Pharmacogenomics and Pharmacometabolic Study of Drug Induced Delayed-Type Hypersensitivity Reactions

  • Chung, Wen-Hung (PI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details


Drug induced delayed-type hypersensitivity reactions, involving in the activation of T cells, include variable clinical manifestations, ranging from mild skin rash, maculopapular exathem (MPE), fixed drug eruption (FDE), with increasing severity to and acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The notorious drugs associated with delayed drug hypersensitivity include 3 major categories: anticonvulsants (e.g phenytoin, carbamazepine, lamotrigine), antibiotics (e.g. amino-penicillins, vancomycin, sulfamethoxazole, cephalosporins, anti-tuberculosis), and NSAIDs. Severe drug induced hypersensitivity reactions, such as SJS, TEN and DRESS may lead to complex complications with high morbidity and mortality. In Taiwan, SJS/TEN cause more than 50% annual compensation funds from the Drug Relief Foundation. As a high proportion of patients in Taiwan frequently expose to multiple drugs and are at higher risk to develop drug hypersensitivity with undesirable outcome and high costs, the identification of risk factors as well as the genetic susceptibility of individuals who are at risk for severe ADRs is an urgent issue. Pharmacogenetics is the tailoring of drug treatment according to individual genotype, which has been widely proclaimed as a first step toward personalized medicine. If the genetic susceptibility of individuals to drug hypersensitivity is known, a simple genetic test could be performed before the prescribing and therefore avoid the patient morbidity and mortality caused by adverse drug reactions. Although HLA may link to some drugs induced delayed-type hypersensitivity reactions (e.g. HLA-B*1502 to carbamazepine induced-SJS/TEN and HLA-B*5801 to allopurinol induced SJS/TEN and DRESS), there are still many culprit drugs without findings of their genetic association. It has also been proposed that abnormal drug metabolism (pharmacometabolism) can also result in serious and unexpected adverse events, the pharmacometabolic study in discovery of defects in drug metabolic enzymes or abnormal pharmacokinetics of drugs/metabolites elimination in severe drug induced hypersensitivity is still lacking. In this 3-year project, we will investigate the pharmacogenomics and pharmacometabolism (drug metabolism) of drug induced delayed-type hypersensitivity reactions in 3 years: Specific aims: (1)To establish a biomaterial repository of patients with drug induced delayed-type hypersensitivity reactions and drug tolerant controls. (2). To identify the genetic susceptibility in immune molecules and drug metabolism pathways of delayed-type drug induced hypersensitivity (3) To investigate the specific drug-HLA interaction or binding affinity to further verify potential role of a specific HLA molecule linking to a specific drug-induced hypersensitivity reactions. (4). To investigate pharmacokinetics and plasma drug/metabolite levels of patients with drug induced delayed-type hypersensitivity and its correlation with clinical severity or prognosis We anticipate that this project will further our understanding of variable drug hypersensitivity, translate the genetic determinants to clinical tests, and provide a better approach to predict individual drug handling. In a broader view, this project will reduce the incidence and prevent delayed-type drug hypersensitivity, and drive the optimum drug selection for therapy.

Project IDs

Project ID:PC10301-0850
External Project ID:NSC101-2628-B182-001-MY3
Effective start/end date01/08/1431/07/15


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