Physiologically-based pharmacokinetic modeling for investigating the effect of simeprevir on concomitant drugs and an endogenous biomarker of OATP1B.

ABSTRACT: The orally available anti-hepatitis C virus (HCV) drug simeprevir exhibits nonlinear pharmacokinetics at the clinical doses due to saturation of cytochrome P450 (CYP) 3A4 metabolism and organic anion transporting peptide (OATP) 1B mediated hepatic uptake. Additionally, simeprevir increases exposures of concomitant drugs by CYP3A4 and OATP1B inhibition. The objective of this study was to develop physiologically-based pharmacokinetic (PBPK) models that could describe drug-drug interactions (DDIs) of simeprevir with concomitant drugs via CYP3A4 and OATP1B inhibition, and also to capture the effects on coproporphyrin-I (CP-I), an endogenous biomarker of OATP1B. PBPK modeling estimated unbound simeprevir inhibitory constant (K_i ) of 2.89 μM against CYP3A4 in the DDI results between s

SUBMITTER: Nakayama S 

PROVIDER: S-EPMC10583237 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature