Pharmacokinetic Interactions of Topiramate

Abstract

Topiramate is a new antiepileptic drug (AED) that has been approved worldwide (in more than 80 countries) for the treatment of various kinds of epilepsy. It is currently being evaluated for its effect in various neurological and psychiatric disorders. The pharmacokinetics of topiramate are characterised by linear pharmacokinetics over the dose range 100-800 mg, low oral clearance (22-36 mL/min), which, in monotherapy, is predominantly through renal excretion (renal clearance 10-20 mL/min), and a long half-life (19-25 hours), which is reduced when coadministered with inducing AEDs such as phenytoin, phenobarbital and carbamazepine. The absolute bioavailability, or oral availability, of topiramate is 81-95% and is not affected by food. Although topiramate is not extensively metabolised when administered in monotherapy (fraction metabolised approximately 20%), its metabolism is induced during polytherapy with carbamazepine and phenytoin, and, consequently, its fraction metabolised increases. During concomitant treatment with topiramate and carbamazepine or phenytoin, the (oral) clearance of topiramate increases 2-fold and its half-life becomes shorter by approximately 50%, which may require topiramate dosage adjustment when phenytoin or carbamazepine therapy is added or discontinued. From a pharmacokinetic standpoint, topiramate is a unique example of a drug that, because of its major renal elimination component, is not subject to drug interaction due to enzyme inhibition, but nevertheless is susceptible to clinically relevant drug interactions due to induction of its metabolism. Unlike old AEDs such as phenytoin and carbamazepine, topiramate is a mild inducer and, currently, the only interaction observed as a result of induction by topiramate is that with ethinylestradiol. Topiramate only increases the oral clearance of ethinylestradiol in an oral contraceptive at high dosages (>200 mg/day). Because of this dose-dependency, possible interactions between topiramate and oral contraceptives should be assessed according to the topiramate dosage utilised. This paper provides a critical review of the pharmacokinetic interactions of topiramate with old and new AEDs, an oral contraceptive, and the CNS-active drugs lithium, haloperidol, amitriptyline, risperidone, sumatriptan, propranolol and dihydroergotamine. At a daily dosage of 200 mg, topiramate exhibited no or little (with lithium, propranolol and the amitriptyline metabolite nortriptyline) pharmacokinetic interactions with these drugs. The results of many of these drug interaction studies with topiramate have not been published before, and are presented and discussed for the first time in this article.

A Nonlinear Mixed Effects Modelling Analysis of Topiramate Pharmacokinetics in Patients with Epilepsy

“…21,23) Enzyme induction by carbamazepine is associated with an approximately 2 to 3-fold increase in topiramate metabolic clearance. 7,10,22,24) It is interesting to note that in some studies in patients taking carbamazepine, topiramate renal clearance was also found to be significantly increased. 10,22) In contrast to carbamazepine, drug interaction with phenobarbital is considered as minor.…”

“…4,7,10,[20][21][22][23][24] Carbamazepine significantly reduces topiramate concentration-to-dose ratio compared to topiramate monotherapy in both children and adults. 21,23) Enzyme induction by carbamazepine is associated with an approximately 2 to 3-fold increase in topiramate metabolic clearance.…”

“…3,7,8) With the commonly used dosage regimen, serum topiramate concentrations in the range between 16 and 60 mmol/l have been reported.…”

“…4,6) At steadystate the renal clearance of topiramate is 1.02 l/h 6) and its elimination half-life (t 1/2 ) varies from 20 to 30 h. 1,4) Consequently, the steady-state is being reached in 4 to 8 d. 2) Over the dose range 100-800 mg the relationship between topiramate dose and serum concentration is linear in both adults and children. 3,7,8) With the commonly used dosage regimen, serum topiramate concentrations in the range between 16 and 60 mmol/l have been reported. 3) A wide range of doses and serum concentrations have been associated with optimal clinical response.…”

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

“…TPM is orally well absorbed with a bioabailability of 81∼95% [211] and there is a linear relationship between TPM dose and serum concentrations [212,213]. In three double-blind placebo-controlled add-on trials, seizure control was improved with serum TPM concentrations in the narrow range of 10 to 15 μmol/l and adverse events were also generally associated with higher TPM concentrations [214].…”