Genetic variants linked to skin reactions from epilepsy drug

Researchers in Taiwan have identified genetic variants that are associated with severe adverse skin reactions to the drug phenytoin.

Phenytoin, a widely prescribed anti-epileptic drug, can cause cutaneous adverse reactions ranging from maculopapular exanthema to drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis, the study notes. The pharmacogenomic basis of these phenytoin-related reactions is unknown.

A research team headed by Wen-Hung Chung, M.D., Ph.D., of Chang Gung Memorial Hospital, Keelung, Taiwan, investigated the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. The study, conducted from 2002 until this year, involved 105 cases of phenytoin-related severe cutaneous adverse reactions (61 Stevens-Johnson syndrome/toxic epidermal necrolysis and 44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3,655 population controls from Taiwan, Japan and Malaysia.

Next: Considering risk factors

“Our study identified genetic variants of metabolizing enzymes, including CYP2C9*3, known to delay the drug clearance, as the important risk factors for phenytoin-related severe cutaneous adverse reactions,” study author Shuen-Iu Hung, PhD., of the Institute of Pharmacology at National Yang-Ming University, Taipei, Taiwan, tells Dermatology Times.

“Patients with such deficient variant have 11 times the increased risk to develop cutaneous adverse reactions when taking phenytoin. In addition, delayed clearance of the drug was also noted in some patients without the risk variants.”

Dr. Hung advises that to avoid severe cutaneous adverse reactions, physicians should “consider the risk factors, including genetic variants of metabolizing enzymes (e.g., CYP2C9*3), the renal and hepatic function, and concurrent use of substances that may compete or inhibit the drug metabolic enzymes, before prescribing the drug.”

The study concludes that more research is needed to replicate the genetic association in different populations and to determine the test characteristics and clinical utility.

The findings were published online Aug. 6 in JAMA.