Small Molecule Metabolites in Drug Discovery and Development
An ISSX Virtual Workshop Event | March 1-3, 2023
Thursday, March 2, 2023
10:00 am - 2:00 pm ET (US)
Session 2
Chairs: Aaron Teitelbaum, Bingming Chen, Carley Heck, and Matthew Albertolle
10:00 am - 10:05 am | Welcome and Introduction
10:05 am - 10:45 am | The Human ADME Study: Comparison of Various Strategies and Technical Approaches
Chandra Prakash, Agios
Abstract: Human absorption, distribution, metabolism, and excretion (ADME) study (also referred to as mass balance or radiolabel study) is a key study in the Clinical Pharmacology package of new drug application. It is typically conducted by administration of a single dose of drug containing a radioactive nuclide at a metabolically stable position followed by collection of excreta and blood samples. Samples are analyzed for both total radioactivity and the profile of drug-related material in urine, feces, and plasma. The data gathered from this study provides a quantitative and comprehensive overall picture of the disposition of a drug, including excretion pattern and metabolite profiles in circulation and excreta and are highly informative for developing a cohesive strategy for clinical pharmacology studies, drug-drug interaction, organ impairment, monitoring of metabolite(s), and to obtain a waiver for the bioequivalence study. Recently, US Food and Drug Administration (FDA) issued a guidance describing the recommendations regarding clinical pharmacology considerations for conducting human radiolabeled mass balance studies of investigational drug. This presentation will describe the highlights of this regulatory guidance and various strategies and technical approaches for conducting the human radiolabeled ADME studies.
About the Speaker: Dr. Prakash is a Senior Research Fellow in Drug Metabolism, Pharmacokinetics and Clinical Pharmacology department at Agios, Cambridge, MA. He obtained his Ph.D. in synthetic organic chemistry. He held several academic appointments prior to joining the pharmaceutical industry He worked for sixteen years at Pfizer Global Research and Development, Groton, CT and six years at Biogen, Cambridge where he managed a metabolism group and served as a DMPK representative on discovery and development teams. He joined Agios in June 2015. For the last 30 years, Dr. Prakash has been involved in the drug metabolism and clinical pharmacology studies to support drug discovery, development and registration. His research is primarily focused on the development and utilization of novel approaches and techniques which include in vitro methods using human and animal hepatic cellular and subcellular systems, recombinant human drug metabolizing enzymes, sensitive analytical technologies and in silico computational models to assess the metabolism aspects of the new chemical entities. His research interests includes application of LC-MS and radio detection techniques, development of chemical model to mimic CYP metabolic activities, metabolic bioactivation, and reaction phenotyping of metabolizing enzymes to facilitate the discovery and development of new chemical entities as drug candidates. He has also expanded research efforts to develop label free tissue distribution of parent compounds and their metabolites and identification of biomarkers using MS imaging. He is the author of more than 265 manuscripts, book chapters, presentations and patents. He also coedited five volumes of Handbook of Metabolic Pathways of Xenobiotics. Dr. Prakash is a member of American Society of Pharmacology and Experimental Therapeutics, American Society of Clinical Pharmacology and Therapeutics, International Society for the Study of Xenobiotics and Asian Federation of Clinical Pharmacologist. He served as the editor-in-chief of the Journals “Current Drug Metabolism” and "Drug Metabolism Letters" (2000-2015) and editorial board member of Annals of Medicinal Chemistry and Research, Current Biotechnology and journal of Pharmaceutics. He served as the chair of ISSX publication committee and a member of ISSX financial committee.
10:45 am - 11:30 am | Accelerator Mass Spectrometry for the Support of Microtracer Studies @ Boehringer-Ingelheim, Technical Aspects of AMS' Deep Dive on How AMS Actually Works
Stefan Blech and Ralf Laux, Boehringer Ingelheim
Abstract: Accelerator Mass Spectrometry (AMS) in combination with a carbon dioxide gas inlet interface represents currently the most advanced technology for the quantitative analysis of trace amounts of 14C labelled compounds for biomedical applications. The technology in combination with microtracer trial designs for human ADME- and absolute bioavailability studies offers several advantages over the classical approaches, which were largely unchanged over the last decades.
This presentation attempts to cover a wide range including detailed basic technology principles, practical steps of implementation for full automated AMS analysis for routine industry use in bio applications, together with actual performance data. We additionally discuss strategies of implementation in Boehringer-Ingelheim’s drug development processes and the advantages when compared to established, classical approaches with respect to (1) redundant work packages and (2) shifting hADME studies to earlier times in drug development.
About Dr. Stefan Blech: Dr. Stefan Blech studied chemistry with a focus on organic and analytical chemistry at the University of Cologne, Germany, and graduated with a Ph.D. under the mentorship of Professor Dr. H. Budzikiewicz in the field of applied mass spectrometry and pharmacology. He began his industrial career in 1994 as analytical scientist and study director at A&M, Germany where he investigated the metabolism of pharmaceutical drugs and plant protecting agents. Subsequently, he joined the department of Pharmacokinetics and Drug Metabolism of Boehringer-Ingelheim in 1997 where he applied his expertise in analytical chemistry and drug metabolism to early drug discovery projects for drug candidate optimization and selection. Following that, Dr. Blech spent more than 11 years in pure drug metabolism, with a focus on ADME studies gaining expertise in BI’s therapeutic areas as DMPK and drug metabolism representative for R&D teams. Subsequently, after an internal move to BI’s quality assurance department, he rejoined DMPK as Director of the Bioanalysis Group of Boehringer-Ingelheim in 2014. He is based at BI’s R&D site of Boehringer-Ingelheim in Biberach, Germany. Stefan’s research interests include the area of drug metabolism and pharmacokinetics together with applied analytical science for the analysis of low-level compounds in complex biological matrix including microtracer studies and sophisticated targeted and untargeted mass spectrometry-based technologies especially for biomarker discovery. Stefan is author of several publications in the field of drug metabolism and analytical science.
About Dr. Ralf Laux: Ralf Laux completed his vocational training as chemical laboratory assistant at Boehringer-Ingelheim Pharma (previous Dr. Karl Thomae GmbH) in 1991. After various positions in labs of the Biopharmaceutical Department, he joined the Department of Pharmacokinetics and Drug Metabolism in 1995. Within the Bioanalysis Group his main task was to establish LCMS technology for fast quantification. After his shift to the Drug Metabolism Group in 1998, Ralf Laux applied his expertise in LC MS technology to support early drug discovery projects for drug candidate optimization and selection. Following four years of early PK-Profiling and structure elucidation work, he spent more than 11 years dedicated to drug metabolism, with a focus on ADME studies. Subsequently he took over the role as lab supervisor in 2013. In 2021 he joined again the Bioanalysis Group, this time as head of the newly founded AMS lab to build up the AMS function. He is based at BI’s R&D site of Boehringer-Ingelheim in Biberach, Germany. Ralf’s research interests include applied analytical science with a strong focus on mass spectrometry technology for the analysis of low level compounds as well as detection of 14C labelled compounds in biological matrices.
11:30 am - 11:45 am | Break
11:45 am - 12:30 pm | How to Deal with Metabolites from Human ADME: Part 1. MIST
Yuexia Liang, Merck
Abstract: Metabolite evaluation plays a critical role in drug development. There are several important considerations on drug metabolite assessment, such as metabolite in safety testing (MIST), contributions of pharmacologically active metabolites to efficacy, and metabolites associated with drug-drug interaction (DDI). This presentation summarizes regulatory guidance around MIST and human ADME study, as well as strategies on how to apply metabolite information from human ADME study for MIST evaluation to ensure patient safety. Three case studies are presented to illustrate the application of issue-driven approaches to support clinical trials and filings.
About the Speaker: Yuexia Liang is a principal scientist within Preclinical Development of Merck & Co.. She has been with Merck for more than 20 years and provided ADME supports for multiple programs from discovery through clinical development. In recent years, she has been working primarily on conducting mechanistic studies to address metabolism-related program issues, leading FIH/MIST metabolite profiling and assessment efforts and hADME studies. Yuexia received her M.S. degree in Physical Chemistry from University of Notre Dame.
12:30 pm - 1:15 pm | Assessing Metabolite Contribution to Target Activity and DDI
Sheila Peters, Boehringer Ingelheim
Abstract: Human ADME and mass balance studies help identify and quantify metabolites in plasma, urine and feces. The quantification of metabolites in plasma could trigger in vitro investigation to evaluate DDI potential of metabolites with significant plasma exposure and/or pharmacological activity. Active metabolites would need to be evaluated as victim of CYP enzymes/transporters to consider implications on overall drug activity and safety. The inclusion of metabolite data in predictive models could improve quantitative predictions of the overall risk for DDI resulting from parent and metabolite. If metabolites unique to human have been identified in ADME studies they require further evaluation of pharmacological activity and safety.
About the Speaker: Dr. Sheila Annie Peters has a PhD in Chemistry. She started her career in Pharma R&D in 1999, working at Cyprotex, UK. Later, she worked for AstraZeneca, Mölndal, where she used a generic whole-body PBPK model in MATLAB® to support several drug discovery and early development projects across different R&D sites with innovative approaches to identifying potential limitations to drug disposition. Sheila served as Head of Translational Quantitative Pharmacology group at Merck KGaA, Darmstadt for 6 years before taking her current position as Early Asset Lead at Boehringer Ingelheim. Sheila is the European Federation of Pharmaceutical Industries and Associations (EFPIA) Topic leader for the ICH M12 group focused on harmonizing drug-drug interaction (DDI) guidelines. She has participated in the writing of a white paper for the PBPK WG of IQ Consortium and contributed to discussions on PBPK at an EMA-organized meeting held in London. She has published several papers on PK, PBPK, human dose predictions, gut metabolism and DDI in high impact journals and authored a book on PBPK.
1:15 pm - 2:00 pm | Roundtable Discussion with Speakers
2:00 pm - 2:30 pm | Break
2:30 pm - 3:30 pm | Poster Session 1
