Factors influencing plasma level/dose ratios of carbamazepine and its major metabolites in epileptic children.

The relationship between daily dose and plasma concentrations of carbamazepine (CBZ), CBZ-10,11-epoxide (CBZ-EP), and 10,11-dihydro-10,11-trans-dihydroxy-CBZ (CBZ-DIOL) was investigated in 21 children aged 7-16 years who received CBZ monotherapy, twice daily in equally divided doses. Significant linear correlations between CBZ dose and plasma levels were obtained for CBZ and its metabolites (p less than 0.01). In addition, the effects of daily dose and patients' age on the plasma level/dose ratios for CBZ, CBZ-EP, and CBZ-DIOL were evaluated. A significant negative correlation was observed between the daily dose of CBZ and the CBZ plasma level/dose ratio (p less than 0.01). By contrast, plasma level/dose ratios for CBZ-EP and CBZ-DIOL were independent of dose (p greater than 0.1). On the basis of these observations, we consider that the decrease in CBZ plasma level/dose ratio with increasing CBZ dose appears to be due to dose-dependent metabolic clearance of CBZ. The influence of age on plasma level/dose ratios for CBZ and its metabolites was not significant (p greater than 0.05). However, there was considerable interdose and diurnal variation in the plasma level/dose ratios, particularly for CBZ (28-41%); this must be taken into account when making dose adjustments based on plasma level/dose ratios.