Physiologically-based pharmacokinetic model-based translation of OATP1B-mediated drug-drug interactions from coproporphyrin I to probe drugs.

ABSTRACT: The accurate prediction of OATP1B-mediated drug-drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically-based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP-I) by CysA. In vivo K_i of unbound CysA for OATP1B (K_i,OATP1B ), and the overall intrinsic hepatic clearance per body weight of CP-I (CL_int,all,unit ) were optimized to account for the CP-I data (K_i,OATP1B , 0.536 ± 0.041 nM; CL_int,all

SUBMITTER: Mochizuki T 

PROVIDER: S-EPMC9199885 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature