Drug Interaction and Pharmacokinetic Modeling of Oxcarbazepine in Korean Patients With Epilepsy

Abstract

To determine first whether there was a clear relationship between concentrations of the active metabolite of oxcarbazepine (OXC), 10-hydroxycarbamazepine (OHC), and dose adjusted for weight, and second, whether the clearance of OHC was influenced by comedication with enzyme-inducing antiepileptic drugs (EIAED). We analyzed 254 cases (patients 3-80 years of age) of OXC therapeutic drug monitoring, retrospectively. The cases were categorized into OXC monotherapy (n = 78), OXC in combination with EIAED (n = 73), and OXC in combination with non-EIAED (n = 103). The serum OHC concentrations of predose samples were measured by high-performance liquid chromatography. A population pharmacokinetic model was developed using NONMEM. The mean ± SD serum concentration of OHC was 14.47 ± 8.28 μg/mL at a mean daily dose of 16.22 ± 7.99 mg/kg. The serum concentration of OHC was correlated with the OXC dose per body weight (r = 0.6005; P < 0.0001). No association was found between OHC concentration and patient age, weight, sex, or seizure type. The concentration-to-dose ratio on OXC in combination with EIAED was significantly lower than that on OXC monotherapy (P = 0.002) or OXC in combination with non-EIAED (P < 0.0001). In population pharmacokinetic modeling, the apparent clearance of OHC was higher by 31.2% in combination with EIAED than in other groups. The serum concentration of OHC was statistically significantly correlated with the dose of OXC and negatively correlated with comedication of EIAED. Population pharmacokinetic analysis showed that the apparent clearance of OHC increased with comedication with EIAEDs.