CONTEMPORARY ISSUES IN TOXICOLOGY Drug Metabolites in Safety Testing Thomas A. Baillie,* Mitchell N. Cayen,† Hassan Fouda,‡ Ronald J. Gerson,§ James D. Green, Scott J. Grossman,§ Lewis J. Klunk, ¶ Bernard LeBlanc,‡ Darcy G. Perkins,** and Lisa A. Shipley†† *Merck Research Laboratories, West Point, Pennsylvania 19486; †Schering-Plough Research Institute, Kenilworth, New Jersey 07033; ‡Pfizer Central Research, Groton, Connecticut 06340; §Bristol-Myers Squibb, Wilmington, Delaware 19880; ¶ Bristol-Myers Squibb, Princeton, New Jersey 08543; Biogen, Inc., Cambridge, Massachusetts 02142; **GlaxoSmithKline R&D, Research Triangle Park, North Carolina 27709; and ††Lilly Research Laboratories, Indianapolis, Indiana 46285 Received December 11, 2001; accepted April 17, 2002 Drug Metabolites in Safety Testing. Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Green, J. D., Grossman, S. J., Klunk, L. J., LeBlanc, B., Perkins, D. G., and Shipley, L. A. (2002). Toxicol. Appl. Pharmacol. 182, 188 –196. This report summarizes the deliberations of a multidisciplinary committee, sponsored by the Pharmaceutical Research and Man- ufacturers of America, on current “best practices” within the U.S. pharmaceutical industry in assessing the role of drug metabolites as potential mediators of the toxicity of new drug products. Input to the document was obtained from numerous sources, including members of the pharmaceutical industry, academic investigators, and representatives of regulatory agencies who attended a work- shop on the subject in November 2000. The overall goal of the paper is to define practical and scientifically based approaches to the use of metabolite data that address contemporary issues in the safety evaluation of drug candidates. Although there remains a lack of consensus on how best to deal with several aspects of this complex subject, this paper raises a number of points to consider, which emphasize the need to treat drug metabolite issues on a case-by-case basis. It is hoped that the discussion will promote continued dialog among industrial scientists and regulators charged with ensuring the clinical safety of new therapeutic agents. © 2002 Elsevier Science (USA) Key Words: drug metabolites; toxicity; safety assessment. BACKGROUND In the course of modern drug development, there are four areas in which issues pertaining to drug metabolites need to be addressed, namely (1) drug metabolites as components of (plasma) drug assays, (2) drug metabolites in bioavailability studies, (3) drug metabolites in bioequivalence studies, and (4) drug metabolites in safety testing. While the first three of these areas have formed the subject of various scientific symposia and regulatory guidances over the past few years (Cayen, 2000), the issue of drug metabolites in safety testing has not benefited from similar in-depth treat- ment. However, in light of the increased attention being paid by both pharmaceutical companies and regulatory agencies to the role of metabolites as potential mediators of the toxicity of new drug products, it was felt that an analysis of the issues and a survey of current best practices in dealing with metabolite questions would represent a timely contribution to the fields of industrial safety evaluation and regulatory toxicology. Conse- quently, in 1999, the Pharmaceutical Research and Manufac- turers of America (PhRMA) commissioned a body composed of members of the Drug Metabolism, Clinical Pharmacology, and Safety Assessment (DruSafe) PhRMA subcommittees to review the topic and to present their findings at a workshop organized jointly by PhRMA member companies and the U.S. Food and Drug Administration (FDA). Many of the issues discussed at this workshop, which was held in Bethesda, Mary- land, on November 14 –15, 2000, together with the delibera- tions of the Metabolites in Safety Testing (MIST) committee, are summarized below. The goal of this document is to define practical and scientifically based approaches to the use of metabolite data that address contemporary issues in the safety evaluation of drug candidates. It should be emphasized that, while there remains a lack of consensus within the pharmaceu- tical industry on how best to approach several of the issues dealt with in this document and while the views expressed herein do not necessarily reflect the individual policies of the companies with which the authors are affiliated or those of the FDA, it is nevertheless hoped that the list of points to consider will form the basis for continued dialog among relevant indus- try and regulatory agency representatives. INTRODUCTION This overview focuses on metabolites in preclinical safety assessment and, by extension, relevant aspects of metabolites as components of drug assays in support of safety studies. The discussion is restricted to small molecules given by the oral Toxicology and Applied Pharmacology 182, 188 –196 (2002) doi:10.1006/taap.2002.9440 188 0041-008X/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.