Developmental and Therapeutic Pharmacology of Antiepileptic Drugs

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Zonisamide (ZNS) is a new antiepileptic drug developed in Japan. It is absorbed slowly from the gastrointestinal tract, and its biological half-life is long as compared with those of other prevalent antiepileptic drugs. We investigated drug interaction between ZNS and carbamazepine (CBZ) in children with cryptogenic localization-related epilepsies whose seizures were not controlled by a once-daily dose of ZNS monotherapy, despite maintaining high plasma levels.Twelve patients aged 5 to 16 (mean, 12 years and 1 month) were first treated with ZNS alone, CBZ was thenadded. After combination therapy with ZNS and CBZ,drug therapy was changed to CBZ monotherapy in 9 of the 12 patients. ZNS was ingested once a day in the morning. Blood samples for determination of plasma concentrations were taken before and 4 hours after the morning dose, each representing the trough and peak levels in a day. CBZ was prescribed in two divided doses per day.When the daily dosage of 15.1<plus-minus>3.0mg/kg of CBZ was added to ZNS monotherapy (11.1<plus-minus>2.5mg/kg/day) in 12 patients, trough and peak levels of ZNS decreased from 35.4<plus-minus>10.0 to 22.2<plus-minus>9.8mug/ml and 43.0<plus-minus>11.3 to 28.1<plus-minus>12.5mug/ml, respectively. Plasma levels of CBZ and its main metabolite carbamazepin-10,11-epoxide (CBZ-E) before the morning dose were 6.05<plus-minus>1.98 and 1.32<plus-minus>0.23mug/ml, and those 4 hours after the morning dose were 9.06<plus-minus>2.83 and 1.61<plus-minus>0.35mug/ml, respectively. On the other hand, there were no significant differences in plasma levels of CBZ nor CBZ-E,whether CBZ was used alone or combined with ZNS in 9 patients in whom drug therapy was changed from combination with CBZ and ZNSConcurrent administration of CBZ decreases plasma concentrations of ZNS,but ZNS has no effect on plasma concentrations of both CBZ and CBZ-E.