Quantitative Prediction of OATP-Mediated Drug-Drug Interactions With Model-Based Analysis of Endogenous Biomarker Kinetics

Quantitative prediction of the magnitude of transporter-mediated clinical drug-drug interactions (DDIs) solely from in vitro inhibition data remains challenging. The objective of the present work was to analyze the kinetic profile of an endogenous biomarker for organic anion-transporting polypeptides 1B (OATP1B), coproporphyrin I (CPI), and to predict clinical DDIs with a probe OATP1B substrate (pravastatin) based on "in vivo" inhibition constants (K-i). The CPI kinetics in the presence and absence of strong and weak OATP1B inhibitors (rifampin and GDC-0810) were described well with a one-compartment model, and in vivo K-i were estimated. Clinical DDIs between pravastatin and these inhibitors were predicted using physiologically based pharmacokinetic (PBPK) models coupled with the estimated in vivo K-i and predicted magnitude matched well with the observed DDIs. In conclusion, model-based analysis of the CPI profile has the potential to quantitatively predict liability of a new molecular entity (NME) as an OATP1B inhibitor early in drug development.