Evaluating the utility of endogenous OCT2 and MATE1/2-K biomarkers for DDI assessment in early clinical settings.

With growing interest in a biomarker-based approach for drug-drug interaction (DDI) predictions, creatinine, N1-methylnicotinamide (NMN), and N1-methyladenosine (mA) have been identified as endogenous substrates of organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2-K, though clinical validation remains limited. This study builds on recent advancements by evaluating these biomarkers retrospectively using samples from a clinical pharmacology study that assessed DDI via renal cationic transporters between fedratinib (inhibitor) and metformin (substrate) in healthy participants. Fedratinib reduced renal clearance for all endogenous substrates, with mA (38 %) and NMN (36 %) showing reductions comparable to metformin (40 %), while creatinine exhibited slightly lower (29 %), likely reflecting its limited contribution to transporter-mediated renal tubular secretion. Simulations focused on mA due to its favorable characteristics over NMN, particularly its minimal diurnal and intra-participant variability, demonstrating that reliable DDI assessments can still be achieved despite sampling constraints typical in oncology settings. Collectively, our study supports the predictive capabilities of endogenous substrates as biomarkers for renal cation transporter inhibition, with mA in particular showing promise for early DDI assessments in the Phase 1 studies.