Evaluation of Clinical and Genetic Factors in the Population Pharmacokinetics of Carbamazepine.

AIMS Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11-epoxide metabolite but not by carbamazepine. Hypothetically, certain SNPs might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics of carbamazepine and three metabolites known to be chemically reactive or formed through reactive intermediates. METHODS A combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 SNPs in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11-epoxide. Nonlinear mixed effects modelling was used to build a population-PK model. RESULTS In total 248 observations were collected from 80 subjects. A one-compartment PK model with first-order absorption and elimination best described the parent carbamazepine data, with a total CL of 1.96 L/h, central Vd of 164 L and ka of 0.45 h-1 . Total daily dose and co-administration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1-416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11-epoxide. CONCLUSION Our data indicate that carbamazepine clearance was affected by total dose and phenytoin co-administration, but not by genetic factors, while carbamazepine 10,11-epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.