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August 20, 2014
Identification of Genetic Variants Linked to Phenytoin
Skin Reactions Keelung, Taiwan—Phenytoin is the most frequently used first-line antiepileptic drug (AED) in hospitalized patients and is widely prescribed on an outpatient basis. While effective, the drug also can cause unpredictable cutaneous adverse reactions ranging from mild to severe. Now, a new study reports on research identifying genetic variants that are associated with severe adverse skin reactions to phenytoin. The results were published recently in the Journal of the American Medical Association. The case-control study, involving researchers from Chang Gung Memorial Hospital in Keelung, Taiwan, was conducted in 2002-2014. Researchers focused on 105 cases with phenytoin-related severe cutaneous adverse reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis, eosinophilia and systemic symptoms, and maculopapular exanthema. A genome-wide association study (GWAS) was conducted, comparing phenytoin-related severe cutaneous adverse reactions to a control group. The researchers found that variants of the gene CYP2C, including CYP2C9*3, were associated with phenytoin-related severe cutaneous adverse reactions. The statistically significant association between CYP2C9*3, which has a role in drug clearance, and phenytoin-related severe cutaneous adverse reactions was replicated by samples from Taiwan, Japan, and Malaysia. A meta-analysis indicated that patients with that genetic variant had an 11 times higher odds of experiencing cutaneous adverse reactions with phenytoin use. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a clinical link of the associated variants to the disease, the authors report. They add, however, that delayed clearance was also noted in patients with severe cutaneous adverse reactions without CYP2C9*3, suggesting that nongenetic factors such as renal insufficiency, hepatic dysfunction, and concurrent use of substances that compete with or inhibit the enzymes may also affect phenytoin metabolism and contribute to severe skin reactions. “This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions,” the authors write. “These findings may have potential to improve the safety profile of phenytoin in clinical practice and offer the possibility of prospective testing for preventing phenytoin-related severe cutaneous adverse reactions. More research is required to replicate the genetic association in different populations and to determine the test characteristics and clinical utility.” |
U.S. Pharmacist Social Connect
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