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Managing the challenge of chemically reactive metabolites in drug development

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.

Abstract

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.

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Figure 1: An ideal working relationship between chemistry and drug metabolism.
Figure 2: Examples of possible decision scheme structures for handling bioactivation information in various stages of drug research.

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Acknowledgements

The authors would like to acknowledge the Medical Research Council (MRC) and The Association of British Pharmaceutical Companies (ABPI). The Merck retrospective analysis was conducted in-house with a crossfunctional team led by D.N.-G. with recognition to J. Monroe and F. Sistare for curating the safety assessment data, members of DMPK for CB data and the sponsorship of L. Shipley, J. Harrelson and D. Dean. An industrial–academic workshop that was held in Liverpool, UK, on 13 and 14 April 2010 formed the initiative for the development of this manuscript.

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Correspondence to B. Kevin Park or Donald J. Tweedie.

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Competing interests

Scott Obach is an employee and shareholder of Pfizer — a company that is engaged in the discovery, development and sale of pharmaceuticals for profit.

Philip Routledge is head of the section of Pharmacology, Therapeutics & Toxicology at Cardiff University, UK, which has a clinical lectureship that is unconditionally part-funded by AstraZeneca under the Association for British Pharmaceutical Industries (ABPI) Clinical Pharmacology Training Scheme and part-funded by the Welsh Assembly Government.

Deborah Nicoll-Griffith is an employee of Merck & Co.

All other authors declare no competing financial interests.

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Park, B., Boobis, A., Clarke, S. et al. Managing the challenge of chemically reactive metabolites in drug development. Nat Rev Drug Discov 10, 292–306 (2011). https://doi.org/10.1038/nrd3408

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