AUC0–t (h μmol l−1)

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

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

<bold>Plasma</bold>

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

<bold>Brain microdialysates</bold>

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

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

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

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      8

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

b


Rectal hydrogel (F8)

      0
      1
      2

      0
      Parameter
      Commercial capsule
      Rectal hydrogel (F8)

      1
      Dose (mg/kg)
      50
      50

      2
      Cmax (µg/ml)
      33.877 ± 2.16
      45.425 ± 2.745

      3
      tmax (h)
      1
      4

      4
      t1/2el (h)
      5.137 ± 0.027
      6.910 ± 0.003

      5
      AUC0−24 (µg h/ml)
      129.489 ± 13.55
      463.481 ± 48.207

      6
      AUC0−∞ (µg.h/ml)
      129.489 ± 13.55
      514.033 ± 48.207

      7
      MRT (h)
      3.923 ± 0.24
      9.512 ± 0.233

      8
      Relative bioavailability
      –
      357.93%

CAPTION: Pharmacokinetic parameters of Tolmetin Sodium estimated after oral and rectal administration of commercial capsule suspension (treatment I) and F8 hydrogel (treatment II) to six rats
FOOTER: All values are Mean ± SD

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Mean AUClast (ng h/mL) [% CV]

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

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

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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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CL70kg,i, L/hr per 70kg

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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t1/2 (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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h


tmax, hoursb

Baseline‐Corrected Pharmacokinetic Parameters for sFetot in Healthy Volunteers After Intravenous Administration of Ferric Pyrophosphate Citrate Iron

AUC0‐t, area under the serum concentration‐time curve from 0 to the time of the last quantifiable concentration; CL, total drug clearance; Cmax, maximum serum concentration; FPC, ferric pyrophosphate citrate; λz, terminal rate constant; sFetot, serum total iron; t½app, apparent terminal‐phase half‐life; tmax, time to maximum serum concentration.aValues are expressed as mean (SD) unless otherwise indicated.bMedian value.

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AUC (pg.h/mL)

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)

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ka (1/h)

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Population parameters	Interindividual variation (std. dev.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sex on km
	Covariate effect	0.15	0.05	31	0.001

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

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

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

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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MRTlast [hr]

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

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

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t1/2 (h)c

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

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

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

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

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

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

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

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

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

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

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

3.6	1	43.3	10.0	100

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

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

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

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

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Exposure duration (mins)

Experimental design

      0
      1
      2
      3

      0
      Nominal particle diameter (nm)
      Exposure duration (mins)
      Total animals
      Post-exposure sacrifice time (group size)

      1
      Main study – Clearance and translocation
      Main study – Clearance and translocation
      Main study – Clearance and translocation
      Main study – Clearance and translocation

      2
      10*
      120
      36
      0 h (6), 24 h (4), 3d (4), 7d (4), 14d (4), 30d (5), 63d (4), 90d (5)

      3
      15
      75
      35
      0 h (10), 24 h (5), 2d (4), 5d (4), 9d (4), 28d (4), 109d (4)

      4
      35
      180
      36
      0 h (6), 24 h (6), 3d (4), 7d (4), 14d (4), 28d (4), 64d (4), 589d (4)

      5
      75
      60
      9
      0 h (5), 30d (4)

      6
      Supplementary study A – Clearance
      Supplementary study A – Clearance
      Supplementary study A – Clearance
      Supplementary study A – Clearance

      7
      15
      10
      5
      nan

      8
      15
      20
      5
      nan

      9
      15
      40
      5
      nan

      10
      15
      60
      5
      nan

      11
      Supplementary study B – Additional samples for imaging
      Supplementary study B – Additional samples for imaging
      Supplementary study B – Additional samples for imaging
      Supplementary study B – Additional samples for imaging

      12
      10
      120
      6
      24 h (2), 5d (2), 30d (2)

      13
      75
      60
      6
      24 h (2), 5d (2), 30d (2)

CAPTION: Experimental design
FOOTER: *For the 10 nm study additional animals (system controls) were exposed in the same system to gases without nanoparticles for 120 mins and sacrificed at 3 and 7 days post-exposure

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V/F (liters)

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

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

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

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

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

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

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

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

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

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

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

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

AUC0–∞ (h · μg/ml)	61.4 (33.0–231)

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

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

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

V

F

l

i

t

e

r

s


t1/2 (h)

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

t

h


PappA‐B (10–6cm/s)

      0
      1
      2
      3
      4
      5

      0
      Compound
      Cell line
      PappA‐B (10–6cm/s)
      PappB‐A (10–6cm/s)
      PappB‐A/PappA‐B
      Net efflux ratio (Pgp substrate)

      1
      Canagliflozin
      MDR1‐MDCKII_inhibitor
      10.8 ± 1.4
      14.1 ± 0.1
      1.300000
      17.1 (S)

      2
      Canagliflozin
      MDR1‐MDCKII_control
      4.0 ± 1.8
      89.2 ± 8.2
      22.000000
      17.1 (S)

      3
      DPTQ
      MDR1‐MDCKII_inhibitor
      48.9 ± 5.9
      53.5 ± 0.4
      1.100000
      1.3 (NS)

      4
      DPTQ
      MDR1‐MDCKII_control
      43.0 ± 4.5
      62.6 ± 2.6
      1.500000
      1.3 (NS)

CAPTION: In vitro permeability and net efflux ratio in P‐gp assay
FOOTER: NoteIncubation contained 5 µmol/L compound with and without 2.5 µmol/L P‐gp inhibitor, as described in Materials and Methods. Results shown represent means ± SD (n = 3).Abbreviations: S, substrate; NS, non‐substrate.

P

a

p

p

A

B

c

m

s


Emax (1/h)

      0
      1
      2

      0
      Parameters
      Population mean (%CV)
      Inter-individual variability (%CV)

      1
      ADC
      ADC
      ADC

      2
      Emax (1/h)
      0.0407 (5.5)
      0.0945 (25.4)

      3
      Km (nmol/L)
      0.959 (1.68)
      ––

      4
      Vc (L)
      0.0996 (2.6)
      0.0118 (36.9)

      5
      CLd (L/h)
      0.00197 (1.9)
      –

      6
      Vp (L)
      0.183 (8.7)
      0.230 (25.4)

      7
      λ [Weibull scale parameter]
      1.51 (0.9)
      –

      8
      κ [Weibull shape parameter]
      1.10 (0.6)
      –

      9
      Fmp
      0.783 (2.2)
      –

      10
      Fmd
      0.0242 (30.9)
      1.78 (34.2)

      11
      MMAE
      MMAE
      MMAE

      12
      CLm (L/h)
      2.27 (8.3)
      0.333 (20.2)

      13
      Vm (L)
      1.00 (0.3)
      –

      14
      CLmd (L/h)
      23.0 (0.7)
      –

      15
      Vmp (L)
      88.4 (4.8)
      0.0670 (31.9)

      16
      σacMMAE [Residual error for acMMAE]
      0.257 (4.6)
      –

      17
      σAb [Residual error for Tab]
      0.194 (4.1)
      –

      18
      σMMAE [Residual error for unconjugated MMAE]
      0.327 (8.9)
      –

Model Parameters for the Final Integrated Model

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

E

m

a

x

h


θCL/F, CrCL

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.

θ

C

L

F

C

r

C

L


Cmax

Statistical Analysis of Lopinavir and Ritonavir Pharmacokinetic Parameters in Part 2

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Geometric Least‐Squares Mean Ratio, % (90%CI)

Parameter	Lopinavir	Ritonavir

AUCτ
	73 (56, 96)	69 (48, 98)

Cmax
	77 (62, 95)	67 (46, 98)

AUCτ, area under the plasma concentration‐time curve following last dose on day 13 (12 hours); Cmax, maximum plasma concentration; CI, confidence interval.

C

m

a

x


AUC0-t (hr*μg/mL)

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

A

U

C

t

h

r

μ

g

m

L


Bioavailability (%)

PK parameters of NP046

<!DOCTYPE html>

PK parameter	Oral	IV

<bold>Nominal Dose (mg/kg)</bold>
	50	10	5

<bold>Apparent t</bold>
<bold>1/2</bold>
<bold>(h)</bold>
	4.4 ± 0.60	3.1 ± 0.46	3.2 ± 0.35

<bold>Blood CL</bold>
<bold>total</bold>
<bold>(mL/min/kg)</bold>
	—	—	62.2 ± 3.0

<bold>Vd (L/Kg)</bold>
	—	—	16.9 ± 1.3

<bold>C</bold>
<bold>max</bold>
<bold>(μM)</bold>
	0.47 ± 0.10	0.13 ± 0.06	—

<bold>T</bold>
<bold>max</bold>
<bold>(min)</bold>
	30	48	—

<bold>AUC</bold>
<bold>0 - ∞</bold>
<bold>(min. μmol/L)</bold>
	80 ± 8.8	30 ± 14.7	248 ± 12.6

<bold>Bioavailability (%)</bold>
	3.2 ± 0.47	6.0 ± 2.9	N/A

B

i

o

a

v

a

i

l

a

b

i

l

i

t

y


Q 2 (L/min)

The comparison of typical estimates obtained in this study (surgery cancer patients) and results obtained by Schnider et al. (volunteers) and Eleveld et al. (patients and volunteers)

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Parameter (unit)	This study, patients	Schnider, volunteers	Eleveld, volunteers	Eleveld, patients

Typical (median)	Typical (median)	Bias (%)	Typical (median)	Bias (%)	Typical (median)	Bias (%)

<italic>V</italic>
<italic>P</italic> (L)	5.11	4.27	16	5.18	−1.4	8.16	−60

<italic>CL</italic> (L/min)	2.38	1.94	28	1.96	18	1.64	31

<italic>V</italic>
<italic>T1</italic> (L)	14.2	16.2	−14	10.5	26	31.4	−121

<italic>Q</italic>
<italic>1</italic> (L/min)	1.17	1.12	4.3	1.20	−4.6	1.27	−8.5

<italic>V</italic>
<italic>T2</italic> (L)	189	238	−26	231	−22	105	44

<italic>Q</italic>
<italic>2</italic> (L/min)	0.608	0.836	−38	1.38	−127	0.41	32

<italic>MDPE</italic>
	−0.50	−8.4	−1.0 %	−29.4

<italic>MDAPE</italic>
	12.1	13.6	9.3 %	29.4

All parameters were scaled to the typical patient of this study. The bias indicates the relative difference in parameters between studies. The median prediction error (MDPE) and median absolute prediction error (MDAPE) are provided to compare models performance

Q

L

m

i

n


α (h-1)

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

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

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

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

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

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

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

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

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

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

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

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

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

α (h-1)
	1.2 ± 0.0
	-
	-

β (h-1)
	9.2 ± 0.0
	-
	-

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

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

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

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

α

h


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

V


AUC0-t, ng/mL*h

Pharmacokinetic (PK) parameters of recombinant human growth hormone (r-hGH) in serum (n = 28, PK population)

Geomean (geo CV%) and range, for tmax median and range are given.AUC0-t, area under the serum concentration-time curve from time 0 to the last measurable concentration time point after drug administration; AUC0-∞, total area under the serum concentration-time curve extrapolated to infinity; Cmax, maximum serum concentration; CL/f, apparent clearance; CV, coefficient of variation; t1/2, terminal elimination half life; tmax, time to reach Cmax; Vz/f, apparent volume of distribution.A = r-hGH liquid multi-dose, 5.83 mg/mL.B = r-hGH liquid multi-dose, 8.0 mg/mL.C = r-hGH freeze-dried 8.8 mg, reconstituted in 1.51 mL.

A

U

C

t

n

g

m

L

h


Tmax (h)

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

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Dose	Day 1	Day 7

1%	3%	1%	3%

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

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

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

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

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

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

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

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

T

m

a

x

h


RBC1, 10∧9/L

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

      0
      Variable
      N (%) or Mean ± SD
      Comparison with 7 days post-dosea
      P-value of ticagrelor
      P-value of ticagrelor
      P-value of ticagrelor
      P-value of ticagrelor
      P-value of M8
      P-value of M8
      P-value of M8
      P-value of M8
      RT50†
      RECDAY†

      1
      Unnamed: 0_level_1
      Unnamed: 1_level_1
      Unnamed: 2_level_1
      t1/2
      Tmax
      Cmax
      AUC
      t1/2
      Tmax
      Cmax
      AUC
      Unnamed: 11_level_1
      Unnamed: 12_level_1

      2
      Age (years)
      24.51 ± 2.32
      /
      0.632
      0.748
      0.137
      0.986
      0.163
      0.366
      0.107
      0.675
      0.109
      0.012

      3
      Male
      27 (52.94%)
      /
      0.004
      0.010
      0.122
      0.865
      0.497
      0.034
      0.007
      <0.001
      0.149
      0.014

      4
      BMI, kg/m2
      20.69 ± 2.32
      /
      0.986
      0.805
      0.079
      0.696
      0.358
      0.757
      0.125
      0.062
      0.130
      0.108

      5
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS
      LABORATORY CHARACTERISTICS

      6
      FIB, g/L
      2.74 ± 0.46
      0.880
      0.206
      0.072
      0.219
      0.165
      0.345
      0.198
      0.060
      0.003
      0.702
      0.469

      7
      APTT, sec
      38.24 ± 3.69
      0.108
      0.346
      0.838
      0.900
      0.859
      0.577
      0.798
      0.735
      0.208
      0.750
      0.284

      8
      TT, sec
      16.34 ± 0.90
      0.880
      0.079
      0.788
      0.601
      0.526
      0.769
      0.042
      0.788
      0.012
      0.551
      0.206

      9
      PT-A, %
      98.29 ± 8.68
      0.018
      0.209
      0.374
      0.624
      0.191
      0.253
      0.505
      0.245
      0.166
      0.989
      0.754

      10
      PT, sec
      13.3 ± 0.46
      <0.001
      0.531
      0.502
      0.864
      0.402
      0.456
      0.456
      0.190
      0.124
      0.369
      0.643

      11
      INR
      1.01± 0.05
      <0.001
      0.459
      0.209
      0.734
      0.349
      0.978
      0.560
      0.814
      0.204
      0.206
      0.983

      12
      WBC, 10∧9/L
      6.05 ± 1.06
      0.075
      0.472
      0.692
      0.167
      0.692
      0.580
      0.506
      0.150
      0.458
      0.675
      0.835

      13
      RBC1, 10∧9/L
      4.86 ± 0.62
      0.261
      0.069
      0.155
      0.174
      0.953
      0.420
      0.116
      0.014
      <0.001
      0.345
      0.353

      14
      MCH, pg
      29.30 ± 2.16
      0.698
      0.817
      0.768
      0.609
      0.493
      0.626
      0.394
      0.747
      0.449
      0.397
      0.921

      15
      PLT, 10∧9/L
      229.49 ± 47.84
      0.154
      0.483
      0.758
      0.923
      0.356
      0.937
      0.324
      0.751
      0.502
      0.269
      0.414

      16
      URIC, umol/L
      342.81 ± 76.14
      0.305
      0.004
      0.029
      0.996
      0.054
      0.529
      0.778
      0.121
      0.036
      0.198
      0.036

      17
      CREA, umol/L
      71.13 ± 13.97
      0.007
      0.064
      0.030
      0.009
      0.058
      0.960
      0.144
      0.055
      <0.001
      0.988
      0.326

      18
      ALT, U/L
      17.33 ± 9.86
      0.569
      0.312
      0.791
      0.011
      0.589
      0.414
      0.327
      0.003
      0.007
      0.794
      0.923

      19
      TP, g/L
      73.46 ± 5.01
      0.164
      0.985
      0.998
      0.975
      0.768
      0.682
      0.975
      0.312
      0.560
      0.558
      0.066

      20
      ALB, g/L
      46.01 ± 2.96
      0.205
      0.756
      0.457
      0.127
      0.427
      0.567
      0.835
      0.071
      0.407
      0.754
      0.004

      21
      DBIL, umol/L
      4.48 ± 0.92
      0.502
      0.806
      0.328
      0.168
      0.170
      0.136
      0.388
      0.286
      0.003
      0.576
      0.860

      22
      TBIL, umol/L
      15.80 ± 5.51
      0.004
      0.578
      0.386
      0.201
      0.500
      0.691
      0.975
      0.073
      0.018
      0.574
      0.590

      23
      Heart rate, bpm
      67.51 ± 9.31
      0.873
      0.302
      0.580
      0.304
      0.425
      0.008
      0.020
      0.491
      0.331
      0.365
      0.385

      24
      T interval, ms
      408.43 ± 25.45
      0.379
      0.226
      0.908
      0.368
      0.718
      0.046
      0.039
      0.378
      0.393
      0.660
      0.326

      25
      ADP, %
      68.18 ± 6.35
      /
      0.439
      0.724
      0.941
      0.829
      0.710
      0.950
      0.938
      0.350
      0.154
      0.038

      26
      ERYb
      6 (11.76%)
      /
      0.952
      0.339
      0.244
      0.492
      0.720
      0.731
      0.227
      0.698
      0.453
      0.576

      27
      RBC2
      –
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /

      28
      OB
      –
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /
      /

CAPTION: Baseline clinical characteristics and their effects on pharmacokinetics and the recovery of platelet function in 51 healthy subjects.
FOOTER: BMI, body mass index; FIB, fibrinogen; APTT, activated partial thromboplastin time; TT, thrombin time; PT-A, prothrombin activity; PT, prothrombin time; INR, international normalized ratio; WBC, white blood cell count; RBC1, red blood cell count; MCH, mean corpuscular hemoglobin; PLT, platelet count; URIC, uric acid; CREA, creatinine; ALT, alanine aminotransferase; TP, total protein; ALB, albumin; DBIL, direct bilirubin; TBIL, total bilirubin; ADP, RBC2, red blood cell in urine; ERY, erythrocyte; OB, stool occult blood test; C max, Peak concentration; T max, time of peak concentration; t1/2, elimination half-life; AUC, area of plasma concentration–time curve; RT50, time to 50% recovery of maximum drug effect; RECDAY, recover day to the baseline PA. All correlation analyses were undertaken using Spearman correlation coefficients except those variables marked a, b.aRepeated measures data ANOVA.bMann-Whitney U-test.†RT50 and RECDAY were successfully acquired in 47 subjects.The color values refer to the results with P < 0.05 that considered as significant.

R

B

C

L


T1/2 (plasma) (h)

Liver Microsomal Stability and in Vivo Pharmacokinetic Properties of Selected Compoundsa

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 	% of parent compound
remaining at 60 min vs <italic>T</italic> = 0 min

 	human liver microsomes
	mouse liver microsomes
	mouse in vivo pharmacokinetics properties

compd	1 μM	10 μM	1 μM	10 μM	route of
administration (dose, mg/kg)	<italic>C</italic>max (ng/mL)	AUClast (h·ng/mL)	<italic>T</italic>1/2 (plasma) (h)	<italic>B</italic>/<italic>P</italic>

<bold>5a</bold> (TG4-155)	0.1	10.6	0.2	4.8	iv (3)	2400 ± 350	749 ± 24	0.45	0.3

ip (3)	738 ± 207	457 ± 64	0.58

<bold>5c</bold> (TG7-98)	20.9	24.0	18.3	13.0	nd	ND	ND	ND	ND

<bold>5d</bold> (TG6-10-1)	2.3	39.9	2.0	23.1	ip (5)	115 ± 44	453 ± 49	1.6	1.8

po (10)	248 ± 61	475 ± 60	1.8	1.6

<bold>5g</bold> (TG7-74)	0.8	5.8	0	0.2	nd	ND	ND	ND	ND

<bold>5h</bold> (TG7-76)	12.4	18.6	0.2	0.1	nd	ND	ND	ND	ND

<bold>5j</bold> (TG7-186)	0.4	21.4	0.1	51.7	nd	ND	ND	ND	ND

<bold>6a</bold> (TG8-4)	16.2	43.8	1.7	8.7	ip (5)	1510 ± 142	1050 ± 58	1.49	<0.1

po (10)	128 ± 23	197 ± 26	1.44	<0.1

<bold>6c</bold> (TG8-21)	58.5	70.4	7.1	19.3	ND	ND	ND	ND	ND

aMale or female C57Bl/6 mice were used for in vivo pharmacokinetic study. Formulation used: 5% DMA, 50% PEG400, and 45% saline for compound 5a; 10% DMSO, 50% PEG400, 40% sterile water for 5d; and 2.5% DMA, 12.5% propylene glycol, and 85% phosphate-buffered saline (pH 7.4) for 6a. DMA = N,N-dimethylacetamide. Cmax is the maximum observed concentration that occurs at Tmax. T1/2 is the terminal half-life. AUC = area under the curve from time zero to the time of the last measurable observation (AUClast). B/P = brain to plasma ratio, calculated from drug concentrations in plasma and brain tissue at 1 and 2 h. ND = not determined.

T

p

l

a

s

m

a

h


AUC0–∞ (ng h/mL)

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

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

A

U

C

n

g

h

m

L


AZ13569724 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.

A

Z

C

m

a

x

n

g

m

L


Cmax (μg/mL)

C

m

a

x

μ

g

m

L


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.

A

U

C

D

o

s

e


AUC0-24h (ng*h/mL)

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

A

U

C

h

n

g

h

m

L


tmax (h)

Difference in pharmacokinetic parameters of sildenafil between the two combination therapies

Data are expressed as the median (interquartile range). S+B, coadministration of sildenafil with bosentan; S+A, coadministration of sildenafil with ambrisentan; tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; AUC0‐8, area under the plasma concentration‐time curve from 0 to 8 hours; CL/F, oral clearance.

t

m

a

x

h


Cmax (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

C

m

a

x

n

m

o

l

L


AUC0–∞ (μg ⋅ h/ml)

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

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

A

U

C

μ

g

h

m

l


Cmax (ng/mL)

C

m

a

x

n

g

m

L


inf

      0
      1
      2
      3

      0
      Parameters
      Population median CPT-11 plasma conc- profile
      CPT-11 experimental data
      Predictive error (%)

      1
      AUC_tEnd [μmol*min/l]
      1296.060000
      1504.960000
      13.88

      2
      Cmax μmol/l
      9.860000
      11.600000
      15

      3
      Tmax [h]
      1.500000
      1.560000
      3.846

      4
      Half life [h]
      29.210000
      inf
      __

CAPTION: Comparison of population median plasma profile and experimental plasma profile pharmacokinetics
FOOTER: []

i

n

f


Cmax (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.

C

m

a

x

n

g

m

L


Cl (L/h/kg)

Pharmacokinetic profile of NAT after intravenous administration in NZ rabbit.

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Parameters	Estimates

<italic>C</italic>0 (ng/mL)	537±322

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

<italic>t</italic>1/2 (h)	1.4±0.4

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

Cl (L/h/kg)	6.6±1.9

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

C

l

L

h

k

g


AUCinf

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

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

PK parameter	Geometric mean ratio

Point estimate	90% CI

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

AUCt
	0.999	0.892‐1.117

AUCinf
	0.995	0.891‐1.111

A

U

C

i

n

f


C max (μg/mL)

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

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

C

m

a

x

μ

g

m

L


CL/F (mL/min/kg)

Pharmacokinetic parameters for caffeine in five studied conditions – means and ranges.

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 	Mean values ± SD (range)

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

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

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

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

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

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

A: hot coffee 20 min; B: cold coffee 2 min; C: cold coffee 20 min; D: sugar-free energy drink 2 min; E: sugar-free energy drink 20 min.a -RM ANOVA p ≤ 0.05.b Values normalized by mg/kg dose of caffeine.

C

L

F

m

L

m

i

n

k

g


CL(L/h)

Mean administered doses (total mg) and mean (±SD) predicted values of Cmax (mg/L), AUC (mg*L/h), systemic CL (L/h) and fraction of dose excreted in urine (fe) for gadofosveset in simulated populations

*P < 0.05, **P < 0.01, ***P < 0.001 statistical significant differences with control group (healthy volunteers).

C

L

L

h


t1/2 (h)

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

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

t

h


AUCc(0-∞) (ng•h/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.

A

U

C

c

n

g

h

m

L


V ss (mL/kg)

V

s

s

m

L

k

g


k43 (1/h)

Final population PK model parameter estimates

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Population parameters	Interindividual variation (std. dev.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sex on km
	Covariate effect	0.15	0.05	31	0.001

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

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

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

Residual error terms

b_1	Proportional error selexipag	0.75	0.01	2

b_2	Proportional error ACT‐333679	0.49	0.01	2

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      0
      1
      2
      3
      4
      5
      6
      7
      8
      9

      0
      Unnamed: 0_level_0
      % of parent compound remaining at 60 min vs T = 0 min
      % of parent compound remaining at 60 min vs T = 0 min
      % of parent compound remaining at 60 min vs T = 0 min
      % of parent compound remaining at 60 min vs T = 0 min
      Unnamed: 5_level_0
      Unnamed: 6_level_0
      Unnamed: 7_level_0
      Unnamed: 8_level_0
      Unnamed: 9_level_0

      1
      Unnamed: 0_level_1
      human liver microsomes
      human liver microsomes
      mouse liver microsomes
      mouse liver microsomes
      mouse in vivo pharmacokinetics properties
      mouse in vivo pharmacokinetics properties
      mouse in vivo pharmacokinetics properties
      mouse in vivo pharmacokinetics properties
      mouse in vivo pharmacokinetics properties

      2
      compd
      1 μM
      10 μM
      1 μM
      10 μM
      route of administration (dose, mg/kg)
      Cmax (ng/mL)
      AUClast (h·ng/mL)
      T1/2 (plasma) (h)
      B/P

      3
      5a (TG4-155)
      0.100000
      10.600000
      0.200000
      4.800000
      iv (3)
      2400 ± 350
      749 ± 24
      0.45
      0.3

      4
      5a (TG4-155)
      0.100000
      10.600000
      0.200000
      4.800000
      ip (3)
      738 ± 207
      457 ± 64
      0.58
      nan

      5
      5c (TG7-98)
      20.900000
      24.000000
      18.300000
      13.000000
      nd
      ND
      ND
      ND
      ND

      6
      5d (TG6-10-1)
      2.300000
      39.900000
      2.000000
      23.100000
      ip (5)
      115 ± 44
      453 ± 49
      1.6
      1.8

      7
      5d (TG6-10-1)
      2.300000
      39.900000
      2.000000
      23.100000
      po (10)
      248 ± 61
      475 ± 60
      1.8
      1.6

      8
      5g (TG7-74)
      0.800000
      5.800000
      0.000000
      0.200000
      nd
      ND
      ND
      ND
      ND

      9
      5h (TG7-76)
      12.400000
      18.600000
      0.200000
      0.100000
      nd
      ND
      ND
      ND
      ND

      10
      5j (TG7-186)
      0.400000
      21.400000
      0.100000
      51.700000
      nd
      ND
      ND
      ND
      ND

      11
      6a (TG8-4)
      16.200000
      43.800000
      1.700000
      8.700000
      ip (5)
      1510 ± 142
      1050 ± 58
      1.49
      <0.1

      12
      6a (TG8-4)
      16.200000
      43.800000
      1.700000
      8.700000
      po (10)
      128 ± 23
      197 ± 26
      1.44
      <0.1

      13
      6c (TG8-21)
      58.500000
      70.400000
      7.100000
      19.300000
      ND
      ND
      ND
      ND
      ND

Liver Microsomal Stability and in Vivo Pharmacokinetic Properties of Selected Compoundsa

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Cmax (ng/mL)

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

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

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C ss,ave (µmol/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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Race (Black) on Vc/Fb

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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Mean Tmax—h (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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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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t1/2el (h)

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

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Parameter	Commercial capsule	Rectal hydrogel (F8)

Dose (mg/kg)	50	50

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

tmax (h)	1	4

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

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

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

MRT (h)	3.923 ± 0.24	9.512 ± 0.233

Relative bioavailability	–	357.93%

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CMAX (ng/mL/ mg dose)

A comparison of the artemether pharmacokinetic properties to literature values

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Tmax, h

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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t1/2 (h)

The ratio and the P-values of pharmacokinetic parameters of the fed vs. fasting study with the test drug from the same sponsor.

*Another fasting (study 3) vs. fasting (study 5) with drug from sponsor 2; # the Wilicoxon test was used to compare the Tmax between the fasting study and the fed study; e.g., the AUC0−t of R under fed conditions vs. AUC0−t of R under fasting conditions with drug from sponsor 1 from Table 3 is equal to 5483/3475 = 1.58.

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AUC0‐t, 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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Geometric mean Cmax(0–tlast) (se) (pg/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)]

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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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Cmax (ng/mL)

Doxorubicin and doxorubicinol pharmacokinetics (geometric mean+/−standard error)

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<bold>Doxorubicin</bold>

<bold>Doxorubicinol</bold>

<bold>With enalapril</bold>

<bold>Without enalapril</bold>

<bold>With enalapril</bold>

<bold>Without enalapril</bold>

Cmax (ng/mL)	88.79 ± 0.30	79.96 ± 5.16	27.81 ± 3.59	29.66 ± 4.68

AUC(0-∞) ng-hr/mL	1185.56 ± 44.64	1167.73 ± 45.26	1040 ± 80.6	1056.32 ± 92.03

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Cmax (nM)

Non-compartmental PK parameters of TAC TAb and ac-dmDNA31 following a single IV administration of TAC in mice infected with S. aureus.

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 	TAC Total Antibody
	Antibody-conjugated dmDNA31

PK Parameters	25 mg/kg	50 mg/kg	25 mg/kg	50 mg/kg

Cmax (nM)	3850	7640	5060	13100

AUC0-inf (day • nM)	29560	53720	12630	24390

Clearance (mL/day/kg)	5.78	6.37	26.6	27.5

Vss (mL/kg)	115	123	114	110

t1/2λz (day)	14.0	13.8	3.81	3.73

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Weight or volume (g or ml)

      0
      1
      2

      0
      Tissue
      Blood flow (ml/min)
      Weight or volume (g or ml)

      1
      Brain
      700
      1400

      2
      Muscle
      750
      35000

      3
      Kidneys
      1240
      310

      4
      Liver
      1450
      1800

      5
      Gut
      1100
      1650

      6
      Lungs
      5600
      1000

      7
      Remainder
      360
      24290

      8
      Arterial blood
      –
      1000

      9
      Venous blood
      –
      3550

CAPTION: Parameters for the PBPK model of LSF used for simulations of pharmacokinetics and tissue distribution of this compound in a 70-kg human subject (Brown et al. 1997; Davies and Morris 1993)
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Kd (nM)

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

K

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Vz (mL/kg)

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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C max (DN), μg/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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D

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m

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CL/F (L/h)

Summary statistics of midazolam plasma PK parameter values

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

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Cmax/ng/L

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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C max (ng/mL)

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

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

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

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

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

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

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

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

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

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

t


kmet (1/h)

Final population PK model parameter estimates

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m

e

t

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MAT (min)

Pharmacokinetic parameters for caffeine in five studied conditions – means and ranges.

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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tmax, 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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m

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h


AUC0.5–48 value for:

Skin distribution of the deoxycholate form of AmB and AmBisome in uninfected and L. major-infected mice after a single i.v. 1-mg/kg dosea

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Skin site	AUC0.5–48 value for:

DAmB
	LAmB

Uninfected	Infected	Uninfected	Infected

Rump (lesion site)	1,586 ± 495	6,035 ± 273	863 ± 365	5,270 ± 1,003

Back (control site)	1,269 ± 190	710 ± 194	573 ± 142	915 ± 312

Rump-to-back ratio	1.3	8.5	1.5	5.8

aAUC0.5–48 values are calculated from skin PK profiles shown in Fig. 1c, d, e, and f.

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l

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λ (min−1)

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

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

<inline-formula id="IEq5"><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
				\usepackage{amsmath}
				\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)

λ

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i

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C0 (ng/mL)

Pharmacokinetic profile of NAT after intravenous administration in NZ rabbit.

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Parameters	Estimates

<italic>C</italic>0 (ng/mL)	537±322

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

<italic>t</italic>1/2 (h)	1.4±0.4

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

Cl (L/h/kg)	6.6±1.9

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

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C max

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

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Parameter	Study

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

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

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

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

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

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

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

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

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

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

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

C

m

a

x


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

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

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

Cmin1
	20.7	24.1	53.6	27.5	−61.0

Cmax1
	71.2	18.9	178.0	25.2	−60.0

Cavg1
	32.4	18.3	85.7	22.0	−62.0

Cminss
	78.3	71.8	206.0	64.0	−62.0

Cmaxss
	152.0	44.7	393.0	39.6	−61.0

Cavgss
	101.0	58.1	268.0	52.3	−62.0

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

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t1/2 (h)

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

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

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

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

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

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

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

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

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

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

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

3.6	1	43.3	10.0	100

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

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

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

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

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h


T 1/2, h

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.

T

h


T > MIC (%)

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

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

T

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C


AUC(0–24h), µg⋅h/mL

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

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

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MTT (h)

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

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Parameter (unit)	Definition of parameter	Bootstrap

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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T

T

h


MRT (min)

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