Physiologically-based pharmacokinetic modeling of coproporphyrin I, an endogenous OATP1B substrate, in cynomolgus monkeys: Bridging the inhibitory effect of rifampicin to humans.

Coproporphyrin I (CP-I), an endogenous substrate of OATP1B, is gaining attention as a biomarker for predicting drug-drug interactions (DDIs) mediated by hepatic organic anion transporting polypeptide 1B (OATP1B). Its application for bridging preclinical and clinical DDI predictions has been widely studied in cynomolgus monkeys. This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of CP-I in monkeys based on our human CP-I model. First, reported DDIs involving an OATP1B substrate pitavastatin and an OATP1B inhibitor rifampicin at several doses were simultaneously analyzed using PBPK coupled with a cluster Gauss-Newton method (CGNM), estimating the in vivo inhibition constant (Ki,u,OATP1B,PTV) in the cynomolgus monkeys. Considering substrate-dependent difference in Ki,u,OATP1B (CP-I vs. pitavastatin) examined in plated monkey hepatocytes, the in vivo Ki was converted to that for CP-I (Ki,u,OATP1B,CP-I). A middle-out approach enabled simultaneous fitting using plasma CP-I and rifampicin. The synthesis rate and hepatic overall intrinsic clearance of CP-I were found to be identifiable by the CGNM. Both parameters were several-fold higher in monkeys than in humans, suggesting the difference in the DDI sensitivity. In conclusion, this study demonstrates that the integrated PBPK-CGNM approach enables quantitative assessment of OATP1B-mediated DDIs in preclinical species while accounting for interspecies differences.