Abstracts

RATIONALE: Zonisamide is a newly approved antiepileptic drug (AED) with little information on pharmacokinetics available. The results of plasma level data from the double-blind study are reported here. METHODS: Patients taking either carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) having at least four complex partial seizures per month were randomized into a multicenter placebo controlled double-blind study. Zonisamide (ZNS) was started at 100 mg/day and increased weekly to achieve plasma levels of up to 40 ?g/ml or a maximum daily dose of 600 mg. Doses of concurrent AEDs were kept constant throughout the study. Trough serum levels (total and free) of ZNS and the concurrent AEDs were obtained prior to each dosage increase of ZNS. RESULTS: Clearnace (Cl) of ZNS decreased as plasma levels increased. Free Cl decreased from 0.5181 1/h (levels < 10 ?g/ml) to 0.01730 l/h (levels >40 ?g/ml). Protein binding decreased with higher plasma levels (38.8% bound - ZNS < 10 ?g/ml; 64.6% bound - ZNS >40?g/ml). The plasma levels from the first 4 weeks of treatment showed non-linear dose-level relationship. Michaelis-Menten kinetic constans could be calculated during acute (weeks 1-4) and chronic (weeks 8-24) treatment in eight patients. The Km did not change from acute (15.4 ?g/ml) to chronic (16.3?g/ml) periods. Vmax increased in six patients from a mean of 0.36783 (acute) to a mean of 0.59588 with chronic dosing. No change was found in the other two with a Vmax being 0.3039 L/kg/h with both acute and chronic dosing. CONCLUSIONS: The clearance of ZNS increases with time indicating that some autoinduction occurs with chronic dosing. Calculation of the Michaelis-Menten kinetic constants indicate that metabolism becomes non-linear at plasma levels at which ZNS is effective but not toxic.