PT - JOURNAL ARTICLE AU - Asano, Daigo AU - Nakamura, Koichi AU - Nishiya, Yumi AU - Shiozawa, Hideyuki AU - Takakusa, Hideo AU - Shibayama, Takahiro AU - Inoue, Shin-ichi AU - Shinozuka, Tsuyoshi AU - Hamada, Takakazu AU - Yahara, Chizuko AU - Watanabe, Nobuaki AU - Yoshinari, Kouichi TI - Physiologically based pharmacokinetic modeling for quantitative prediction of exposure to a human disproportionate metabolite of the selective Na<sub>v</sub>1.7 inhibitor DS-1971a, a mixed substrate of cytochrome P450 and aldehyde oxidase, using chimeric mice with humanized liver AID - 10.1124/dmd.122.001000 DP - 2022 Jan 01 TA - Drug Metabolism and Disposition PG - DMD-AR-2022-001000 4099 - http://dmd.aspetjournals.org/content/early/2022/10/23/dmd.122.001000.short 4100 - http://dmd.aspetjournals.org/content/early/2022/10/23/dmd.122.001000.full AB - In a previous study on the human mass balance of DS-1971a, a selective NaV1.7 inhibitor, its CYP2C8-dependent metabolite M1 was identified as a human disproportionate metabolite. The present study assessed the usefulness of pharmacokinetic evaluation in chimeric mice grafted with human hepatocytes (PXB-mice) and physiologically based pharmacokinetic (PBPK) simulation of M1. After oral administration of radiolabeled DS-1971a, the most abundant metabolite in the plasma, urine, and feces of PXB-mice was M1, while those of control SCID mice were aldehyde oxidase-related metabolites including M4, suggesting a drastic difference in the metabolism between these mouse strains. From a qualitative perspective, the metabolite profile observed in PXB-mice was remarkably similar to that in humans, but the quantitative evaluation indicated that the area under the curve (AUC) ratio of M1 to DS-1971a (M1/P ratio) was approximately only half of that in humans. A PXB-mouse-derived PBPK model was then constructed to achieve a more accurate prediction, giving an M1/P ratio (1.3) closer to that in humans (1.6) than the observed value in PXB-mice (0.69). In addition, simulated maximum plasma concentration (Cmax) and AUC values of M1 (3429 ng/mL and 17,116 ng·h/mL, respectively) were similar to those in humans (3180 ng/mL and 18,400 ng·h/mL, respectively). These results suggest that PBPK modeling incorporating pharmacokinetic parameters obtained with PXB-mice is useful for quantitatively predicting exposure to human disproportionate metabolites. Significance Statement The quantitative prediction of human disproportionate metabolites remains challenging. We provided a successful case study on the practical estimation of exposure (Cmax and AUC) to DS-1971a and its CYP2C8-dependent, human disproportionate metabolite M1 by PBPK simulation utilizing pharmacokinetic parameters obtained from PXB-mice and in vitro kinetics in human liver fractions. This work adds to the growing knowledge regarding metabolite exposure estimation by static and dynamic models.