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:

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

Yuichi Sugiyama, Ph.D

Josai International University (JIU)

Yuichi Sugiyama has been serving as Special Professor Emeritus at Josai International University since April 1, 2021. He received his Ph.D. from the School of Pharmacy at the University of Tokyo in 1978. After retiring from the University of Tokyo in 2012, he continued his research as the head of the Sugiyama Laboratory at the RIKEN Innovation Center.

Dr. Sugiyama’s pioneering work in physiologically based pharmacokinetics has significantly advanced quantitative in vitro–in vivo extrapolation, particularly in developing predictive models for drug clearance and the extent of drug-drug interactions in humans. His research on membrane transporters—including their functional and kinetic characterization and the influence of genetic variations—has been fundamental to understanding their role in drug disposition.

He has received numerous prestigious awards, including the American Association of Pharmaceutical Scientists (AAPS) Award in 2003, the Host-Madsen Gold Medal from the International Pharmaceutical Federation (FIP) in 2009, the B.B. Brodie Award from the American Society for Pharmacology and Experimental Therapeutics (ASPET) in 2012, the R.T. Williams Distinguished Scientific Achievement Award from ISSX in 2013, the Rawls-Palmer Progress in Medicine Award from the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in 2014, and The Order of the Sacred Treasure, Gold Rays with Neck Ribbon from the Government of Japan in 2020.

In addition to his scientific contributions, Dr. Sugiyama has held key leadership roles, including Chair of the Board of Pharmaceutical Sciences (BPS) of FIP, and President of both the International Society for the Study of Xenobiotics (ISSX) and the Japanese Society for the Study of Xenobiotics (JSSX), where he has actively promoted global research in drug metabolism, disposition, and transporters.

Hiroyuki Kusuhara, Ph.D.

University of Tokyo

Hiroyuki Kusuhara received his BSc, MSc and PhD (Pharmaceutical Sciences) from the University of Tokyo (Japan). Hiroyuki started his carrier as an academic scientist in The University of Tokyo as Assistant Professor of Pharmaceutical Sciences (1998). He was promoted to Associate Professor (2004) and Professor (2012) of Graduate School of Pharmaceutical Sciences, The University of Tokyo. He is currently professor and chair of Laboratory of Molecular Pharmacokinetics at Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. Hiroyuki’s major research interests encompass interindividual variability in human drug disposition, specifically focusing on the identification of drug transporters involved in tissue distribution and clearance, pharmacokinetics, modeling and simulation, in vitro-in vivo extrapolation, and drug-drug interactions, including biomarker studies. Currently, he is also investigating the mechanisms underlying drug-induced gut toxicity using intestinal crypt-derived cells. He is the author of 276 research papers in these areas.

Hiroyuki has experience as Council and Director in Japanese societies; JSSX Council (2004-present), Director (2014-2017, 2021-2022), Vice-president (2023-present, President-elect); APSTJ Council (2010-present), Director (2017-2018), Vice-president (2021-2023), President (2024-present). Editorial Board membership: Drug Metabolism & Disposition; Biopharmaceutics and Drug Disposition. Society membership: ISSX, AAPS, ASPET and Japanese Societies; JSCPT, APSTJ, JPS, JSDDS. International Society: ISSX since 2013 Scientific Affairs Committee (2014-2016), and Nominations Committee (2014-2016, 2021-present).

Bhagwat Prasad (Moderator)

Cincinnati Children's Hospital Medical Center

Dr. Bhagwat Prasad serves as Division Director of Translational and Clinical Pharmacology Cincinnati Children's and Professor of Pediatrics at the University of Cincinnati. Previously, Dr. Prasad was an Associate Professor in the Department of Pharmaceutical Sciences, Washington State University (WSU) in Spokane, WA. Prior to WSU, Dr. Prasad was an assistant professor at the University of Washington (UW) Seattle and was affiliated with the UW research affiliate program on transporters (UWRAPT) as a co-director. Dr. Prasad has published 75 peer-reviewed articles and 100 conference abstracts and delivered over 60 invited talks at various conferences such as ASPET (EB), ISSX, and ACCP. Dr. Prasad is the recipient of 2018 ISSX North American New Investigator Award. Dr. Prasad's work was selected for the Early Career Faculty Showcase at the 2018 ASPET meeting. Dr. Prasad also serves as a Secretary of the Drug Metabolism and Disposition Division of ASPET. He co-organized 2018 ISSX workshop on quantitative proteomics and was a member of organizing committee for the 12th international ISSX meeting, 2019 held in Portland, OR. Dr. Prasad is a member of editorial board of Drug Metabolism and Disposition. Dr. Prasad obtained his MS in 2006 and Ph.D. in 2010 in Pharmaceutical Sciences from NIPER, Mohali, India and he was a postdoc in the UW Seattle from 2011-2014.

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

11/21/2025 at 10:00 AM (EST) | 60 minutes

11/21/2025 at 10:00 AM (EST) | 60 minutes 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.