Pharmacokinetics and metabolism of topiramate

The pharmacokinetics and pharmacokinetic interactions of topiramate (TPM) in humans have been studied quite extensively The available information on TPM pharmacokinetics is derived from studies that were specifically designed for this purpose. In contrast to most conventional antiepileptic drugs, the pharmacokinetic profile of TPM combines most of the properties that are desirable for an antiepileptic drug. Topiramate is rapidly absorbed, with a high bioavailability that is not affected by concomitant food intake. The volume of distribution is 0.6-0.8 l/kg, suggesting distribution into total body water. The binding of TPM to serum proteins is low, which precludes the displacement interactions that are seen between highly bound drugs such as valproate and phenytoin. The elimination kinetics of TPM are strictly linear and, accordingly, there is a linear relationship between maintenance dose and steady-state plasma levels. Topiramate is excreted predominantly by the kidneys as unmetabolized drug. This is generally associated with lower interpatient variability in elimination kinetics. Approximately 20% of orally administered TPM is metabolized in the liver and this fraction may increase up to 50% in the presence of enzyme-inducing drugs, such as phenytoin or carbamazepine. During chronic ingestion of TPM, there is no clinically significant accumulation of any active metabolite, even in patients taking enzyme-inducing drugs. The elimination half-life of TPM is relatively long and does not require more frequent than twice-daily dosing. Finally, TPM has a relatively low potential for drug interactions. The clinically significant pharmacokinetic interactions between TPM and other antiepileptic drugs are limited to an increase in the clearance of TPM when inducing drugs such as phenytoin or carbamazepine are added. TPM has little or no effect on the pharmacokinetics of other antiepileptic drugs, but it can increase the clearance of the estrogenic component of oral contraceptives by up to 30%.