Prediction of OCT2-MATE-mediated renal elimination by integrating endogenous biomarkers, extended clearance concepts, and PBPK modeling

Drug-drug interactions (DDIs) mediated by renal transporters such as OCT2 and MATE1/2K pose significant challenges in drug development and clinical pharmacology. Traditional approaches to assess DDI risk often rely on in vitro inhibition data and clinical studies using probe drugs. However, recent advances, including the use of endogenous biomarkers, extended clearance concepts, and physiologically based pharmacokinetic (PBPK) modeling, offer promising alternatives for early prediction and mechanistic understanding of transporter-mediated DDIs. Despite these advances, there remains a lack of consensus on how to incorporate substrate-dependent inhibition kinetics, pre-incubation effects, and biomarker variability into predictive frameworks. Moreover, the impact of renal impairment, particularly in chronic kidney disease (CKD), on transporter function and DDI risk assessment is not fully understood. This webinar addresses the urgent need for translational strategies that bridge in vitro findings with clinical relevance, especially in vulnerable populations. It will equip researchers, clinicians, and regulatory scientists with the latest insights and tools to improve DDI prediction and decision-making in drug development.

 Learning Objectives

By the end of this webinar, participants will be able to:

1. Explain the roles of OCT2 and MATE1/2K transporters in renal drug clearance and DDI mechanisms.
2. Describe the extended clearance concept and its application in PBPK modeling for transporter-mediated DDIs.
3. Evaluate the utility of endogenous biomarkers (e.g., N1-methylnicotinamide, N1-methyladenosine, creatinine) in assessing OCT2/MATEs inhibition in healthy volunteers and CKD patients.
4. Interpret substrate-dependent inhibition kinetics and pre-incubation effects in in vitro studies and their implications for in vivo DDI prediction.
5. Discuss the limitations of the intact nephron hypothesis when evaluating impact of renal impairment on transporter function and DDI risk assessment.
6. Apply current recommendations and identify knowledge gaps in the prediction of transporter-mediated DDIs for investigational drugs.