Topiramate and Phenytoin Pharmacokinetics During Repetitive Monotherapy and Combination Therapy to Epileptic Patients

Abstract

Summary:Purpose: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment.Methods: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations.Results: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (±SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 ± 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 M (11% inhibition) and 900 M (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy Conclusions: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT. Key Words: Topiramate-PhenytoinAntiepileptics-Pharmacokinetics-Drug interactionsEpilepsy.Topiramate [TPM; Topamax; 2,3:4,5-bis-O-(1-methylethylidene)-␤-D-fructopyranose sulfamate] (Fig. 1) is a structurally novel, sulfamate-substituted monosaccharide, the antiepileptic activity of which is mediated by multiple mechanisms of action (1,2). The mechanism of action of TPM include interference with voltage-gated Na + channels, blockade of kainate/AMPA-type glutamate receptors, enhancement of ␥-aminobutyric acid (GABA)-receptor action by interaction with a nonbenzodiazepine (non-BZD) receptor site, inhibitory effect on Ca 2+ activated L-channel currents, and inhibition of carbonic anhydrase isoenzymes (2,3). TPM is currently approved in more than 80 countries and is available as tablets and as a sprinkle formulation for adult and pediatric (age 2-16 years) use (4).The pharmacokinetics of TPM are characterized by rapid absorption, a long half-life (...

The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

“…Six metabolites of TPM were detected in human urine without significant clinical activity [168]. TPM can partially inhibit CYP2C19 [169]. …”

Review of topiramate for the treatment of epilepsy in elderly patients

“…Factors that may slow the absorption include high fat foods and concomitant medications, such as valproate, carbamazepine, and phenytoin, which produce changes consistent with the metabolic changes resulting from cytochrome P450 enzyme induction 32,33…”

“…The six known metabolites of TPM themselves show little to no pharmacological activity 37. While TPM alone does not appear to either inhibit or induce drug metabolizing enzymes at clinical doses, it does inhibit CYP2C19 at plasma concentrations doses equivalent to 5% to 15% times higher than recommended 33. Regression analysis has found that when combined with PHT, CBZ, phenobarbital, and oxcarbazepine, TPM concentrations were significantly lower, compared with TPM concentrations during monotherapy 40.…”

Required propofol dose for anesthesia and time to emerge are affected by the use of antiepileptics: prospective cohort study

“…Valproate inhibits CYP2C9 in vitro [ 17 ]. Clinically, phenytoin inhibits CYP2C9, and similarly, topiramate inhibits CYP2C19 [ 18 , 19 ]. Carbamazepine inhibits 2C19 [ 20 ].…”