Albert P. Li - Transporters and Drug-Metabolizing Enzymes in Drug Toxicity

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

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

Albert P. Li

In vitro ADMET Laboratories, Inc., 9221 Rumsey Road, Suite 8, Columbia, MD, 21045, USA

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 scientifically acceptable approaches to prevent or delay the onset of common but deadly disorders. The explosion in knowledge of the human genome has been instrumental in the development of novel therapeutic targets in the past decade, allowing the development of small molecules, biologics, and gene therapy to retard or completely abolish the progression of diseases via the modulation of key pathways. Human life span has been extended in most developed countries due to enhancements in health care approaches.

Unexpected human‐specific drug toxicity has been, and continues to be a major challenge in drug development (1–5). Pharmaceuticals by nature are biologically active chemicals designed to interact with biological pathways. Key uncertainties are the unintended biological effects which may lead to damage. Unintended drug toxicity is one of the major reasons for clinical trial failures as well as withdrawal or greatly limited use of drugs that have received regulatory approval. Unintended and unexpected drug toxicities are responsible for the high costs and time required for drug development. The most recent estimation of the cost for development of a new drug is over $1 billion USD, with the average time span from discovery to market of over 10 years (6, 7).

In drug development, approaches to develop drugs with acceptable safety margin to patients involve extensive preclinical evaluation in multiple species of laboratory animals. Only after the preclinical data support the safety of a drug candidate can it be submitted for approval by regulatory agencies for phase 1, 2, and 3 clinical trials. A drug is approved for marketing after the clinical trials support its safety and efficacy. The occurrence of unexpected toxicity for drug candidates with acceptable safety profile from preclinical safety studies is one of the major reasons for clinical trial failure, illustrating that nonhuman animals may not provide adequate information for the assessment of human drug toxicity. However, numerous drugs approved for marketing based on clinical trial demonstration of safety have been withdrawn from the market or have been restricted in use due to unacceptable adverse events leading to deaths. The occurrence of unacceptable drug toxicity after a drug is marketed to the human population illustrates that clinical trials do not have the statistical power to assure safety when millions of patients are exposed to a new drug. The paradigm for drug safety evaluation of preclinical safety in laboratory animals followed by regulatory human clinical trials therefore is not always adequate.