Quantitative prediction of OATP1B-mediated drug-drug interactions using endogenous biomarker coproporphyrin I

Abstract

Evaluation of the organic anion transporting polypeptide (OATP) 1B-mediated drug-drug interaction (DDI) potential is important for drug development. The focus of this study was coproporphyrin I (CP-I), an endogenous OATP1B biomarker.We investigated a new approach to OATP1B-mediated DDI prediction based on the mechanistic static pharmacokinetics (MSPK) model.The ratio of the area under the plasma concentration-time curve (AUCR) with and without co-administration of rifampicin (a typical OATP1B inhibitor) was found for CP-I and OATP1B substrate, respectively, and was then used to derive the correlation curve equation. The AUCR with and without co-administration of another OATP1B inhibitor than rifampicin was then predicted for the OATP1B substrates by substituting the AUCR of CP-I in the correlation curve equation to verify the predictability of the AUCR of the OATP1B substrates.The derived correlation curve equation between CP-I and the OATP1B substrates of the AUCRs with and without co-administration of rifampicin matched the observed AUCRs well. Regarding pitavastatin, rosuvastatin, and pravastatin, 92.9% of the predicted AUCR values were within a two-fold range of the observed values, indicating that this approach may be a good way to quantitatively predict DDI potential.

Keywords: Coproporphyrin I; OATP1B; biomarker; drug–drug interaction; endogenous substrate; prediction.