Comprehensive evaluation of the utility of 20 endogenous molecules as biomarkers of OATP1B inhibition compared to rosuvastatin and coproporphyrin I.

Endogenous biomarkers can be clinically relevant tools for the assessment of transporter function in vivo and corresponding drug-drug interactions (DDIs). The aim of this study was to perform systematic evaluation of plasma data obtained for 20 endogenous molecules in the same healthy subjects (n=8-12) in the absence and presence of OATP inhibitor rifampicin (600mg s.d.). The extent of rifampicin DDI magnitude (AUCR), estimated fraction transported (fT) and baseline variability were compared across the biomarkers and relative to rosuvastatin and coproporphyrin I (CPI). Out of 20 biomarkers investigated TDA, HDA, GCA GDCA, TDCA and CPIII showed high AUCRs (2.1 8.5) and fT (0.5 0.76), indicative of substantial OATP1B-mediated transport. A significant positive correlation was observed between the individual GDCA and TDCA AUCR and the magnitude of rosuvastatin-rifampicin interaction. CPI and CPIII AUCR were significantly correlated, but no clear trend was established with rosuvastatin AUCR. Moderate inter-individual variability (15-62%) in baseline exposure and AUCR were observed for TDA, HDA and CPIII. In contrast, bile acids demonstrated high inter-individual variability (69-113%) and significant decreases in baseline plasma concentrations during the first 4 hours. This comprehensive analysis in the same individuals confirms that none of the biomarkers supersede CPI in the evaluation of OATP1B-mediated DDI risk. Based on current dataset, combined monitoring of CPI and CPIII or CPI and fatty acids AUCR did not recover extent of rosuvastatin DDI. Monitoring of CPI and GDCA/TDCA may be beneficial for dual OATP1B-NTCP inhibitors with consideration of challenges associated with large inter- and intra-individual variability observed for bile acids.