Abstracts

The dose of carbamazepine (CBZ) required to achieve optimal seizure control varies widely from patient to patient. Genetically-determined variability in the activity and/or capacity of various drug metabolising enzymes (DMEs) is believed to influence the pharmacokinetics, and thereby dosage requirements, of a number of therapeutic agents. We have investigated polymorphic variants in the genes encoding DMEs involved in the metabolism of CBZ in an effort to identify predictors of CBZ maintenance dose., A total of 70 epilepsy patients (49% male; median age 34 years, range 14 - 72 years) who had benefited ([ge]50% reduction in seizure frequency) from treatment with CBZ monotherapy were included in the analysis. Individuals who did not tolerate the drug and/or those who did not experience significant efficacy were specifically excluded. Common genetic variants in CBZ-related DMEs, including specific cytochrome P450s (CYP3A4, CYP3A5 and CYP1A2) and microsomal epoxide hydrolase (EPHX1), were screened by conventional polymerase chain reaction - restriction fragment length polymorphism (PCRRFLP) or direct sequencing. Associations were identified and characterised by multiple logistic and linear regression analyses, respectively., All genotype frequencies were consistent with Hardy-Weinberg equilibrium (p[gt]0.05). No single clinical characteristic or genetic variant was sufficient to predict CBZ maintenance dose. However, a multiple logistic regression model incorporating patient age at time of optimal seizure control (OR=1.03, 95%CI 1.00-1.07, p=0.024), genotype of EPHX1 c.337T[gt]C (OR=0.44, 95%CI 0.22-0.87, p=0.018) and genotype of EPHX1 c.416A[gt]G (OR=0.46, 95%CI 0.22-0.98, p=0.044) demonstrated a significant association with maintenance dose (r²=0.16; p=0.009)., This analysis suggests that a combination of age and genetic variants of the EPHX1 gene can be used to predict optimal maintenance doses of CBZ. Further investigations are required in an effort to strengthen the predictive value of this observation before its clinical utility can be realistically assessed., (Supported by: MMB is supported by a studentship from the Government of Malaysia and Universiti Kebangsaan Malaysia.)