New study uncovers genetic basis of adverse reactions to epilepsy drug

A new study has shed light on why some patients experience severe negative skin reactions when treated with a certain antiepileptic drug (AED).

Carried out by the Chang Gung Memorial Hospital in Taiwan and the Journal of the American Medical Association, the study has identified genetic variants that are associated with adverse skin reactions to phenytoin, one of the most frequently prescribed first-line AEDs given to hospitalised patients.

A case-control study was conducted between 2002 and 2014 among 105 patients who had experienced phenytoin-related severe cutaneous adverse reactions, 78 people affected by a less severe type of rash called maculopapular exanthema, 130 phenytoin-tolerant participants and 3,655 population controls.

At the same time, a genome-wide association study was conducted using 60 samples from patients with phenytoin-related severe cutaneous adverse reactions and 412 population controls.

It was revealed that variants of the gene CYP2C, including CYP2C9*3, tended to be associated with the most severe adverse skin reactions. This gene is known to reduce drug clearance, the process through which a drug is eliminated from the body.

A meta-analysis showed that the odds of experiencing serious reactions with this variant was 11 times higher, with delayed clearance of blood-borne phenytoin detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers.

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 the use of enzyme-inhibiting canmay also affect phenytoin metabolism, with negative consequences.

The study authors concluded: “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.”

Phenytoin is approved in the UK for the treatment of partial epilepsy, generalised epilepsy, trigeminal neuralgia and preventing or treating seizures caused by brain surgery or a head injury.

Posted by Steve Long

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