Animal models of idiosyncratic drug reactions

Abstract

If we could predict and prevent idiosyncratic drug reactions (IDRs) it would have a profound effect on drug development and therapy. Given our present lack of mechanistic understanding, this goal remains elusive. Hypothesis testing requires valid animal models with characteristics similar to the idiosyncratic reactions that occur in patients. Although it has not been conclusively demonstrated, it appears that almost all IDRs are immune-mediated, and a dominant characteristic is a delay between starting the drug and the onset of the adverse reaction. In contrast, most animal models are acute and therefore involve a different mechanism than idiosyncratic reactions. There are, however, a few animal models such as the nevirapine-induced skin rash in rats that have characteristics very similar to the idiosyncratic reaction that occurs in humans and presumably have a very similar mechanism. These models have allowed testing hypotheses that would be impossible to test in any other way. In addition there are models in which there is a delayed onset of mild hepatic injury that resolves despite continued treatment similar to the "adaptation" reactions that are more common than severe idiosyncratic hepatotoxicity in humans. This probably represents the development of immune tolerance. However, most attempts to develop animal models by stimulating the immune system have been failures. A specific combination of MHC and T cell receptor may be required, but it is likely more complex. Animal studies that determine the requirements for an immune response would provide vital clues about risk factors for IDRs in patients.