Abstracts

Rationale: Clinical pharmacology of oxcarbazepine was investigated in several studies. However, there is limited information about the relationship between pharmacokinetics and drug responses of patients treated with oxcarbazepine. The purpose of the present study was to demonstrate the adverse effects associated with the concentration of the active metabolite of oxcarbazepine, 10,11-dihydro-10-hydrocarbamazepine (MHD), supported by population pharmacokinetic modeling.Methods: Patients who had been enrolled in Epilepsy Registry Cohort of Seoul National University Hospital since Feb. 2011 was analyzed in this study. Total 711 oxcarbazepine drug spot samples from 618 patients with epilepsy were analyzed retrospectively. Electronic medical records were respectively reviewed and analyzed. Last dosage to sample time, serum drug concentration was measured. For quantitative determination of oxcarbazepine and MHD, we used a liquid chromatography – tandem mass spectrometry (LC-MS/MS). The population pharmacokinetic model for MHD was developed using NONMEM.Results: Median age of the patients was 38 (range 16–89) and 42.7% was female. Daily oxcarbazepine dose was ranged from 150 mg to 3300 mg with mean 1019 ± 364 mg. Most (64.6%) patients received polytherapy, and mean number of anti-epileptic drugs was 2.1 ± 1.1 (range 1-6). The serum concentration of MHD (15.88 ± 7.6 mg/L) was correlated with the oxcarbazepine daily dose per body weight (r = 0.583, p < 0.001). Oxcarbazepine-associated adverse effects were evaluated with two groups divided by adverse-event and no-adverse-event samples during the last follow-up period. Adverse-event group (22 samples) was treated with higher dose of oxcarbazepine compared with no-adverse-event group (685 samples); daily doses per body weight were 17.1 ± 6.0 versus 15.3 ± 5.2 mg/kg and the MHD concentrations were 17.4 ± 6.8 versus 15.8 ± 7.7 mg/L, respectively. However, concentration-to-dose ratio, MHD concentration divided by oxcarbazepine daily dose adjusted for body weight, was not different between two groups (1.11 vs. 1.03). Hyponatremia, which is defined by serum sodium level below 135 mEq/L, was observed in 89 (16.2 %) from 548 available samples, and the MHD concentration showed inverse relationship with the serum sodium level (r = -0.178, p < 0.001). Predicted MHD concentration fits well with observation by population pharmacokinetic modeling.Conclusions: The adverse effects of oxcarbazepine were related with higher dose and serum concentration. Hyponatremia, the representative adverse event of oxcarbazepine, was correlated with MHD concentration. Further elaborate analyses to combine clinical information and population pharmacokinetic modeling will be conducted.