Daily Variations in Steady-State Plasma Concentrations of Carbamazepine and its Metabolites in Epileptic Children

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Abstract
Total plasma carbamazepine, carbamazepine-10,11-epoxide (CBZ-EP) and 10,11-dihydro-10,11-trans-dihydroxy-carbamazepine (CBZ-DIOL) concentrations were measured during a 24h period in 21 patients receiving carbamazepine monotherapy, in equally divided doses, every 12h. Interdose and diurnal variations in plasma concentrations of parent drug and metabolites were assessed. Carbamazepine and both metabolites showed significant differences in mean 4h post-dose plasma concentrations between day and night dosing (p < 0.001). Significant linear correlations were obtained between carbamazepine dose and plasma concentrations of carbamazepine, CBZ-EP and CBZ-DIOL when sampling times were standardised (p < 0.01). Comparisons of plasma concentrations of the parent compound with those of its 2 main metabolites revealed significant linear correlations in all cases (p < 0.01). The effects of daily fluctuations in plasma concentrations of all 3 compounds on their relative concentrations (CBZ-EP: carbamazepine, CBZ-DIOL: carbamazepine and CBZ-DIOL: CBZ-EP) during the 24h period were also determined: the plasma concentration ratios CBZ-EP: carbamazepine and CBZ-DIOL: carbamazepine were significantly related to the dose of carbamazepine at fixed sampling times (p < 0.05, with 1 exception). The large interdose and diurnal variation in plasma carbamazepine concentrations observed in this study (approximately 40% decrease from peak to trough) has important implications both clinically and in relation to therapeutic drug monitoring.