Developmental and therapeutic pharmacology of antiepileptic drugs

We investigated the clinical effects and plasma levels of zonisamide (ZNS) in children with cryptogenic localization-related epilepsies. ZNS is absorbed slowly from the gastrointestinal tract, and its biological half-life is long as compared with that of other common antiepileptic drugs. The peak-to-trough plasma level ratios during a day were as small as 1.28 +/- 0.15 in children taking a daily dose of 8 mg/kg of ZNS once a day as a single drug. The plasma level (microg/ml) to dose (mg/kg/day) ratios estimated by the trough and peak plasma levels both increased with advancing age, but the peak-to-trough plasma level ratios were maintained almost uniformly throughout the pediatric age period. A wide range of the plasma levels was associated with complete freedom from seizures. The range of the plasma levels in patients who did not respond to ZNS was higher than that in the controlled group. However, the clinical effects of ZNS were in agreement with the range of generally accepted therapeutic plasma levels of ZNS, 15-40 microg/ml. Any patient who receives polytherapy is at risk to develop 1 or more drug interactions. Concurrent administration of carbamazepine (CBZ) decreases plasma concentrations of ZNS. However, ZNS does not alter plasma concentrations of CBZ or its primary metabolite, carbamazepine-10,11-epoxide (CBZ-E). It is evident that the concurrent administration of lamotrigine (LTG) affects plasma concentrations of CBZ-E, while plasma CBZ levels remain unaltered. However, the effect of LTG on plasma concentrations of CBZ-E is small, and none of the study patients showed toxic plasma concentrations of CBZ-E or associated clinical toxicity. Drug-protein binding interactions are another source of side effects. A simultaneous administration of valproic acid increases the total plasma CBZ-E levels relative to the CBZ dose associated with the raised free fractions of CBZ and CBZ-E. The high free plasma concentrations of CBZ-E above 1.5 microg/ml may be responsible for the side effects.