despite the extensive time and resources spent in preclinical evaluation, 9 out of 10 candidates selected for clinical trial fail due to a host of factors, with the major ones being unexpected toxicity and/or lack of efficacy. Furthermore, numerous marketed drugs have been withdrawn or have their use limited due to severe, often idiosyncratic, adverse drug toxicity.
This book is intended to present information to overcome this challenge. Failure of preclinical studies to predict human safety and efficacy can be attributed to species differences in drug properties. The inability of clinical trials to eliminate drugs with idiosyncratic drug toxicity is likely due to the inadequate number of subjects employed in regulatory clinical trials to identify drugs causing severe idiosyncratic drug toxicity with an incidence of <1/5000. It is, therefore, of utmost importance to fully understand the key determinants of drug toxicity and apply the knowledge to identify drug candidates with human toxicity as well as to identify the at‐risk human populations.
In this book, drug metabolism enzymes, uptake transporters, and efflux transporters are identified as key contributors of drug toxicity. Species differences in these key parameters result in the failure in the selection of drug candidates with the appropriate properties based on results of preclinical trials, resulting in clinical trial failure. Individuals may succumb to life‐threatening toxicity of marketed drugs due to the chance co‐occurrence of genetic and/or environmental risk factors which may exacerbate drug toxicity. Identification of drug candidates with toxicity exacerbated by known genetic and environmental risk factors must be an approach to be considered in drug development and management of drug administration, hopefully leading to the ultimate elimination of idiosyncratic drug toxicity.
I am grateful to the expert chapter authors who, as a result of their painstaking research, have provided significant progress toward the understanding of the contribution of drug metabolism and transport in drug toxicity.
Albert P. Li, Ph.D.
Columbia, MD
List of Contributors
Michael Arand Institute of Pharmacology and Toxicology University of Zürich Zürich Switzerland
Kristin Ashby Division of Bioinformatics and Biostatistics National Center for Toxicological Research U.S. Food and Drug Administration Jefferson AR USA
Kim L.R. Brouwer Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill NC USA
Gian Camenisch ADME Department of PK Sciences Translational Medicine Novartis Institutes for Bio Medical Research Basel Switzerland
Minjun Chen Division of Bioinformatics and Biostatistics National Center for Toxicological Research U.S. Food and Drug Administration Jefferson AR USA
Ann K. Daly Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne UK
Mark P. Grillo Myo Kardia, Inc.Brisbane CA USA
Paavo Honkakoski Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill NC USA
School of Pharmacy Faculty of Health Sciences University of Eastern Finland Kuopio Finland
Tao Hu Department of Pharmaceutical Sciences University of Maryland School of Pharmacy Baltimore MD USA
Felix Huth ADME Department of PK Sciences Translational Medicine Novartis Institutes for Bio Medical Research Basel Switzerland
Vlasia Kastrinou‐Lampou ADME Department of PK Sciences Translational Medicine Novartis Institutes for Bio Medical Research Basel Switzerland
Institute of Pharmacology and Toxicology University of Zürich Zürich Switzerland
Stefanie Kennon‐Mc Gill Department of Environmental and Occupational Health Fay W. Boozman College of Public Health University of Arkansas for Medical Sciences Little Rock AR USA
Gerd A. Kullak‐Ublick Department of Clinical Pharmacology and Toxicology University Hospital Zürich University of Zurich Zürich Switzerland
Mechanistic Safety CMO & Patient Safety Global Drug Development Novartis Basel Switzerland
Albert P. Li In vitro ADMET Laboratories, Inc. Columbia MD USA
Stacey Line Department of Pharmacology and Therapeutics University of Manitoba Winnipeg MBCanada
Chuang Lu Sanofi USWaltham MA USA
Kazuya Maeda Laboratory of Molecular Pharmacokinetics Graduate School of Pharmaceutical Sciences The University of Tokyo Bunkyo‐ku Tokyo Japan
Mitchell R. McGill Department of Environmental and Occupational Health Fay W. Boozman College of Public Health University of Arkansas for Medical Sciences Little Rock AR USA
Donald Miller Department of Pharmacology and Theurapetics Max Rady College of Medicine University of Manitoba Winnipeg MB Canada
William A. Mturphy Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill NC USA
Birk Poller ADME Department of PK Sciences Translational Medicine Novartis Institutes for Bio Medical Research Basel Switzerland
Nur A. Safa Department of Pharmacology and Therapeutics University of Manitoba Winnipeg MB Canada
Chitra Saran Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, and Department of Pharmacology UNC School of Medicine University of North Carolina at Chapel Hill Chapel Hill NC USA
Hongbing Wang Department of Pharmaceutical Sciences University of Maryland School of Pharmacy Baltimore MD USA
Qingping Wang Sanofi US Waltham MA USA
Yue Wu Division of Bioinformatics and Biostatistics National Center for Toxicological Research U.S. Food and Drug Administration Jefferson AR USA
Yan Zhang DMPK Nuvation Bio, Inc. New York NY USA
1 Overview: Drug Metabolism, Transporter‐Mediated Uptake and Efflux, and Drug Toxicity
Albert P. Li
In vitro ADMET Laboratories, Inc., 9221 Rumsey Road, Suite 8, Columbia, MD, 21045, USA
1.1 Drug Toxicity as a Challenge in Drug Development
Drug discovery and development is critical to human health. In recent decades, there have been numerous exciting breakthroughs in the development of novel approaches to cure previously difficult to manage diseases, alleviate pain and discomfort, as well as
