SINGLE-DOSE PHARMACOKINETICS AND EFFECT OF FOOD ON THE BIOAVAILABILITY OF TOPIRAMATE, A NOVEL ANTIEPILEPTIC DRUG

Topiramate, a new antiepileptic drug effective in controlling partial- onset seizures, was administered to humans for the first time as singl e oral doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg in a phas e I safety and pharmacokinetic study. Model-independent pharmacokineti c data analysis was performed on plasma concentration and renal excret ion data for topiramate. Maximum plasma concentrations (C-max) were ob served between 1.4 and 4.3 hours after administration. Mean values for plasma C-max and area under the concentration-time curve (AUC) increa sed linearly with dose; however, a greater-than-proportional increase in both parameters was observed, probably due to saturable binding of the drug to erythrocytes, Mean oral clearance (Cl/F) was 22.5 to 36.1 mL/min and mean volume of distribution (Vd/F) was 38.5 to 58.0 L. Appr oximately 50% of the dose was excreted renally and cumulative urinary excretion increased linearly and proportion ally over the 200 mg to 1, 200 mg dose range. Elimination half-life (t(1/2)) values calculated fr om plasma (21.5 hrs) and urinary data (18.5 hrs) were consistent and i ndependent of dose. Intersubject variability was low for all parameter s. Renal clearance was 13.9 mL/min, suggesting that renal tubular reab sorption may be prominently involved in the renal handling of topirama te. The elimination profile of topiramate indicated that longer sampli ng times are necessary in future studies to more accurately determine the t(1/2). Food effect studies indicated a slight reduction in the ra te (similar to 10% decrease in mean C-max and mean t(max) similar to 2 hours later) but not the extent of absorption when topiramate was giv en with food. Topiramate demonstrates a number of favorable pharmacoki netic features, including linear and predictable dose-concentration re lationships, excretion mainly as unchanged drug by the kidney, a dose- independent t(1/2), low intersubject variability in pharmacokinetic pa rameters, and lack of clinically significant effect of food on bioavai lability.