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Gene variations explain drug dose required to control seizures

elative safety for a particular treatment.

Similarly, appropriate doses of carbamazepine take time to determine because of the drug's variable affects on patient metabolism and its potential neurologic side effects.

The team identified genes considered to be obvious candidates underlying patients' drug response, based on their known roles in the metabolism or transport of one or both anti-epileptic drugs. In 425 epileptic patients taking carbamazepine and 281 taking phenytoin, the researchers then searched for an association between clinical use of the drugs and variation in the candidate genes.

One variant of a gene known as CYP2C9, which encodes a liver enzyme involved in drug metabolism, showed a significant association with the maximum dose of phenytoin taken by patients with epilepsy.

Moreover, a variant of a second gene, called SCN1A, with activity in the brain, was found significantly more often in patients on the highest doses of both carbamazepine and phenytoin. SCN1A has been implicated in many inherited forms of epilepsy and is the drug target for phenytoin.

Given its relationship to both anti-epileptic drugs tested, the SCN1A variant may be of particular importance for understanding patient response to drug treatment, said the researchers, noting that many other anti-epilepsy drugs act on related brain proteins.

"The range of doses taken by patients at epilepsy clinics is great," Goldstein said. "For someone at the higher end, it can take months to get their seizures under control. This study uncovers factors that might determine, in advance, which patients will need the higher dose."

Before any such pharmacogenetic approaches can be put into practice, they must be explicitly evaluated for clinical utility in improving patient outcomes, Goldstein said.

The new findings provide a direction for a dosing scheme that could be tested in the clinic to assess whether pharmacogenetic diagnostics can
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Source:Duke University Medical Center


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