Managing the challenge of chemically reactive metabolites in drug development

• Published in: Nature reviews. Drug discovery Vol. 10; no. 4; pp. 292 - 306
• Main Authors: Park, B. Kevin, Tweedie, Donald J, Boobis, Alan, Clarke, Stephen, Goldring, Chris E. P, Jones, David, Kenna, J. Gerry, Lambert, Craig, Laverty, Hugh G, Naisbitt, Dean J, Nelson, Sidney, Nicoll-Griffith, Deborah A, Obach, R. Scott, Routledge, Philip, Smith, Dennis A, Vermeulen, Nico, Williams, Dominic P, Wilson, Ian D, Baillie, Thomas A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2011; Nature Publishing Group
• Subjects: 53; 631/154; 631/154/309/436/1729; 92; 97; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Drug Design; Drug Discovery - methods; Drug Industry - methods; Drug-Related Side Effects and Adverse Reactions; Humans; Medicinal Chemistry; Molecular Medicine; Pharmaceutical Preparations - metabolism; Pharmacology/Toxicology; review-article; Risk Assessment - methods; Risk Management - methods
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd3408

Key Points Metabolism of drugs can generate metabolites that are chemically reactive towards cellular molecules and have the potential to alter biological function and initiate serious adverse drug reactions. This Review details methods for the detection of chemically reactive metabolites (CRMs), and outlines the current industrial and academic knowledge about structural alerts. The physiological response to bioactivation is discussed in the context of the toxicological response and how hypersensitivity reactions may occur. We also discuss the management of CRMs during drug development, taking into account whether the currently used CRM decision trees are relevant to the challenges posed in drug development. Earlier iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without comprising pharmacological activity or the need for extensive safety evaluation beyond standard practices. Finally, we address CRM-related decision-making based on minimal data (avoidance strategy) and how to make decisions based on covalent binding and other data. The implications for drug regulation are outlined. Chemically reactive metabolites (CRMs) can initiate serious adverse drug reactions. In their Review, Park and colleagues discuss current approaches for the evaluation of CRMs and examine how this knowledge can inform the various stages of the drug discovery and development process. The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This Review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.