Development and Application of a Genetic Test to Prevent Phenytoin-Induced Fatal Hypersensitivity Reactions (I)

Drug hypersensitivity may range from mild maculopapular eruption (MPE) to severe life-threatening reactions, including drug rash with eosinophilia and systemic syndrome (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Carbamazepine and phenytoin and allopurinol are the 3 leading causes for severe hypersensitivity reactions worldwide. We previously identified that HLA-B*1502 strongly associated with carbamazepine-induced SJS/TEN [Chung WH, et al. Nature, 2004] and HLA-B*5801 with allopurinol-induced SJS/TEN/DRESS [Hung SI and Chung WH. et al. PNAS, 2005]. Recently we further identified that genetic variants of CYP2C9 and HLA-B*1502 are strongly associated with phenytoin-induced severe hypersensitivity reactions, including SJS, TEN and DRESS [Chung WH et al., JAMA, 2014]. Genetic tests of HLA-B*1502 and HLA-B*5801 have been applied in clinical practice for the prevention of carbamazepine and allopurinol-induced severe hypersensitivity in many countries now. However, it still lacks a feasible rapid genetic test to prevent phenytoin-induced fatal hypersensitivity reactions. Here, we propose a two-year project with the following specific aims to develop a rapid genetic test and evaluate the effectiveness on the prevention of phenytoin-induced hypersensitivity reactions. Specific aim 1: Development of a panel of TaqMan genotyping assay for the detection of risk alleles of phenytoin hypersensitivity and optimization for the prototype by using clinical samples We’ll develop a panel of TaqMan genotyping assay for detection of CYP2C9*3 and HLA-B risk alleles of phenytoin hypersensitivity. The prototype of this assay will be tested in clinical samples, and the results will be validated and confirmed by other technical platforms, including sequencing-based genotyping. We’ll use 100 retrospective clinical samples of phenytoin hypersensitivity to define the sensitivity and the specificity of the prototype assay before the start of prospective clinical trial. Specific aim 2: A prospective clinical trial for genetic screening of risk alleles of phenytoin hypersensitivity before the therapy in multiple centers We will conduct a multi-center clinical trial in Taiwan, and apply the genetic screening assay to detect the risk alleles of phenytoin hypersensitivity before phenytoin therapy in patients. Physicians will be informed for the genotyping data of the patients with the risk alleles, and advised to avoid the prescription of phenytoin but shift to other alternative antiepileptic drugs such as valproate. We anticipate that this proof-of concept of trial will lead to the generation of a certified IVD kit for preventing phenytoin hypersensitivity and the incidence of phenytoin-induced severe hypersensitivity reactions will decrease. This project will prevent the morbidity and mortality related to fatal adverse drug reactions, and toward personalized medicine.

Project ID:PC10406-0233
External Project ID:MOST104-2325-B182A-006