Plasma concentration of carbamazepine-epoxide in Korean pediatric patients with epilepsy

Background: Carbamazepine-10,11-epoxide(CBZ-E), a major metabolite of carbamazepine (CBZ) has been reported to have antiepileptic and toxic effects. We measured the distribution of the plasma concentrations of CBZ-E and evaluated which factors give an influence on the concentration in Korean epileptic children taking regular dose of CBZ. Methods: Blood samples were drawn at steady-state daily trough CBZ concentrations in 236 pediatric patients with epilepsy (mean age: 8.99 ± 3.84 years, weight: 32.15 ± 14.60 kg) including 145 patients taking CBZ alone (group M) and 91 patients taking CBZ with other antiepileptics (group P). The plasma concentrations of CBZ and its metabolites (CBZ-E and trans-CBZ-diol) were measured using high performance liquid chromatography (HPLC). Results: The steady-state plasma concentration of CBZ and CBZ-E were widely varied among the 236 pediatric patients (range: 0.70 ~ 21.28 μg/μl and 0.16 ~ 7.90 μg/μl, respectively), and their ratio CBZ-E/CBZ showed 24 fold variation (range: 0.07 ~ 1.71). Group P showed significantly higher CBZ-E concentrations (1.72 ± 1.31 μg/μl) and CBZ-E/CBZ ratios (0.33 ± 0.28) than those of group M (1.23 ± 0.77 μg/μl and and 0.20 ± 0.11, respectively) with no significant difference in the CBZ dose. The patients taking CBZ and two or more antiepileptics including valproic acid showed higher CBZ-E concentrations and CBZ-E/CBZ ratios than patients taking other combinations. In group M, the CBZ-E concentrations and CBZ-E/CBZ ratios in pediatric patients with ≥ 10 years were significantly lower than those of patient subgroups with age of ≤ 5 years and age of 5 ~ 10 years. The relationships between CBZ-E concentrations and CBZ daily doses or CBZ concentrations were higher in group M compared to those of group P, but those correlations obtained in all study patients were generally low (r<0.30). CBZ-E/CBZ and trans-CBZ diol/CBZ ratios also showed low correlations (r<0.25) with daily CBZ doses. Conclusions: These data suggest that the plasma concentrations of CBZ-E are highly variable and are poorly predicted from CBZ dose and/or its concentration in pediatric patients with epilepsy. Polytherapy and age appear to be main factors to perturbate the CBZ-E formation and/or elimination in pediatric patients.