Elucidating Contributions of Drug Transporters/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by PBPK Modeling With a Cluster Gauss-Newton Method.

ABSTRACT: Grazoprevir (GZR), a direct-acting agent for hepatitis C virus, is recognized as a substrate for organic anion transporting polypeptide 1B (OATP1B), cytochrome P450 3A (CYP3A), and P-glycoprotein (P-gp). The objective of the present study was to elucidate the contribution of these molecules to the nonlinear pharmacokinetics of GZR using a physiologically based pharmacokinetic (PBPK) model. Utilizing plasma concentration-time profiles of GZR derived from reported dose-escalation (50-800 mg) clinical studies and cumulative excretion data, around 10 parameters, including Michaelis constants (K_m) for OATP1B, CYP3A, and P-gp, were estimated via a cluster Gauss-Newton method (CGNM). Parameter combinations that could reproduce the clinical data of GZR were obtained; however, discrepanc

SUBMITTER: Yoshikado T 

PROVIDER: S-EPMC12001266 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature