Combining “Bottom-up” and “Top-down” methods to assess ethnic difference in clearance: bitopertin as an example

Sheng Feng, Jun Shi, Neil Parrott, Pei Hu, Cornelia Weber, Meret Martin-Facklam, Tomohisa Saito, Richard Peck

J. Shi is the correspondence author.

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Table 1. Summary of Input Parameters for Bitopertin PBPK Model in SimCYP.

Parameters / Bitopertin / Reference
Physicochemical properties
Molecular weight (g/mol) / 543.5
log P / 3.03 / Parrott et al [1]
Compound Type / Neutral / Parrott et al [1]
Blood/plasma ratio / 0.680 / Parrott et al [1]
Fraction unbound / 0.024 / Parrott et al [1]
Absorption
Absorption type / First-Order Absorption Model
fa (×10–4cm/s) / 0.9999 (3 mg), 0.9997 (6 mg), 0.9993 (12 mg), 0.9954 (24 mg), 0.9547 (50 mg), 0.8733 (80 mg), 0.7552 (120 mg), 0.6137 (180 mg), 0.5153 (240 mg) / Parrott et al [1].
ka (1/h) / 1.95 / The geometric mean of parameter estimates based on the individual concentration data in Caucasians
Lag time (h) / 0.456 / The geometric mean of parameter estimates based on the individual concentration data in Caucasians
Distribution
Distribution model / Full PBPK Model
Vss (L/kg) # / 2.85 / Parrott et al [1]
Elimination
Enzymes / CYP3A4
CLint (µL/min/pmol) / 0.410 / Retrograde calculation

fa: fraction available from dosage form, ka: first-order absorption rate constant, Vss: volume of distribution at steady state, #: the tissue distribution is based on Kps (Tissue: plasma partition coefficient) as measured in the rat [1], CLint: in vitro intrinsic clearance.


Table 2. Demographics of the 1000 simulated Caucasian, Chinese and Japanese healthy subjects.

Ethnicity / n / Male/Female / Age (years) / Weight (kg) / Height (cm) / BMI (kg/m2)# / BSA (m2)*
Caucasian / 1000 / 506/494 / 47
(20–70) / 76
(36–152) / 168
(146–202) / 26.8
(16.0–46.2) / 1.86
(1.26–2.76)
Chinese / 1000 / 506/494 / 37
(20–70) / 61
(41–96) / 165
(143–189) / 22.6
(16.4–32.2) / 1.67
(1.31–2.23)
Japanese / 1000 / 506/494 / 44
(20–70) / 59
(36–101) / 161
(137–187) / 22.9
(16.1–39.0) / 1.62
(1.22–2.24)

n: number of the subjects, Data are shown as geometric mean values Mean (range in brackets), #: BMI was calculated by weight (kg)/height2(m), *: BSA was calculated by Du Bois & Du Bois formula: BSA = weight (kg)0.425 × height (cm)0.725 × 0.007184.

REFERENCES

1.  Parrott N, Hainzl D, Alberati D, Hofmann C, Robson R, Boutouyrie B, Martin-Facklam M. Physiologically Based Pharmacokinetic Modeling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin. Clin Pharmacokinet. 2013; 52(8):673-83.