Genotype, Ethnicity, and Drug-Drug Interaction Modeling as Means of Verifying Transporter Biomarker PBPK Model: The Coproporphyrin-I Story.

Abstract

Coproporphyrin-I (CP-I) is a selective endogenous biomarker of organic anion-transporting polypeptide (OATP)1B. Multiple CP-I PBPK models with differing input parameters have been reported so far. This study proposed a harmonized CP-I PBPK model and evaluated its ability to predict the effect of ethnicity, SLCO1B1 genotype c.521T>C, and sex on CP-I baseline and CP-I-drug interactions using the largest clinical dataset to date. The CP-I PBPK model successfully predicted CP-I plasma baseline from 731 subjects, with 97% of predictions within 1.5-fold of the observed data. Prediction of weak, moderate, and strong OATP1B-mediated interactions with probenecid, low-dose cyclosporine, and rifampicin, respectively, was evaluated with 21 datasets. Overall, > 76% of CP-I C_maxR and AUCR were predicted within the Guest criterion. In vivo OATP1B K_i estimated by the biomarker model was up to ninefold lower compared to in vitro values. Sensitivity analyses showed differences in estimated in vivo K_i depending on the assumed contribution of non-inhibited/parallel pathway (renal) for CP-I (0%-15%), highlighting the need to consider this factor when using biomarker PBPK models for such purposes. Finally, the appropriate metric for monitoring CP-I was evaluated for inhibitors with different potency and PK relative to CP-I. In the case of strong/moderate OATP1B inhibitors with short t_1/2, C_maxR was the most sensitive metric for monitoring CP-I OATP1B interactions, whereas both C_maxR and AUCR were applicable for inhibitors with long t_1/2. The current study provides a harmonized CP-I PBPK model, together with recommendations to support the optimal design of prospective clinical trials for the assessment of OATP1B-mediated DDIs using this biomarker.