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

Slope (mL/μg)	0.0599 (35)	—

Proportional residual error (%)	28.3 (3.9)	—

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

TGI model

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

<italic>R</italic>
Growth (cm/week)	0.0169 (17)	93 (17)

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

λDrug (week−1)	0.0609 (8.7)	—

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

<italic>θ</italic>
Rgrowth‐LiverMets
	8.48 (8.5)	—

<italic>θ</italic>
SLD0‐Mets
	0.927 (27)	—

<italic>θ</italic>
KShr,Drug‐Non‐Smoking
	0 fixed	—

Residual error (%)	13.4 (2.1)	—

Dropout model

<italic>h</italic>
0 (week−1)	0.0306 (1.8)

Β	1.56 (8.8)

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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AUC∞,ng/mL*hr

Predicted pharmacokinetics parameters of morphine in virtual neonates after the intravenous administration

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Age years	Body weight kg	Hepatic OCT1nmol/liver	Cmax, ×103ng/mL	AUC∞,ng/mL*hr	CLpediatric,i,L/hr	CL70kg,i, L/hr per 70kg

Predictions by PBPK modeling

Mean	0.10	4.2	10.0	1.80	188	3.55	29.4

SD	0.01	0.6	10.4	0.16	80	1.66	13.5

Minimum	0.08	2.7	0.38	1.41	48	1.14	9.7

Maximum	0.12	6.2	96.2	2.32	474	10.7	94.3

Clinical observations

Patient T.T.	0.1	4.0	NA	2.12	205	2.23	19.1

Patient A.J.	0.1	4.4	NA	2.54	99.7	5.04	40.1

AUC∞, area under the plasma concentration‐time curve extrapolated to infinity; CLpediatric,i, pediatric clearance; Cmax, maximum concentration for simulations (for clinical observations, concentration at time zero); NA, not available; OCT1, organic cation transporter 1; PBPK, physiologically based pharmacokinetic.CL70kg,i (L/hr per 70kg), an allometrically‐scaled clearance with standard body weight of 70kg (i.e., CL70kg, i in Eq. (5), as described in the Method section), which is calculated as follows: CL70kg,i=CLpediatric,i×70 kgBody Weightpediatric,i0.75

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Cmax (mg/liter)

Plazomicin plasma pharmacokinetic parameters by renal function groupa

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PK parameter	Normal renal <break/>function (<italic>n</italic> = 6)	Mild renal <break/>impairment (<italic>n</italic> = 6)	Moderate renal <break/>impairment (<italic>n</italic> = 6)	Severe renal <break/>impairment (<italic>n</italic> = 6)

Cmax (mg/liter)	37.9 ± 5.01	32.8 ± 4.30	39.2 ± 6.43	41.4 ± 7.83

AUC0–∞ (mg · h/liter)	136 ± 17.2	138 ± 23.7	281 ± 96.0	647 ± 259

Vss (liters)	36.0 ± 7.76	28.5 ± 2.17	25.8 ± 6.96	25.1 ± 7.89

CLT (liters/h)	4.64 ± 1.17	3.98 ± 0.481	2.25 ± 0.685	0.96 ± 0.379

aAll values are reported as mean ± SD. PK, pharmacokinetics; Cmax, maximum concentration of drug in plasma; AUC0–∞, area under the concentration-time curve from 0 h to infinity; Vss, volume of distribution at steady state; CLT, total clearance.

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CL/F (L/h/kg)

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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Tmax (min)

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 	Mean values ± SD (range)

Condition	Cmax (μg/mL)<xref rid="TF2" ref-type="table-fn">
a
</xref>	Dose-normalized<xref rid="TF3" ref-type="table-fn">
b
</xref> Cmax (μg/mL)	Tmax (min)	AUC0–∞ (μg/mL min)	Dose-normalized<xref rid="TF3" ref-type="table-fn">
b
</xref> AUC0–∞ (μg/mL min)	MRT (min)	MAT (min)	CL/F (mL/min/kg)	Vd,ss/F (mL/kg)<xref rid="TF2" ref-type="table-fn">
a
</xref>	t1/2 (min)

A (hot coffee – 20 min)	3.74 ± 1.09 (1.96–5.95)	1.69 ± 0.43 (1.07–2.40)	59 ± 27 (20–120)	2312 ± 1338	1035 ± 541	601 ± 263	12 ± 11	1.2 ± 0.6	623 ± 129	408 ± 178 (210–990)

B (cold coffee – 2 min)	3.64 ± 1.36 (1.81–8.17)	1.57 ± 0.59 (0.981–3.13)	62 ± 32 (40–120)	2447 ± 1781	1047 ± 725	607 ± 267	14 ± 10	1.3 ± 0.7	626 ± 145	411 ± 183 (187–966)

C (cold coffee – 20 min)	3.56 ± 1.06 (1.69–5.77)	1.60 ± 0.44 (0.917–2.79)	64 ± 20 (40–90)	2625 ± 2177	1172 ± 882	673 ± 362	16 ± 6	1.2 ± 0.6	642 ± 151	455 ± 249 (217–1386)

D (energy drink – 2 min)	3.36 ± 1.20 (1.40–5.78)	1.51 ± 0.48 (0.782–2.81)	70 ± 44 (20–240)	2473 ± 2302	1059 ± 834	665 ± 427	15 ± 16	1.4 ± 0.8	712 ± 194	450 ± 295 (154–1386)

E (energy drink – 20 min)	3.14 ± 0.95 (1.87–5.25)	1.41 ± 0.32 (0.940–1.96)	82 ± 42 (40–240)	2107 ± 1504	925.1 ± 565	593 ± 258	17 ± 8	1.5 ± 0.8	708 ± 144	399 ± 177 (187–990)

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CL (l h−1)

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

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

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AUC∞ (h*μg/mL)

Pharmacokinetic parameters – Cycle 1

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

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AUC0-t (ng•h/mL)

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

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Cmax

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

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

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

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t ½, days

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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F/FE

Plasma pharmacokinetic parameters of fexinidazole (single-dose studies)

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

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Tmax (h)

PHARMACOKINETIC PARAMETERS OF COMPOUNDS LM 13765 AND LM 13765-C

aCmax, tmax and AUC observed in compound LM 13765 were measured as compound LM 13765-C as compound LM 13765 was found to get metabolized to its aminal LM 13765-C.

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C max (μ/mL)

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

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

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

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

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

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

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

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

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

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

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

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t1/2,z (day)

Pharmacokinetic parameters and incidence of anti-blisibimod antibodies in patients with systemic lupus erythematosus in the phase 1b study

Abbreviations: AR accumulation ratio, AUC 0-t plasma-concentration curve from time of treatment to the last measurable concentration, C max maximum observed serum concentration, C 0 estimated initial concentration after IV bolus dosing, CL clearance (CL), CL/F apparent clearance, IV intravenous, NA not applicable, NC not calculated, SC subcutaneous, SD standard deviation, t 1/2,z half-life, t max time to Cmax

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AUC0–24h (µmol h/L)

PK parameters (CV %) for vismodegib following single-dose (day 1 or 5) and multiple-dose (day 7 or 11, steady state) administration of oral vismodegib (150 mg QD)

Geometric mean (CV %) data are presented unless indicated CV % coefficient of variation, NC not calculated, PK pharmacokinetic, QD once daily aMedian (min, max) presented for t max and t ss  b t ss estimated after continuous QD dosing (AUC0–24h, C max, and t max estimated after the first dose)

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Pharmacokinetic parameters

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

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t max [h; mean ± SD]

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

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Parameter	Clopidogrel	H3	H4 (active)	CLPM

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

t

m

a

x

h

m

e

a

n

S

D


Tmax (h)

The pharmacokinetic parameters of gefitinib in each study (Geometric Mean (CV%)).

T

m

a

x

h


C max, μg mL−1

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

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

C

m

a

x

μ

g

m

L


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Q

B

Z

R


AUClast (μg.h/mL)

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

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

A

U

C

l

a

s

t

μ

g

h

m

L