Idiosyncratic adverse drug reactions: current concepts

Abstract

Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.

Fig. 1.

CD4+ T-cell subsets involved in immune regulation and pathology.

Fig. 2.

Drug-specific T cell responses. HLA-restriction and mechanisms of antigen presentation. ^AMajor pathway of antigen presentation listed. Hapten-specific T cells are often stimulated with drug-derived antigens binding directly to MHC. For carbamazepine and abacavir, drug-protein antigens have not been characterized. Thus, the hapten hypothesis has not been tested.

Fig. 3.

Clinical and immunologic features of two forms of β-lactam hypersensitivity reaction.

Fig. 4.

The intermediate formed by oxidation of nevirapine partitions between loss of another hydrogen atom to form a quinone methide and oxygen rebound to form a benzylic alcohol. The quinone methide covalently binds in the liver, inactivates P450, and is presumably responsible for idiosyncratic liver injury. The benzylic alcohol travels to the skin where sulfotransferases in the epidermis form a sulfate conjugate that covalently binds and leads to a skin rash.