Genetic predictors of the maximum doses patients receive during clinical use of the antiepileptic drugs carbamazepine and phenytoin.
Tate SK, , Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, et al.;
Commented by , 22 May 2005
Background
Phenytoin and carbamazepine are transported across the blood brain barrier by P-glycoprotein (ref. 1), which is encoded by the ABCB1 gene, and they exert their effects by blocking sodium channels (ref. 2), which are encoded by various genes, including SCN1A.
Phenytoin is also a substrate of the P450 isoenzyme CYP2C9 (ref. 3).
Aim
To assess the contribution of variation in the SCN1A, ABCB1 and CYP2C9 genes to differences in dose requirements of phenytoin and carbamazepine in patients with epilepsy.
Methods
The known functional polymorphism of the CYP2C9 gene, the putatively functional 3435 C>T polymorphism of the ABCB1 gene and 4 SCN1A tagging SNPs were correlated with the maximum prescribed dose of phenytoin in 281 patients and carbamazepine in 425 patients. Associations with adverse drug reactions (ADRs) to these drugs were also investigated.
Results
- An intrinsic polymorphism of the SCN1A gene (IVS5-91 G > A) was highly associated with the maximum dose of both phenytoin and carbamazepine.
- For phenytoin, maximum dose was also associated with the presence of the CYP2C9*3 allele.
- In brain surgical specimens from temporal lobe epilepsy patients, data showed that the IVS5-91 G > A SCN1A polymorphism disrupts the sequence of the 5' splice donor site of the highly conserved alternative exon 5N and affects the proportion of alternative transcripts.
Professor Perucca's comments
This study reports three main findings:
The presence of the CYP2C9*3 allele is associated with reduced phenytoin dose requirements (as assessed by the maximum dose prescribed). This was expected, because phenytoin is metabolised primarily by CYP2C9 (ref. 3) and the *3 allele is known to be associated with reduced enzyme activity (ref. 4; ref. 5). The data from this study, therefore, may be regarded as confirmatory;
- There was no association of the 3435 C>T ABCB1 gene polymorphism with the maximum dose of either drug. Again, this finding was not totally unexpected, because an early report suggesting a causal relationship of the ABCB1 polymorphism with drug refractory epilepsy (ref. 6) had not been fully confirmed by further work (ref. 7; ref. 1). This highlights the difficulties in interpreting association studies.
- Response to phenytoin and carbamazepine (as assessed by maximum doses prescribed) was associated with a probably functional variant of the SCN1A gene. The fact that this variant predicted independently maximum doses of both drugs, coupled with the fact that both drugs act by binding to sodium channels (ref. 2), may be regarded as a "functional" replication of the association. This is by far the most interesting finding.
An association of the SCN1A polymorphism with phenytoin and carbamazepine dose requirements, if confirmed, would be the first example of a functional polymorphism modulating pharmacological response at a major antiepileptic drug target.
Although the authors claim that their findings "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", one needs to be cautious before drawing conclusions, for a number of reasons:
- The reported associations need independent replication. Moreover, even if confirmed, the identified polymorphisms appeared to explain only a small part of the dosing variation in the assessed cohorts (6.5% for phenytoin and 2.5% for carbamazepine).
- The study population was inadequately described, and presumably heterogeneous with respect to types of epilepsy, responsiveness to phenytoin and carbamazepine, and treatment modalities (patients on polytherapy, including those receiving other antiepileptic drugs, were not excluded).
- Dosing information was derived retrospectively. Moreover, maximum dosage is a questionable surrogate marker for drug responsiveness.
- We do not have, as yet, direct information on whether (and how) the reported SCN1A polymorphism affects neuronal sensitivity to phenytoin and carbamazepine.
- No relationship was identified between any of the polymorphisms and a history of ADRs.
Awareness of these limitations should temper over-excitement about this "first" report of a genetic polymorphism affecting antiepileptic drug response at a drug target site. Pharmacogenomics in epilepsy is still in its infancy, and this study should be regarded as a potentially important step forward. Only time will tell if it is also a step in the right direction.
References
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