Endogenous Biomarkers to Evaluate Transporter-Mediated Drug-Drug Interactions: Current Evidence, Impact on Clinical Pharmacology Strategy, Remaining Gaps, and Future Directions.

Endogenous biomarkers have gained considerable attention as tools for assessing transporter-mediated drug-drug interactions (tDDIs). While plasma coproporphyrin I is considered a validated biomarker for assessing hepatic organic anion transporting polypeptide (OATP) 1B-mediated DDI risk, data supporting biomarkers for other major drug transporters, particularly renal transporters, remains limited. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) included endogenous biomarker-based assessments in its recent guidance, ICH M12, as an alternative approach for evaluating tDDIs, which is anticipated to broaden the use of this strategy in early clinical development. However, methodological gaps remain in biomarker measurement, including study design, biological matrix selection, and data analysis. Importantly, consensus is still needed on the most appropriate biomarkers for renal organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) transporters 1 and 2-K, such as creatinine, N1-methylnicotinamide, and N1-methyladenosine, given the influence of various extrinsic and intrinsic factors on their performance. This review aims to summarize the current state of clinical evidence for endogenous biomarkers of major hepatic and renal transporters, including study design considerations relevant to meaningful data interpretation. It also briefly summarizes reported Physiologically based pharmacokinetic (PBPK) models of these biomarkers, highlights key gaps in current understanding, and identifies future work needed to expand the application of a biomarker-based tDDI strategy.