Bringing Practical Applications of Endogenous Biomarkers for Drug Transporters a Step Closer: Current Status and Future Perspectives
An ISSX Virtual Workshop Event | February 28 - March 1, 2024
Wednesday, February 28, 2024
10:00 am - 2:00 pm ET (US)
Session 1: Application of Transporter Biomarker Studies in Drug Development: Study Design, Case Studies, and Regulatory Perspectives
Co-Chairs: Xiaoyan Chu, Merck, Rahway, New Jersey, USA & Hong Shen, Bristol Myers Squibb, Princeton, New Jersey, USA
10:00 am - 10:15 am | Welcome and Overview on Transporter Biomarkers
10:15 am - 10:45 am | Practical Consideration on Designing Clinical Studies to Incorporate Endogenous Biomarkers to Evaluate Transporter DDI and Drive the Decision Making
Kenta Yoshida, Genentech, South San Francisco, USA
Abstract: This presentation will focus on the practical considerations on utilizing endogenous biomarkers in clinical drug development for transporter DDI evaluations. We will discuss kinetic properties of available transporters and their implications on the application of biomarkers in different types of clinical studies, such as ascending dose studies or dedicated clinical pharmacology studies, as well as sample/data collection strategies. The discussion extends to the selection of appropriate exposure metrics along with recommended decision criteria for concomitant medications. We will also discuss utility of model-based approaches that enhance interpretation of clinical observations.
About the Speaker: Kenta Yoshida is a Distinguished Scientist in Modeling & Simulation group of Clinical Pharmacology, Genentech Research and Early Development. His main responsibility is application of pharmacometric models to support development of new medicine across multiple therapeutic areas such as oncology and ophthalmology.
He received his Ph.D. in Pharmaceutical Sciences from the University of Tokyo in 2014, and worked as a postdoctoral researcher at the FDA Office of Clinical Pharmacology prior to joining Genentech in 2016. His expertise and areas of interest include: membrane transporters, drug-drug interactions, PK in special populations, PBPK, population PK/PD, TMDD, survival/time-to-event analysis, longitudinal tumor modeling, and R package development.
10:45 am - 11:25 am | Update from IQ OATP1B Biomarker Working Group
Bridget L. Morse, Eli Lilly, Indianapolis, Indiana, USA
Abstract: Drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptides 1B1/1B3 (OATP1B) can be substantial, however, challenges remain for predicting interaction risk. Emerging evidence suggests that endogenous biomarkers, particularly coproporphyrin-I (CP-I), can be used to assess in vivo OATP1B activity. A knowledge gap remains, however, in the defined magnitude of change in CP-I warranting further in vivo DDI risk assessment. The OATP1B Biomarkers Working Group formed under the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) was aimed primarily at assessing CP-I as a biomarker for informing OATP1B DDI risk, through the following:
Compiling available OATP1B biomarker data, clinical OATP1B DDI data, and in vitro data against enzymes and transporters relevant for the disposition of clinical OATP1B substrates
Using these data to address OATP1B contribution to observed OATP1B substrate DDIs
Evaluating the use of CP-I for refining risk of clinically relevant OATP1B-mediated DDIs
Identifying changes in CP-I exposure associated with OATP1B-mediated DDIs that may be used to prioritize, delay or replace clinical DDI studies
Assessing the relationship between change in CP-I exposure, as a selective OATP1B substrate, and current static models
Providing recommendations for the collection and interpretation of CP-I in clinical studies, including a decision tree for guiding DDI risk assessment
This presentation will cover the body of work above, leading to the conclusion that clinical measurement of CP-I is recommended to inform OATP1B inhibition potential during drug development.
About the Speaker: Dr. Bridget Morse is currently Senior Director in PK/PD and scientific lead of Quantitative Clinical Pharmacology at Lilly Research Laboratories. She received her Pharm.D. from Butler University and her Ph.D. in Pharmaceutical Sciences from the University at Buffalo. Bridget has served in the pharmaceutical industry for 10 years as a subject matter expert in pharmacokinetics, transporters, clinical pharmacology and drug-drug interactions, particularly in the use of pharmacokinetic modeling for substrates of hepatic transporters. She chaired the IQ OATP1B Biomarker Working Group from 2020-2023 and is current Chair of the AAPS Drug Transporter Community. She serves as a peer reviewer for multiple publications and sits on the Editorial Advisory Board for the AAPS Journal. She has over 30 published journal articles and book chapters.
11:25 am - 11:40 am | Break
11:40 am - 12:45 pm | Case Studies: Applying Transporter Biomarker Data to Support Mechanistic Understanding of DDIs and Drive DDI Strategy and Decision-Making in Drug Development: 4 Short Presentations
Dr. Fenglei Huang, "Utilizing Endogenous Biomarkers to Streamline Assessment of Transporter-Mediated Drug-Drug Interactions: Case Studies"
About the Speaker: Fenglei Huang, PhD. FCP, is the Director and Team Lead of Clinical Pharmacology at Boehringer Ingelheim, where he also chairs the Drug-Drug Interaction Expert Group. With a Ph.D. in Pharmaceutical Science from the University of Florida, he is an elected fellow of the American College of Clinical Pharmacology (ACCP). He has made notable contributions to the field, co-authoring over 40 peer-reviewed scientific articles, and presenting at over 60 national and international conferences.
Dr. Xiaoxing Wang, “Evaluation of the Impact of Ritlecitinib on Organic Cation Transporters Using Sumatriptan and Biomarkers as Probes”
About the Speaker: Xiaoxing Wang obtained a PhD in Pharmaceutical Sciences, and a M.A in Statistics, both at the University of Michigan, in 2017. She did post-doctoral training in Pharmacometrics at A2PG in Ann Arbor, prior to joining the Clinical Pharmacology department at Pfizer in January 2018. At Pfizer, Xiaoxing has worked extensively across the I&I portfolio, contributing to the achievement of significant milestones, including major regulatory approvals and submissions.
Dr. Mikko Niemi, “Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin”
About the Speaker: Mikko Niemi, MD, PhD, is Professor of Pharmacogenetics at the University of Helsinki and Head Physician of research & development in genetics and clinical pharmacology at HUS Diagnostic Center, Helsinki University Hospital, Finland. Since 2019, he has lead the Individualized Drug Therapy Research Program at the University of Helsinki. Dr. Niemi obtained his MD degree in 2000, PhD degree in Clinical Pharmacology in 2002, and Medical Specialist degree in Clinical Pharmacology and Pharmacotherapy in 2010 from the University of Helsinki. His main research areas include the pharmacogenetic determinants of pharmacokinetics and drug response, implementation of pharmacogenetic testing, as well as the role of membrane transporters in pharmacokinetics and drug interactions. He has published more than 160 original articles and 20 review articles, which have been highly cited resulting in an h-index of 61 (Web of Science). He has received several awards for his contributions in pharmacogenetics, including the Anders Jahre prize for young scientists from the University of Oslo and the Leon I. Goldberg Young Investigator award from the American Society for Clinical Pharmacology and Therapeutics. Altogether, he has received more than 7.5 million euros of research funding, including the highly competitive European Research Council Starting and Consolidator Grants.
Dr. Tomoki Koishikawa, “Pharmacokinetic Drug-drug Interaction Study Using Cimetidine and Dolutegravir to Elucidate Predictive Performance of the Endogenous Biomarkers for OCT2 and MATEs in Healthy Volunteers”
About the Speaker: A graduate student of school of Pharmaceutical Sciences ,the University of Tokyo.
12:45 pm - 1:15 pm | Regulatory Perspectives on Transporter Biomarkers
Xinning Yang, US FDA, Silver Spring, Maryland, USA
Abstract: There is great interest in utilizing endogenous biomarkers to evaluate the activities of drug transporters in vivo. Extensive research has been conducted by academia and industry to identify appropriate biomarkers for various transporters. There has been effort incorporating measurement of certain biomarkers into drug development programs for assessing the drug-drug interaction (DDI) liability of investigational drugs as inhibitors of transporters. This presentation will share the regulatory perspective on the utility of biomarkers to facilitate DDI evaluation.
About the Speaker: Dr. Xinning Yang is a Policy Lead in Guidance & Policy team (GPT) under the Office of Clinical Pharmacology (OCP), CDER of FDA. He was graduated from the Dept. Pharmaceutical Sciences of State University of New York at Buffalo (SUNY-Buffalo), mentored by Dr. Marilyn Morris. He is the Chair of Transporter Focus Group of International Society of Studying Xenobiotics (ISSX), a committee member of the Regulatory Affairs of ISSX, Co-vice chair of the Membrane Transporter (MT) community of the American Society of Clinical Pharmacology and Therapeutics (ASCPT), a committee member of the PBPK community of ASCPT, and a member of International Transporter Consortium (ITC) committee. He is participating in the International Council Harmonization (ICH) M12 DDI guidance global harmonization working group and serves as the Deputy Topic Lead from FDA.
1:15 pm - 1:55 pm | Roundtable Discussion with Speakers and Dr. Ryota Kikuchi (AbbVie)
Moderated by Xiaoyan Chu, Merck, Rahway, New Jersey, USA and Hong Shen, Bristol Myers Squibb, Princeton, New Jersey, USA
1:55 pm - 2:00 pm | Session Closing Remarks
