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

In a previous study on the human mass balance of DS-1971a, a se-lective 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 chi-meric mice grafted with human hepatocytes (PXB-mice) and physio-logically based pharmacokinetic (PBPK) simulation of M1. After oral administration of radiolabeled DS-1971a, the most abundant metab-olite in the plasma, urine, and feces of PXB-mice was M1, while those of control SCID mice were aldehyde oxidase-related metabolites in-cluding M4, suggesting a drastic difference in the metabolism be-tween 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 plasma concentration-time 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 and AUC val-ues 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 pharma-cokinetic parameters obtained with PXB-mice is useful for quantita-tively predicting exposure to human disproportionate metabolites. SIGNIFICANCE STATEMENT The quantitative prediction of human disproportionate metabolites remains challenging. This paper reports on a successful case study on the practical estimation of exposure (Cmax and AUC) to DS-1971a and its CYP2C8-dependent, human disproportionate me-tabolite M1, by PBPK simulation utilizing pharmacokinetic parame-ters obtained from PXB-mice and in vitro kinetics in human liver fractions. This work adds to the growing knowledge regarding me-tabolite exposure estimation by static and dynamic models.

Automated summary

This study assessed the pharmacokinetics of the human disproportionate metabolite M1 in PXB-mice and showed that the metabolite profile in PXB-mice is remarkably similar to that in humans. Furthermore, the PBPK model incorporating parameters from PXB-mice provided a more accurate prediction of exposure to M1 compared to the observed value in PXB-mice. This study highlights the usefulness of PBPK modeling in predicting exposure to human disproportionate metabolites.