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
Thursday, February 29, 2024
10:00 am - 2:00 pm ET (US)
Session 2: Novel Tools to Improve Understanding of Modulation in Transporter Function in Specific Populations
Co-Chairs: Aleksandra Galetin, University of Manchester, Manchester, UK & Xinning Yang, US FDA, Silver Spring, Maryland, USA
10:00 am - 10:05 am | Welcome and Introductions
10:05 am - 10:45 am | Coproporhyrin I in Different Patient Populations – Implications on DDI Assessment
Manthena Varma, Pfizer, Groton, Connecticut, USA
Abstract: As molecular indicators of drug effect on target to quantitate pharmacodynamics or off-target effects to understand adverse events, endogenous biomarkers have played a significant role in the discovery and development of many successful drugs. The ability to predict pharmacokinetic changes due to drug-drug interactions (DDIs) is essential to minimize unexpected clinical study readouts and manage the associated adverse risks in drug development. The last decade has witnessed considerable efforts towards the identification, characterization, and validation of endogenous biomarkers to monitor transporter activity in human. On the other hand, levels of endogenous biomarkers are likely modulated in several disease states due to pathophysiological changes. This presentation will focus discussion on (i) the utility of coproporphyrin I (CP-I) as a biomarker to evaluate OATP1B-mediated DDIs, (ii) impact of disease states (hepatic impairment, chronic kidney disease, cancer, etc.) on the biomarker levels, and (iii) considerations to biomarker-informed DDI assessment in patient population in the process of drug development.
About the Speaker: Manthena Varma, PhD is Research Fellow, at Pfizer Inc. He received M.S. degree and PhD in Pharmaceutics, from the National Institute of Pharmaceutical Education and Research (NIPER, Punjab). Later, Dr. Varma worked as a Post Doctoral Fellow at the Department of Pharmaceutics, University of Minnesota (Minneapolis). His research is focused on the fields of ADME/PK technologies and strategies in drug discovery and development, role of drug transporters and transporter-enzyme interplay (extended clearance) in ADME/PK, clinical pharmacokinetics and DDI predictions/evaluation via mechanistic (PBPK) modeling. Varma supported preclinical and clinical development of several Pfizer compounds in the oncology and internal medicine therapeutic areas. Dr. Varma holds an Adjunct faculty position in the Department of Pharmacy of the University of Rhode Island. He published more than 140 original articles, reviews or book chapters.
10:45 am - 11:25 am | Endogenous Biomarkers for Renal Drug Transporters in Patients with Impaired Renal Function
Aleksandra Galetin, University of Manchester, Manchester, UK
Abstract: In recent years, endogenous biomarkers have been increasingly used as a clinically relevant tool for evaluation and de-risking of transporter-mediated drug-drug interactions in early drug development. In contrast, there has been far less evidence on the use of endogenous biomarkers to investigate changes in transporter function in specific patient populations (e.g., renal impairment). The presentation will illustrate the extension of mechanistic biomarker models to patients with impaired renal function using 4-pyridoxic acid and creatinine as examples. These examples will demonstrate the role of modelling to differentiate the effect of disease on biomarker synthesis and transporter activity. In addition, challenges to delineate the effect of disease and drug-mediated inhibition of transporters in this patient population will be discussed.
About the Speaker: Dr. Galetin is a Professor of Translational Pharmacokinetics in the School of Health Sciences, University of Manchester, UK and Deputy Director of the Centre for Applied Pharmacokinetic Research. She is currently President of ISSX, in addition to her service on the ISSX Council. Dr Galetin holds long-standing leadership position in the International Transporter Consortium (ITC) where she led multiple white papers defining best practices for the application of endogenous biomarkers and PBPK modelling of transporter-mediated drug-drug interactions among others topics. Dr Galetin did her sabbatical in the US FDA Office of Clinical Pharmacology where she provided expert advice on the PBPK modelling of drug-drug interactions and specific populations in new drug applications. She has published extensively and supervised/mentored over 40 graduate students and postdoctoral research associates (https://research.manchester.ac.uk/en/persons/aleksandra.galetin).
11:25 am - 11:50 am | Break
11:50 am - 12:45 pm | Lightening Talks (Selected from Abstracts)
Moderated by Eva Gil Berglund, Certara, Uppsala, Sweden, and Chitra Saran, Merck, West Point, Pennsylvania, USA
12:45 pm - 1:25 pm | Drug Transporters in Pediatrics: Ontogeny, Variability, and Clinical Significance
Bhagwat Prasad, Washington State University, Spokane, Washington, USA
Abstract: Pediatric pharmacotherapy presents unique challenges due to developmental changes in drug disposition pathways, including drug transporters. This presentation will provide recent updates on the ontogeny, variability, and clinical significance of drug transporters in the liver, intestine, and kidney during childhood. Hepatic drug transporters, such as organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), and multidrug resistance-associated proteins (MRPs), undergo dynamic changes during early life, influencing drug absorption, distribution, metabolism, and excretion. Intestinal transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), exhibit age-dependent expression patterns, affecting oral drug bioavailability and intestinal absorption. Additionally, renal transporters, including organic anion transporters (OATs) and organic cation transporters (OCTs), play pivotal roles in drug excretion and nephrotoxicity, with developmental variations impacting drug renal excretion and tissue concentration. Variability in transporter expression and activity among pediatric populations can also result from genetic polymorphisms, environmental factors, and underlying diseases, leading to complex interindividual differences in drug response and susceptibility to adverse effects. Understanding the ontogeny and variability of drug transporters is crucial for optimizing pediatric pharmacotherapy, dosing regimens, and therapeutic outcomes while minimizing the risk of toxicity. Tailored approaches integrating pharmacogenetics, physiological maturation, and clinical monitoring are essential for safe and effective drug administration in pediatric patients across different developmental stages. The presentation will highlight the need for further research elucidating the complex interplay between drug transporters, pediatric physiology, and drug therapy, which is warranted to advance precision medicine and improve healthcare outcomes in pediatric populations.
About the Speaker: Dr. Bhagwat Prasad is an Associate Professor of Pharmaceutical Sciences at WSU College of Pharamcy and Pharmaceutical Sciences. He leads several federal and industry-funded research programs on characterization of interindividual variability and in vitro to in vivo extrapolation (IVIVE) of drug transport and metabolism by utilizing quantitative proteomics and metabolomics. He serves as the director of proteomics-based research in non-cytochrome P450 enzymes (PRINCE), a consortium funded by multiple pharmaceutical companies. Prior to moving 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). Dr. Prasad has published 125 peer-reviewed articles and delivered over 100 invited talks at various conferences, peer institutes, and FDA. Dr. Prasad is an elected member of Washington State Academy of Sciences and a recipient of ISSX North American New Investigator Award and ASPET Early Career Faculty award. Dr. Prasad has also served as the Secretary of Drug Metabolism and Disposition Division of ASPET. Dr. Prasad is a senior editor of Pharmacology Research and Perspectives and a member of the editorial boards of Drug Metabolism and Disposition, Clinical Pharmacology and Therapeutics, and Trends in Analytical Chemistry. Dr. Prasad obtained his MS and Ph.D. in Pharmaceutical Sciences from NIPER, Mohali, India and postdoc from UW, Seattle, WA.
1:25 pm - 1:55 pm | Roundtable Discussion with Speakers
Moderated by Mitesh Patel, Novartis, Cambridge, Massachusetts, USA and Aleksandra Galetin, University of Manchester, Manchester, UK
1:55 pm - 2:00 pm | Session Closing Remarks
