Abstract & Commentary
By Barry Kosofsky, MD, Attending Pediatrician, New York-Presbyterian Hospital, Professor, Cornell Medical College, Research Associate, Massachusetts General Hospital. Dr. Kosofsky reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
Synopsis: This report provides evidence of a drug target polymorphism in epilepsy patients predictive of their maintenance dose of AEDs.
Source: Tate SK, et al. Genetic Predictors of the Maximum Doses Patients Receive During Clinical Use of the Anti-Epileptic Drugs Carbamazepine and Phenytoin. Proc Natl Acad Sci. 2005:102;5507-5512.
Anti-epileptic drugs (AEDs) are the mainstay in the treatment of epilepsy. Phenytoin and carbamazepine, specifically, are very effective, yet sometimes a challenge to dose accurately in patients with epilepsy, in part because of the narrow therapeutic index of phenytoin and the auto-induction of metabolism of carbamazepine. There is also high individual variability in the required maintenance dosage. Moreover, an acceptable balance between the effective maintenance dose and associated adverse drug reactions can be difficult to achieve. As a result, identifying an acceptable dose and regimen for such AEDs often involves trial and error, which can delay achieving therapeutic efficacy. This impedes prompt adequate control of seizures. Theoretically, genetic diagnostic testing may reduce this delay by offering individualized ways to predict the maximum dose of AEDs for each patient based on genetic predispositions for drug metabolism. This retrospective report investigates this theoretical concept in epilepsy patients who were treated with carbamazepine and/or phenytoin. The genetic targets of investigation for this study were the variant alleles in the phenytoin metabolic pathway, the CYP2C9 alleles 1, 2, 3, as well as the variants of the SCN1A gene. This encodes voltage-sensitive sodium channels, the main therapeutic target of both carbamazepine and phenytoin efficacy. Variations of these genes were investigated in 425 patients taking carbamazepine and 281 patients taking phenytoin.
This report indicates that the CYP2C9*3 allele is significantly associated with the highest plasma levels of phenytoin. Individuals with 0, 1, or 2 copies of the CYP2C93 allele require significantly lower amounts of phenytoin (354mg, 309mg, and 250mg, respectively) as their maximum daily maintenance dose. Recent evidence indicates that individuals with allele 3 have a significant reduction in phenytoin clearance, compared to those with alleles 1 and 2.
Furthermore, variants of SCN 1A were found to have a significant association with maximum doses of both phenytoin and carbamazepine. Overall, individuals with AA, AG, and GG genotypes averaged maximum doses of 373mg, 340mg, and 326mg of phenytoin, respectively and 1313mg, 1225mg, and 1083mg of carbamazepine, respectively. Clinically, this finding suggests the target dose that would be well tolerated is lower in the presence of the GG allele.
Additional molecular genetic insights were reported in this study. The SNP7 polymorphism in the SCN1A gene can influence alternate splicing of exon 5N. Of note, seizures are known to up-regulate exon 5N inclusion in SCNIA a rodent model. Tate and colleagues report significantly higher levels of SCN1A with exon 5N in the cadaveric brain tissue of epilepsy patients (~12.6 %), compared to that of Parkinson’s patients (9.5 %). Furthermore, among epilepsy patients, a more detailed genetic analysis based on the SCN1A gene showed differences in patients who underwent surgery for intractable epilepsy. Brain tissue resection showed that the amount of SCN1A copies with exon 5N was significantly upregulated in the temporal lobe, compared to the hippocampus in individuals with the GG genotype vs other patients with AG and AA genotypes. While the clinical significance of the difference in the presence of exon 5N in extra-hippocampal temporal cortical regions vs hippocampus is unclear, these findings provide evidence of a genetic component related to the SCN1A gene in contributing to the epilepsy in humans.
While these novel findings are intriguing, they probably will not substantially alter our current practice of dose escalation until seizures are well controlled in the absence of clinical toxicity. The maximum recorded doses of these medications imply that a maximum tolerated dose and/or a satisfactory efficacy in preventing seizures is associated with CYP2C9 genotypes.
This paper reveals 2 interesting associations with the G allele of the SCN1A gene; an association with decreased AED doses required for both phenytoin and carbamazepine, and a correlation of increased exon 5N copies in the temporal lobes vs hippocampus of patients with epilepsy who required surgical resection of those structures for intractable epilepsy.
In summary, the findings clearly demonstrate that the CYP2C9 3 and the G allele of SCN1A are associated with lower AED doses for efficacy. Additionally, the G allele of SCN1A is associated with intractable epilepsy. While the direct clinical correlates are yet to be determined, and the specific role of the exon 5N copies of SCN1A in epilepsy are as yet unknown, the evidence provided implies that genotyping may eventually serve as an essential clinical tool in the diagnostic, therapeutic, as well as prognostic components involved in our approaches to epilepsy.