Idiosyncratic drug reactions (IDRs) significantly add to the cost and uncertainty of drug development. The mechanisms of IDRs are not well understood, but there is a large amount of evidence to suggest that most are caused by reactive metabolites of drugs and are immune mediated. However, not all drugs that form reactive metabolites are associated with a significant risk of IDRs. IDRs are also idiosyncratic in animals, and there are very few valid animal models. However, we found that nevirapine causes an immune-mediated skin rash in Brown Norway rats similar to the rash that it causes in humans. We were able to clearly demonstrate that a reactive sulfate metabolite formed in the skin is responsible for the rash. It is known that chemically reactive molecules often cause contact hypersensitivity, and animals deficient in components of the inflammasome are resistant. Inflammasome activation produces IL-1�, and we found an IL-� receptor antagonist attenuated the nevirapine-induced rash. In addition, the reactive sulfate metabolite of nevirapine activates inflammasomes in vitro. Drugs that are designed to covalently bind to their target are being developed, but there is concern that they will cause IDRs. Telaprevir is an a-ketoamide and has a black box warning because of serious skin rashes. We found that telaprevir activates inflammasomes while a similar drug, boceprevir, which is not associated with serious skin rashes did not. Likewise, we compared dimethylfumarate and ethacrynic acid; both of which are reactive Michael acceptors. Dimethylfumarate causes hypersensitivity reactions while ethacrynic acid is remarkably safe. Dimethylfumarate activates inflammasomes while ethacrynic acid does not. This suggests that the mechanism by which drugs and reactive metabolites cause IDRs is by inflammasome activation, and this may provide a way to differentiate which drugs and reactive metabolites will cause IDRs. Supported by grants from the Canadian Institutes of Health Research.

How do reactive metabolites lead to an immune response that can result in an idiosyncratic drug reaction?

248th National Meeting (2014)

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