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Nico Vermeulen in Nature Reviews Drug Discovery

Adverse Drug Reactions (ADRs) are a major complication of drug therapy and an impediment to drug development and clinical use after marketing. Chemically reactive metabolites (CRMs) constitute a major cause of ADRs. Nico Vermeulen (Division of Molecular Toxicology) and a number of other experts in the field have evaluated the current strategies to manage the challenge of chemically reactive metabolites (CRMs) in drug development and proposed new insights and practices to be considered by academia and industry

Recent developments in molecular toxicology have provided multiple new technologies and methodologies that have greatly improved the fundamental understanding of the role of drug metabolism and CRMs in ADRs. However, much remains to be done to enable the translation of this knowledge and methods into reliable predictions of human drug safety. The experts propose new strategies to minimize the chemical liabilities for the formation of CRMs of drug candidates, e.g. by iterations between medicinal chemistry and drug metabolism scientists during early drug discovery, strategies to develop novel biomarkers of exposure to and effects of CRMs, while realizing that many of the current in vitro systems can not predict health risks but can only identify potential health hazards, and finally to not only inform those involved in the drug development process but also those in drug regulation and therapy about the possibilities and the limitations of the current strategies to manage the risks of drug-related CRMs.

It is concluded that handling these risks adequately, new integrated approaches are required which encompass chemoinformatics, systems biology and clinical informatics information.

Managing the challenge of chemically reactive metabolites in drug development

B. Kevin Park, … Nico P.E. Vermeulen, et al. Nature Reviews Drug Discovery10, 292-306 (2011)URL: http://www.nature.com/nrd/journal/v10/n4/full/nrd3408.html