Presented by the Predictive Toxicology Discussion Group
Preclinical Drug–Drug Interaction: Risk Assessment and Toxicity
Posted December 03, 2013
Current work in preclinical drug discovery leads to thousands of new drug candidates each year. In addition to exploring the potential effectiveness of these candidate molecules, drug developers must ensure that the molecules are not likely to cause severe toxicities in humans before clinical testing can begin. However, preclinical drug evaluation does not always predict human toxicity, particularly when it comes to determining how drug candidates will interact with human drug metabolism pathways.
On October 21, 2013, experts in pharmacotoxicology met at a symposium titled Translation of Preclinical Drug–Drug Interaction and Metabolism Data into Risk Assessment of Clinical Toxicity to present and discuss research on new preclinical models, both in vitro and in animals, intended to allow for more effective evaluation of drug candidates. They are looking for new methods to recognize and understand potential drug–drug interactions and studying the effects of drugs on transporters and drug distribution in the body, the formation of reactive metabolites, and rare idiosyncratic drug reactions. Development of new preclinical methods in these areas will be critical to take full advantage of the surging number of drug-candidate molecules that are available. The symposium was presented by the Academy's Predictive Toxicology Discussion Group.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
Sean Hennessy, PharmD, PhD (University of Pennsylvania)
Philip Lazarus, PhD (Washington State University College of Pharmacy)
R. Scott Obach, PhD (Pfizer)
Ida S. Owens, PhD (National Institute of Child Health and Human Development, NIH)
A. David Rodrigues, PhD (Bristol-Myers Squibb)
Robert A. Roth, PhD (Michigan State University)
Jack Uetrecht, MD, PhD (University of Toronto, Canada)
Joseph A. Ware, PhD (Genentech)
The Predictive Toxicology Discussion Group is proudly supported by:
Mission Partner support for the Frontiers of Science program provided by
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Bushey RT, Lazarus P. Identification and functional characterization of a novel UDP-glucuronosyltransferase 2A1 splice variant: potential importance in tobacco-related cancer susceptibility. J Pharmacol Exp Ther. 2012;343:712-24.
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Chen G, Giambrone NE, Lazarus P. Glucuronidation of trans-3′-hydroxycotinine by UGT2B17 and UGT2B10. Pharmacogenet Genomics. 2012;22:183-90.
Erickson-Ridout KK, Sun D, Lazarus P. Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)(7)TAA and UGT1A4 L48V polymorphisms. Pharmacogenet Genomics. 2012;22:561-76.
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R. Scott Obach
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Dahal UP, Obach RS, Gilbert AM. Benchmarking in vitro covalent binding burden as a tool to assess potential toxicity caused by nonspecific covalent binding of covalent drugs. Chem Res Toxicol. 2013. [Epub ahead of print]
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Obach RS. Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacol Rev. 2013;65:578-640.
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Ida S. Owens
Banerjee R, Pennington MW, Garza A, et al. Mapping the UDP-glucuronic acid binding site in UDP-glucuronosyltransferase-1A10 by homology-based modeling: confirmation with biochemical evidence. Biochemistry. 2008;47:7385-92.
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Chakraborty SK, Basu NK, Jana S, et al. Protein kinase Cα and Src kinase support human prostate-distributed dihydrotestosterone-metabolizing UDP-glucuronosyltransferase 2B15 activity. J Biol Chem. 2012;287:24387-96.
Mitra PS, Basu NK, Basu M, et al. Regulated phosphorylation of a major UDP-glucuronosyltransferase isozyme by tyrosine kinases dictates endogenous substrate selection for detoxification. J Biol Chem. 2011;286:1639-48.
Mitra PS, Basu NK, Owens IS. Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer. Biochem Biophys Res Commun. 2009;382:651-6.
A. David Rodrigues
Rodrigues AD, Lai Y, Cvijic ME, et al. Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity: mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab Dispos. 2013. [Epub ahead of print]
Shen H, Yang Z, Mintier G, et al. Cynomolgus monkey as a potential model to assess drug interactions involving hepatic organic anion transporting polypeptides: in vitro, in vivo, and in vitro-to-in vivo extrapolation. J Pharmacol Exp Ther. 2013;344:673-85.
Shirasaka Y, Chang SY, Grubb MF, et al. Effect of CYP3A5 expression on the inhibition of CYP3A-catalyzed drug metabolism: impact on modeling CYP3A-mediated drug–drug interactions. Drug Metab Dispos. 2013;41:1566-74.
Tang H, Shen DR, Han YH, et al. Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research. J Biomol Screen. 2013;18:1072-83.
Zvyaga T, Chang SY, Chen C, et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012;40:1698-711.
Robert A. Roth
Beggs KM, Fullerton AM, Miyakawa K, et al. Molecular mechanisms of hepatocellular apoptosis induced by trovafloxacin-tumor necrosis factor-alpha interaction. Toxicol Sci. 2013. [Epub ahead of print]
Fullerton AM, Roth RA, Ganey PE. 2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury. Toxicol Appl Pharmacol. 2013;266:317-27.
Fullerton AM, Roth RA, Ganey PE. Pretreatment with TCDD exacerbates liver injury from concanavalin A: critical role for NK cells. Toxicol Sci. 2013. [Epub ahead of print]
Lu J, Jones AD, Harkema JR, et al. Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha. Toxicol Sci. 2012;125:126-33.
Lu J, Roth RA, Malle E, et al. Roles of the hemostatic system and neutrophils in liver injury from co-exposure to amiodarone and lipopolysaccharide. Toxicol Sci. 2013. [Epub ahead of print]
Roth RA, Ganey PE. Animal models of idiosyncratic drug-induced liver injury—current status. Crit Rev Toxicol. 2011;41:723-39.
Sharma AM, Klarskov K, Uetrecht J. Nevirapine bioactivation and covalent binding in the skin. Chem Res Toxicol. 2013;26:410-21.
Sharma AM, Novalen M, Tanino T, et al. 12-OH-nevirapine sulfate, formed in the skin, is responsible for nevirapine-induced skin rash. Chem Res Toxicol. 2013;26:817-27.
Sharma AM, Uetrecht J. Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions. Drug Metab Rev. 2013. [Epub ahead of print]
Uetrecht J, Naisbitt DJ. Idiosyncratic adverse drug reactions: current concepts. Pharmacol Rev. 2013;65:779-808.
Zhang X, Sharma AM, Uetrecht J. Identification of danger signals in nevirapine-induced skin rash. Chem Res Toxicol. 2013;26:1378-83.
Joseph A. Ware
Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther. 2012;92:203-13.
Pang J, Dalziel G, Dean B, et al. Pharmacokinetics and absorption of the anticancer agents dasatinib and GDC-0941 under various gastric conditions in dogs—reversing the effect of elevated gastric pH with betaine HCl. Mol Pharm. 2013. [Epub ahead of print]
Smelick GS, Heffron TP, Chu L, et al. Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm. 2013. [Epub ahead of print]
Ware JA, Dalziel G, Jin JY, et al. Impact of food and the proton pump inhibitor rabeprazole on the pharmacokinetics of GDC-0941 in healthy volunteers: bench to bedside investigation of pH-dependent solubility. Mol Pharm. 2013. [Epub ahead of print]
Yago MR, Frymoyer AR, Smelick GS, et al. Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria. Mol Pharm. 2013. [Epub ahead of print]
Websites and Reports
Abarca J, Malone DC, Armstrong EP, et al. Concordance of severity ratings provided in four drug interaction compendia. J Am Pharm Assoc (2003). 2004;44(2):136-41.
FDA Guidance for Industry
Portal to FDA guidance for industry on drug safety, preclinical drug testing, pharmacoepidemiology studies, and other topics related to pharmacotoxicology.
The Human Cytochrome P450 (CYP) Allele Nomenclature Database
Database of genetic variants in human cytochrome P450s.
International Society for Pharmacoepidemiology
Professional organization devoted to the exchange of scientific information in pharmacoepidemiology.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury
National Library of Medicine portal for information on drug-induced liver injuries.
The International Transporter Consortium: Membrane Transporters in Drug Development
Free full text article in Nature Reviews Drug Discovery.
Preventable Adverse Drug Reactions: A Focus on Drug Interactions
Learning module on drug metabolism and drug–drug interactions developed by the FDA.
UDP Glucuronosyltransferases at the HUGO Gene Nomenclature Committee website
Database of UGT isozymes with related database links.
Myrtle Davis, DVM, PhD
National Cancer Institute, NIH
Myrtle Davis holds a PhD in toxicology from the University of Illinois Urbana–Champaign and completed a postdoctoral fellowship in toxicologic pathology at the University of Maryland. She also holds a Doctor of Veterinary Medicine degree from Tuskegee University School of Veterinary Medicine. Davis is the branch chief for toxicology and pharmacology in the Developmental Therapeutics Program of the Division of Cancer Diagnostics and Treatment at the National Cancer Institute, NIH. Davis moved to the National Cancer Institute from Lilly Research Labs, Eli Lilly and Company, where she was a research advisor in the investigative toxicology group. Davis was also an associate professor in the Department of Pathology at the University of Maryland School of Medicine, where she had an active research program exploring the mechanisms of toxicant-induced apoptosis and the role of protein phosphorylation in that process.
Raymond A. Kemper, PhD
Raymond A. Kemper holds a PhD in toxicology from the University of Louisville. He completed postdoctoral training in the Department of Comparative Biosciences at the University of Wisconsin–Madison. In 1999, Kemper joined the biochemical toxicology group at DuPont Haskell Laboratory, where his work focused on comparative absorption, distribution, metabolism, and excretion (ADME) and investigative toxicology. In 2003, he joined the discovery toxicology group at DuPont and became involved in developing predictive models to support early ADME and toxicity screening. He later moved to Boehringer Ingelheim Pharmaceuticals and established an exploratory toxicology group within the nonclinical drug safety division to provide early toxicology support for small-molecule discovery programs. In 2011, Kemper joined the early and investigative safety section at Hoffman-La Roche as head of mechanistic safety for the U.S. This year, he moved to Merck Research Labs, joining the Discovery Sciences Support Section of the Safety Assessment Department.
Marla Weetall, PhD
Marla Weetall has worked in drug discovery and development at PTC Therapeutics since 2002. Before joining PTC, she worked at Novartis/Sandoz Pharmaceuticals. Her efforts have supported the identification and selection of eight compounds for development, of which four have moved into the clinic. Weetall and has co-organized 12 New York Academy of Sciences symposia for the Biochemical Pharmacology and the Predictive Toxicology discussion groups. Weetall holds a PhD in biophysical chemistry from Cornell University.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.
Andrea Gaedigk, PhD
Andrea Gaedigk holds MSc and PhD degrees in biology from the University of Stuttgart, Germany. She completed her doctoral studies at the Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Germany, and the Biocenter at the University of Basel, Switzerland. She trained as a postdoctoral fellow at the Hospital for Sick Children, Canada, where was later a research associate. In 1996, Gaedigk became associate director in the National Institute of Child Health and Human Development, NIH, Pediatric Pharmacology Research Unit Lab at Children's Mercy Hospital; she also joined the faculty at the University of Missouri–Kansas City (UMKC) School of Medicine. Gaedigk now directs the Pharmacogenetics Core Laboratory in the Division of Clinical Pharmacology and Therapeutic Innovation. She also holds an adjunct faculty position at the University of Kansas Medical Center. Gaedigk researches genes involved in the metabolism and disposition of clinically used drugs. She has characterized the genetic variation of cytochrome P450s in adult and pediatric populations and investigated the pharmacogenetics of CYP2D6 and the implementation of genotype data into clinical practice. As a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) she contributes to CYP2D6 gene/drug pair dosing guidelines.
Sean Hennessy, PharmD, PhD
Sean Hennessy is an associate professor of epidemiology and of pharmacology and the director of the Center for Pharmacoepidemiology Research and Training at the Perelman School of Medicine, University of Pennsylvania. His research focus is pharmacoepidemiology, the use of population research methods to study the effects of medications. He focuses on drug–drug interactions and comparative-effectiveness research. He is a past president of the International Society for Pharmacoepidemiology and a past chair of the Drug Safety Scientific Section of the American Society for Clinical Pharmacology and Therapeutics. He is an editor of Pharmacoepidemiology & Drug Safety, co-editor of the book Pharmacoepidemiology, 5th edition, and serves on the editorial board of Clinical Pharmacology and Therapeutics. He is the principal investigator of an NIH-funded study examining the clinical importance of drug–drug interactions and is the recipient of an NIH-funded training grant in pharmacoepidemiology. He helps to lead the FDA-funded Mini-Sentinel Initiative, leads a clinical program to improve outpatient medication use within the University of Pennsylvania Health System, and co-leads the university's global health partnership with Cayetano Heredia University, Peru.
Philip Lazarus, PhD
Philip Lazarus is the chair of the Department of Pharmaceutical Sciences at the College of Pharmacy at Washington State University. His research focuses on metabolism, gene–environment interactions, and pharmacogenetics. Specifically, he has taken a targeted pathway approach to establishing how environmental or drug exposures interact with genetic variation in relevant pathways to alter disease risk or patient response to an agent/drug. This research has spanned the spectrum of cancer causation, prevention, and treatment, focusing on: tobacco carcinogen metabolism and cancer susceptibility, nicotine metabolism and pharmacogenetics; the pharmacogenetics of chemotherapeutic agents, particularly focusing on agents used for the prevention and treatment of breast cancer; the pharmacogenetics of second-generation antipsychotics; and the regulation of metabolism by epigenetic pathways and differential splicing. Before joining Washington State University, Lazarus served as the associate director of the Division of Population Sciences and program leader of the Cancer Control and Molecular Epidemiology Program at the Pennsylvania State Cancer Institute and as the director for the Center for Pharmacogenetics at Pennsylvania State University.
R. Scott Obach, PhD
R. Scott Obach is a senior research fellow in the pharmacokinetics, dynamics, and drug metabolism department at Pfizer. He holds a PhD in biochemistry from Brandeis University and completed a postdoctoral fellowship at the New York State Department of Health Research Laboratories. Obach joined Pfizer as a research scientist in 1992. He currently serves on the editorial boards of Drug Metabolism and Disposition, Chemical Research in Toxicology, Drug Metabolism and Pharmacokinetics, and Xenobiotica. His research interests include the application of in vitro approaches to the study of drug metabolism, the prediction of human pharmacokinetics and drug interactions, and the mechanisms of cytochrome P450 catalysis. He also studies other biotransformation reactions, including the generation of chemically reactive metabolites.
Ida S. Owens, PhD
Ida S. Owens holds a PhD in biochemistry and physiology from Duke University. In 1975, as a member of the Laboratory of Developmental Pharmacology in the National Institute of Child Health and Human Development (NICHD), NIH, Owens initiated a research program investigating the UGT drug detoxifying system. The program is now recognized for its studies on the genetics of human diseases. She was the first to determine genetic defects in children with Crigler-Najjar diseases, thereby uncovering the unique 13-gene UGT1A complex locus, which has been subsequently studied for its relationship to population genetics and other UGT-based biochemical reactions. Her work has shown that UGT isozymes have the unique capacity to detoxify many chemicals derived from metabolism, diet, environmental contaminants, and medications. Her recent publications indicate that each isozyme has a non-fixed element (active-site) that is altered by classic but isozyme-specific phosphate signaling, enabling instant change and unlimited chemical detoxification. Owens is head of the Section on Genetic Disorders of Drug Metabolism in the Program on Developmental Endocrinology and Genetics at the NICHD. She received the NIH Director's Award in 1992 and was recently awarded the inaugural Distinguished Alumni Award from Duke University.
A. David Rodrigues, PhD
A. David Rodrigues is a senior research fellow in pharmaceutical candidate optimization at Bristol-Myers Squibb. He served as executive director of metabolism and pharmacokinetics before joining the research track. He previously worked at Merck, G. D. Searle, and Abbott. Rodrigues holds a PhD in biochemistry from the University of Surrey, UK, and completed postdoctoral training in the laboratory of Dr. Russell Prough at University of Louisville School of Medicine. He is interested in the application of in vitro drug metabolism techniques, animal models, integrative and translational PK-ADME science, problem solving, and the discovery and development of new chemical entities. He is an American Association of Pharmaceutical Scientists (AAPS) fellow and has served on the ISSX Scientific Affairs Committee, as well as on the editorial board of numerous drug metabolism journals. He is the associate editor of Xenobiotica and has served as editor/co-editor of four books, three related to drug interactions and one related to drug metabolism.
Robert A. Roth, PhD, DABT
Robert A. Roth holds a PhD in biochemical toxicology from Johns Hopkins University. After postdoctoral training at Yale University, he joined the faculty at Michigan State University, where he is currently a professor of pharmacology and toxicology. He is active in the Center for Integrative Toxicology at MSU, serving as director of the multidisciplinary graduate program in Environmental and Integrative Toxicological Sciences. Roth has served as chair of the Board of Publications and of the Awards Committee for the Society of Toxicology and as president of the Mechanisms and Food Safety Specialty sections. He has been associate editor of Toxicology and Applied Pharmacology and of the Journal of Pharmacology and Experimental Therapeutics. His research interests focus on the role of the hemostatic system in the progression of acetaminophen hepatotoxicity and on inflammatory stress as a determinant of susceptibility to drug-induced liver injury. He and his colleagues have been working to develop animal and cell-based models for idiosyncratic drug-induced liver injury, with the ultimate goal of understanding mechanisms and developing assays that can predict more effectively which drug candidates are likely to cause these adverse reactions.
Jack Uetrecht, MD, PhD
Jack Uetrecht is a professor of pharmacy and medicine and the Canada Research Chair in Adverse Drug Reactions at the University of Toronto. He received a PhD in organic chemistry from Cornell University and an MD from Ohio State University. He completed an internal medicine residency at the University of Kansas Medical Center and a clinical pharmacology fellowship at Vanderbilt University, subsequently joining the faculty as an assistant professor. He moved to the University of Toronto in 1985 and was awarded the Canada Research Chair in Adverse Drug Reactions in 2001. His research is focused on the mechanism of idiosyncratic drug reactions. He is on the editorial boards of the journals Chemical Research in Toxicology, Current Drug Metabolism, Drug Metabolism Reviews, Expert Opinion on Drug Metabolism and Toxicology, and Drug Metabolism Letters. He has chaired the Medical Research Council of the Canada Grants Committee for Pharmaceutical Sciences and chaired the Health Canada Scientific Advisory Panel for Hepatotoxicity. He has appeared before the FDA and the EMA on several occasions and he received the Janssen–Ortho Research Award in 2001.
Joseph A. Ware, PhD
Joseph A. Ware holds a holds a PhD in pharmaceutical sciences from Wayne State University and completed his postdoctoral training with Dr. Lance R. Pohl in the Molecular Toxicology Section at the National Heart, Lung and Blood Institute (NHLBI), NIH. He also studied renal transporters with Dr. Mark Knepper in the Laboratory of Kidney and Electrolyte Metabolism while at the NHLMI. Ware has subsequently worked for the Pharmacia and Upjohn Company and Pfizer and is now a senior scientist in clinical pharmacology at Genentech, where he is developing an integrated clinical pharmacology strategy to support oncology small-molecule candidate drug development and global registration. He has served as an adjunct professor at the University of Kansas and at the University of West Virginia and is currently a lecturer and contributor to the NIH Principles of Clinical Pharmacology course. Ware is an original member of the International Transport Consortia (ITC), which published Membrane Transporters in Drug Development in Nature Reviews Drug Discovery in 2010 to aid drug development in this rapidly evolving field. In collaboration with the Benet Lab at the University of California, San Francisco, Ware is investigating the impact of pH-dependent solubility on the absorption of anti-cancer drugs.
Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry, and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.