Physiologically based pharmacokinetic modeling for quantitative prediction of exposure to a human disproportionate metabolite of the selective Nav1.7 inhibitor DS-1971a, a mixed substrate of cytochrome P450 and aldehyde oxidase, using chimeric mice with humanized liver

Daigo Asano; Koichi Nakamura; Yumi Nishiya; Hideyuki Shiozawa; Hideo Takakusa; Takahiro Shibayama; Shin-ichi Inoue; Tsuyoshi Shinozuka; Takakazu Hamada; Chizuko Yahara; Nobuaki Watanabe; Kouichi Yoshinari

doi:10.1124/dmd.122.001000

Article Figures & Data

Additional Files

Data Supplement

Supplemental Data -
Supplementary Table S1. Plasma PK parameters of DS-1971a and its metabolites in SCID mice and PXB-mice after oral administration of DS-1971a at 10 mg/kg in the fasted condition.

Supplementary Table S2. Plasma PK parameters of DS-1971a and M1 after intravenous and/or oral administration of DS-1971a or M1 to SCID mice and/or PXB-mice in the fasted condition.

Supplementary Table S3. Observed PBPK parameters of DS-1971a and M1 in PXB-mice.

Supplementary Table S4. Inputted parameters in the PBPK model for PXB-mice.

Supplementary Table S5. Observed and PBPK model-simulated plasma PK parameters for PXB-mice after oral administration of DS-1971a at 10 mg/kg in the fasted condition.

Supplementary Fig. S1. Time-dependent changes in the plasma concentrations of DS-1971a and its metabolites in the plasma obtained from SCID mice (A and B) and PXB-mice (C and D) after oral administration of DS-1971a at 10 mg/kg in the fasted condition.

Supplementary Fig. S2. Simulated plasma PK profiles of DS-1971a (A and B) and M1 (C and D) in PXB-mice after oral administration of DS-1971a at 10 mg/kg in the fasted condition using the dynamic PBPK model.

Supplementary Fig. S3. Radiochromatograms of metabolites in (A) PXB cells incubated with DS-1971a at 1 μM and (B) the liver from PXB-mice after oral administration of DS-1971a at 10 mg/kg in the fasted condition.

Supplementary Fig. S4. The simulated plasma PK profiles of DS-1971a (A) and M1 (B) in humans with the optimized ka1, ka2, and kt values after oral administration of DS-1971a at 400 mg in the fed condition using the dynamic PBPK model.