Idiosyncratic reactions: New methods of identifying high-risk patients

Abstract

This article describes the mechanisms of idiosyncratic drug reactions (IDRs) and provides an analysis of potential methods for identifying patients at high risk for antiepileptic idiosyncratic drug reactions. IDRs may be caused by toxic metabolites, either directly or indirectly (by way of an immunologic response or a free radical-mediated process). Four methods to potentially identify patients at high risk for AED IDRs are discussed: development of an 'at-risk' clinical profile for a particular AED; identification of biomarkers that measure the formation of a toxic metabolite by a previously unrecognized bioactivation pathway for a particular AED; identification of biomarkers indicating deficient detoxification abilities [e.g., deficient free radical scavenging enzyme activities or low calculated oxidative protection (COP) ratios 1 and 2]; and identification of at-risk genetic markers. Clinical profiles for patients receiving valproic acid (VPA), felbamate (FBM), and lamotrigine (LTG) and who are at risk for development of AED IDRs are presented. Patients with VPA IDRs have deficient erythrocyte glutathione peroxidase activity, low plasma selenium concentrations, low COP1 ratios, and low COP2 ratios compared with age-matched controls. Patients with FBM-associated aplastic anemia have deficient erythrocyte glutathione peroxidase, superoxide dismutase (SOD), and glutathione reductase activities compared with age-matched controls. Use of at-risk clinical profiles (for VPA, FBM, and LTG) and measurement of erythrocyte glutathione peroxidase activity, erythrocyte SOD activity, and calculation of COP1 and COP2 ratios (for VPA and FBM) are inexpensive, simple methods of identifying high-risk patients for IDRs. Research is needed to further characterize the mechanism of IDRs, to investigate the clinical utility of free radical-scavenging enzyme activity measurement and calculation of COP ratios for other AED IDRs, and to develop additional methods of identifying patients at high risk for AED IDRs.