Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin

Abstract

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Fig. 1.

Distribution of maximum phenytoin doses.

Fig. 2.

Distribution of maximum carbamazepine doses.

Fig. 3.

Distribution of maximum carbamazepine doses for each SCN1A IVS5-91 G>A genotype.

Fig. 4.

The position of the SCN1A IVS5-91 G>A polymorphism and how it correlates with the proportion of 5N in total SCN1A in the temporal lobe and hippocampus of epileptic individuals. (A) Genomic structure of SCN1A surrounding exons 5N and 5A, and regulation of exon 5N in epileptic tissues. (B) Proportion of SCN1A 5N transcript in brain tissue from patients with a history of epilepsy.

Fig. 5.

Association of 20 unlinked markers with maximum carbamazepine dose.