PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3.

Abstract

The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP‐I), a biomarker supporting the prediction of drug‐drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B), using clinical DDI data with an OATP1B inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (K i,u,OATP1Bs) and multidrug resistance‐associated protein two‐mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively, from previous reports. Sensitivity analysis demonstrated that the K i,u,OATP1Bs and biosynthesis rate of CP‐I affected the magnitude of the interaction. K i,u,OATP1Bs values optimized by nonlinear least‐squares fitting were ~0.5‐fold of the initial value. It was determined that the blood concentration‐time profiles of four statins were well‐predicted using corrected individual K i,u,OATP1B values (ratio of in vitro K i,u(statin)/in vitro K i,u(CP‐I)). In conclusion, PBPK modeling of CP‐I supports dynamic prediction of OATP1B‐mediated DDIs.