Preclinical and Translational Sciences
Hiroyuki Kusuhara, PhD (he/him/his)
Professor
Graduate School of Pharmaceutical Sciences, the University of Tokyo
Tokyo, Japan
Yurong Lai, PhD (he/him/his)
Executive Director
Gilead Sciences, Inc.
Foster City, California
Drug transporters play important roles in tissue distribution and subsequent metabolism/excretion of drugs. They also serve as site for drug-drug interactions (DDI) that are accompanied with an increase in the systemic exposure of the substrate drugs and the risk of occurrence of adverse events. To avoid the DDI in clinical settings, quantitative evaluation of the transporter-mediated DDI is one of important issues in the clinical development. Recently, endogenous metabolites, such as coproporphyrin I, are emerging biomarkers for drug transporters in the liver and kidney, such as OATP1B, OAT1, OAT3, OCT2/MATE1/2-K for assessing the inhibition potency of drug transporter-mediated DDI risk of new drugs in clinical development. This presentation will introduce the clinical data we have collected using established transporter inhibitors in healthy volunteers (pyrimethamine for MATE1/2-K, and rifampicin and cyclosporin A for OATP1B) and performance of the endogenous metabolites as biomarker of the drug transporter-mediated DDI. Physiologically-based pharmacokinetic (PBPK) model analysis of the endogenous biomarker data is informative to gain an insight into the DDI mechanism, and translation of the biomarker data to the DDI with the transporter substrate drugs. Leverage of the endogenous biomarkers appropriate for DDI risk assessment has been referred to ICH-M12. The endogenous biomarkers are valuable to capture the risk in early phase of clinical drug development, and in patients including special populations who receive clinically relevant doses of test drugs.