Abstracts

This study was designed to assess the safety and pharmacokinetics (PK) of zonisamide (ZNS) in pediatric patients with epilepsy. This phase II, multicenter, open-label study included pediatric patients with epilepsy on a stable dose of [le]2 other antiepileptic drugs (AEDs). Patients were grouped according to age: Group 1, 5 through 11 years; and Group 2, 12 through 15 years. Zonisamide was initiated at 1 mg/kg per day and titrated to 12 mg/kg per day or the maximum tolerated dosage. Steady-state serum ZNS concentration-time profiles were obtained at the 1-, 7-, and 12-mg/kg per day dosage levels on Days 13, 40, and 60, respectively. Pharmacokinetic parameters of enzyme-induced patients (ie, patients taking a known or expected inducer of ZNS metabolism, including carbamazepine, phenobarbital, phenytoin, or primidone) and those of noninduced patients were evaluated for each age group. Safety was evaluated via reports of treatment-emergent adverse events (TEAEs). Thirty-three patients were enrolled; 31 provided data for PK analysis. Sixteen patients (11 in Group 1 and 5 in Group 2) were taking inducers of ZNS metabolism. In both noninduced and induced patients, serum ZNS concentrations appeared to be dose dependent. In noninduced patients, Group 1 had lower maximum concentration (Cmax), area under the concentration-time curve to 12 hours (AUC0-12h), and apparent oral clearance (CL/F) values compared to Group 2. Group 2 had higher total body weight-normalized apparent oral clearance (CL/F/TBW) values compared to Group 1. However, none of these differences were statistically significant. In induced subjects, no significant differences in steady-state Cmax, AUC0-12h, CL/F, and CL/F/TBW were seen between Groups 1 and 2. Induced patients had apparently lower Cmax and AUC0-12h values compared with noninduced patients; mean CL/F and CL/F/TBW values were higher in induced versus noninduced patients. In both groups, greater than dose-proportional increases in Cmax and AUC0-12h were seen between the 1- and 7-mg/kg per day dosage levels; however, these values were dose proportional between the 7- and 12-mg/kg per day levels. All 33 patients reported at least 1 TEAE, most being mild to moderate in intensity. The most commonly reported ([ge]5 patients) ZNS-related TEAEs were somnolence (30.3%), anorexia (27.3%), asthenia (21.2%), and dizziness and nervousness (15.2% each). The frequency of TEAEs was similar between the 2 age groups. In 2 patients, 3 serious AEs (1 fatal and 2 nonfatal) were reported, which were considered unrelated to ZNS. Zonisamide PK were dose dependent in both age groups. Adjustment of ZNS dosing may be required when enzyme-inducing AEDs are introduced or discontinued in ZNS-treated pediatric patients. Zonisamide was found to be generally safe and well tolerated in this group of pediatric patients. (Supported by Eisai Inc.)