TOPIRAMATE - A REVIEW OF PRECLINICAL, PHARMACOKINETIC, AND CLINICAL-DATA

The antiepileptic drug (AED) topiramate is a monosaccharide derivative with a sulfamate functionality. It modulates voltage-dependent sodium conductance, potentiates gamma-aminobutyric acid-evoked currents, and blocks the kainate/AMPA lpha-amino-3-hydroxy-5-methylisoxazole-4-prop ionic acid) subtype of the glutamate receptor. Topiramate is rapidly a bsorbed and has linear, proportional, steady-state pharmacokinetics. I t has no known clinically significant effect on plasma levels of carba mazepine, valproic acid, or phenobarbital, although it may increase pl asma concentrations of phenytoin in some patients. When topiramate is used with hepatic enzyme-inducing AEDs, its plasma concentrations are approximately 50% lower than when it is administered alone. The effica cy of topiramate 200 to 1000 mg/d administered in two divided doses as adjunctive therapy for partial-onset seizures was investigated in fiv e double-masked, placebo-controlled trials. The median percentage redu ction in average monthly seizure frequency from baseline was 12% for p lacebo, compared with 30% for the 200-mg/d group and 48% for the 400-m g/d group. At a dosage of 400 mg/d, a seizure reduction of 75% or grea ter was seen in 22% of topiramate patients, compared with 7% of those receiving placebo; up to 9% of topiramate patients, compared with none of those receiving placebo, became seizure free. Although little addi tional efficacy was seen at dosages of 600, 800, and 1000 mg/d, dosing should be individualized, because some patients may respond to higher dosages. When topiramate is combined with other AEDs, the most common side effects at dosages of 200 to 400 mg/d are somnolence, dizziness, ataxia, psychomotor slowing, hesitant speech, and word-finding diffic ulties. Most patients who experienced adverse events during the first 8 weeks of the trials no longer experienced them by their last visit. Although there was a 1.5% incidence of renal stones that may be associ ated with carbonic anhydrase inhibition, more than 75% of patients exp eriencing a stone continued on therapy.