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 100–800mg, 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 200mg, 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.
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This research work was conducted and funded by Johnson & Johnson Pharmaceutical Research and Development. The work of Professor Meir Bialer was carried out in his capacity as a consultant to Johnson & Johnson Pharmaceutical Research and Development.
Maryanoff BE, Nortey SO, Gardocki JF, et al. Anticonvulsant O-alkyl sulfamates: 2,3:4,5-bis-O-(1-methylethylidene)-β-Dfructopyranose sulfamate and related compounds. J Med Chem 1987; 30: 880–7PubMedCrossRefGoogle Scholar
Shank RP, Gardocki JF, Vaught JL, et al. Topiramate: preclinical evaluation of a structurally novel anticonvulsant. Epilepsia 1994; 35: 450–60PubMedCrossRefGoogle Scholar
Ben-Menachem E. Topiramate. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 1063–70Google Scholar
Doose DR, Streeter AJ. Topiramate: chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott, Williams & Wilkins, 2002: 727–34Google Scholar
Gidal BE. Topiramate: drug interactions. In: Levy RH, Mattson TH, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott, Williams & Wilkins, 2002: 735–9Google Scholar
Doose DR, Walker SA, Gisclon LG, et al. Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug. J Clin Pharmacol 1996; 36: 884–9PubMedGoogle Scholar
Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia 2000; 40 Suppl. 1: S61–5CrossRefGoogle Scholar
Sachdeo RC, Sachdeo SK, Walker SA, et al. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 1996; 37: 774–80PubMedCrossRefGoogle Scholar
Sachdeo RC, Sachdeo SK, Levy RH, et al. Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia 2002; 43: 691–6PubMedCrossRefGoogle Scholar
Wu WN, McKown LA. Recent advances in biotransformation of CNS and cardiovascular agents. Curr Drug Metab 2000; 1: 255–70PubMedCrossRefGoogle Scholar
Riffits JM, Gisclon LG, Stubbs TJ, et al. A capillary gas Chromatographic assay with nitrogen phosphorous detection for the quantification of topiramate in human plasma, urine and whole blood. J Pharm Biomed Anal 1999; 19: 363–71CrossRefGoogle Scholar
Britzi M, Soback S, Isoherranen N, et al. Analysis of topiramate and its metabolites in plasma and urine of healthy subjects and patients with epilepsy by use of a novel liquid chromatography-mass spectrometry assay. Ther Drug Monit 2003; 25: 314–22PubMedCrossRefGoogle Scholar
Bajpai N, Roskos LK, Shen DD, et al. Routes of cytochromes P4502C9 and cytochrome 2C19 in stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 1996; 24: 1401–3PubMedGoogle Scholar
Faught E, Wilder BJ, Ramsay RE, et al. Topiramate placebocontrolled dose-ranging trial in refractory partial epilepsy using 200-, 400- and 600-mg daily dosages. Neurology 1996; 46: 1684–90PubMedCrossRefGoogle Scholar
Rosenfeld WE, Liao S, Kramer LD, et al. Comparison of the steady-state pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 1997; 38: 324–44PubMedCrossRefGoogle Scholar
Granneman GR, Marriott TB, Wang SI, et al. Aspects of the dose-dependent metabolism of valproic acid. In: Levy RH, Pitlick WH, Eichelbaum M, et al., editors. Metabolism of antiepileptic drugs. New York: Raven Press, 1984: 97–103Google Scholar
Anderson GD, Acheampong AA, Wilensky AJ, et al. Effect of valproate dose on formation of hepatotoxic metabolites. Epilepsia 1992; 33: 736–42PubMedCrossRefGoogle Scholar
Doose DR, Walker SA, Pledger G, et al. Evaluation of phenobarbital and primidone/phenobarbital (primidone active metabolite) plasma concentrations during administration of addon topiramate therapy in five multicenter, double blind, placebo controlled trials in outpatients with partial seizures [abstract]. Epilepsia 1995; 36 Suppl. 3: 158Google Scholar
Stephens LJ, Sill GJ, Brodie MJ. Lamotrigine and topiramate may be a useful combination. Lancet 1998; 351: 958–9Google Scholar
Doose DR, Brodie MJ, Wilson EA, et al. Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epileptic patients. Epilepsia 2003; 44: 917–22PubMedCrossRefGoogle Scholar
May TW, Rambeck B, Juregns U. Serum concentrations of topiramate in patients with epilepsy; influence of age and comedication. Ther Drug Monit 2002; 24: 366–74PubMedCrossRefGoogle Scholar
Berry DJ, Besag FM, Pool F, et al. Lack of an effect of topiramate on lamotrigine serum concentrations. Epilepsia 2002; 43: 818–23PubMedCrossRefGoogle Scholar
Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isozymes. Epilepsia 2000; 41 Suppl. 1: S35–9PubMedCrossRefGoogle Scholar
Swenson ER. Respiratory and renal roles of carbonic anhydrase in gas exchange and acid-base regulation. In: Chegwidden WR, Carter ND, Edwards YH, editors. The carbonic anhydrases: new horizons. Basel: Birkhauser-Verlag, 2000: 281–341Google Scholar
Fromming JS, Francis Lam YW, Jann MW, et al. Pharmacokinetics of haloperidol. Clin Pharmacokinet 1989; 17: 396–423CrossRefGoogle Scholar
Shultz P, Dick P, Blaschke TF, et al. Discrepancies between pharmacokinetic studies of amitriptyline. Clin Pharmacokinet 1985; 10: 257–68CrossRefGoogle Scholar
Colangelo PM, Blouin RA, Steinmetz JE, et al. Age and propranolol stereoselective disposition. Clin Pharmacol Ther 1992; 51: 489–94PubMedCrossRefGoogle Scholar
Little PJ, Jennings GL, Skews H, et al. Bioavailability of dihydroergotamine in man. Br J Pharmacol 1982; 13: 785–90CrossRefGoogle Scholar
Doose DR, Wang S-S, Padmanabhan P, et al. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia 2003; 44: 540–9PubMedCrossRefGoogle Scholar
Rosenfeld WE, Doose DR, Walker SA, et al. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38: 317–23PubMedCrossRefGoogle Scholar
Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the pharmacokinetics of oral contraceptive in healthy women. Epilepsia 2002; 43: 697–702PubMedCrossRefGoogle Scholar
Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine and valproate monotherapy: double blind comparison in newly diagnosed epilepsy. Acta Neurol Scand 2003; 107: 165–75PubMedCrossRefGoogle Scholar
Gilliam FG, Veloso F, Bomhof MAM, et al. A dose-comparison trial of topiramate as monotherapy in recently diagnosed partial epilepsy. Neurology 2003; 60: 196–202PubMedCrossRefGoogle Scholar
Mathew NT, Schmitt J, Jacobs D, et al. Topiramate in migraine prevention (MIGR-002): effect on migraine frequency [abstract]. Neurology 2003; 60 Suppl. 1: A336Google Scholar
Lainez MJA, Pascual J, Pasual AM, et al. Topiramate in the prophylactic treatment of cluster headache. Headache 2003; 43: 784–9PubMedCrossRefGoogle Scholar