Topiramate pharmacokinetics

Rosenfeld, W. E. et al., A study of topiramate pharmacokinetics and tolerability in children with epilepsy, Pediatr. Neurol, 20 339-344, 1999. 

Lamotrigine had no effect on topiramate pharmacokinetics in one study in 13 patients. The oral clearance of topiramate 4(X) mg daily was 2.6 L/hour when given alone, and 2.7 L/hour when given with lamotrigine, and the AUC and plasma levels of topiramate were also similar. ... 

Wilensky AJ, Ojemann LM, ChemeUr T, Margul BL, Doose DR. Topiramate pharmacokinetics in epileptic patients receiving carbamazepine. Epilepsia (1989) 30, 645-6. 

The pharmacokinetics of topiramate are linear with peak plasma concentrations (occurring in about 2 hours) of 25 pM after 400 mg daily (Shank et al., 2000). Topiramate is poorly bound to plasma proteins (15%) and it binds to erythrocytes. In rats the maximal concentration in the brain when administered at 10 mg/kg was 10 pM (Shank et ah, 2000). It is not extensively metabolized in humans and is eliminated (70%) unchanged in urine. Six minor metabolites have been identified, none with anticonvulsant activity. The average elimination half-life is 21 hours (Shank et ah, 2000). 

Pharmacokinetics Topiramate is well absorbed, with an oral bioavailability of 80 percent. Peak concentrations occur in about two hours. Some 30 percent of each dose is metabolized, the remainder is excreted unchanged in the urine. The half-life of topiramate is about 20 to 25 hours. 

Outlook Among the newer antiepileptics, gabapentin, oxycarbazepine, lamotrigine, and topiramate are now endorsed as primary monotherapeutics for both partial and generalized seizures. Their pharmacokinetic characteristics are generally more desirable than those of the older drugs. 

Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000 41 (Supp11) S3-9. 

Pemcca E, Bialer M. The clinical pharmacokinetics of the newer antiepUeptic dmgs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996 31(1) 29 6. 

Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997 38(3) 317-23. 

Sachdeo RC, Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kunze KL, Mather GG, Roskos LK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Bialer M. Topiramate and pheny-toin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia 2002 43(7) 691-6. 

Perucca E. Pharmacokinetic profile of topiramate in comparison with other new anti-epileptic drugs. Epilepsia 1996 37(Suppi 2) S8-13. 

Langtry HD, Gillis JC, Davis R. Topiramate A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy. Drugs 1997 54 752-773. 

PHARMACOKINETICS Topiramate is rapidly absorbed after oral administration, exhibits little (10-20%) binding to plasma proteins, and is mainly excreted unchanged in the urine. Its tj is -1 day. Reduced plasma concentrations of estradiol occur with concurrent topiramate, suggesting that low-dose oral contraceptives should be avoided in this setting. 

In children from 4 to 17 years of age, topiramate exhibits linear pharmacokinetics, with a 50% increase in clearance rate compared to adults (95). Topiramate may require up to a 50% dose reduction in patients with renal insufficiency, and a replacement dose may be needed after renal dialysis. Topiramate has demonstrated teratogenicity in animal studies. 

Sachdeo, R. C., Topiramate clinical profile in epilepsy, Clin. Pharmacokinet., 34 335-346, 1998. 

Topiramate does not appear to alter the pharmacokinetics of lamotrigine, although one study su ested that it reduced lamotrigine levels. Lamotrigine has no effect on topiramate levels. 

The balance of the evidence suggests that there is no important pharmacokinetic interaction between topiramate and lamotrigine. No special precautions appear to be necessary during concurrent use. 

There appears to be no pharmacokinetic interaction between pregabalin and carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, alcohol, lorazepam, or oxycodone. However, the impairment of cognitive and gross motor function caused by oxycodone was additive with pregabalin, and pregabalin may potentiate the effects of alcohol and lorazepam. 

The clearance of retigabine is increased by carbamazepine and phenytoin, but not by phenobarbital, topiramate, or valproate. Ret abine does not alter the pharmacokinetics of any of these antiepileptics. There is a modest pharmacokinetic interaction between retigabine and lamotrigine. 

The preliminary report of a study notes that the pharmacokinetics of retigabine and topiramate were not altered by concurrent use in patients with epilepsy. No special dosing precautions are necessary. 

In a study in 12 epileptic patients topiramate titrated up to a maximum of 400 mg twice daily had no effect on the steady-state plasma levels of carbamazepine 300 to 800 mg every 8 hours or on its main metabolite, carbamazepine-10,11-epoxide. An earlier study in epileptic patients also reported that topiramate does not affect the pharmacokinetics of carbamazepine. In contrast, another report describes 2 patients taking a maximum tolerated dose of carbamazepine who started treatment with topiramate and subsequently developed symptoms suggestive of carbamazepine toxicity. In both these cases, the symptoms resolved when the carbamazepine dose was reduced, and this enabled continued titration of the topiramate dose in one. A review of the clinical use of these two drugs found another 23 cases that fitted this pattern. Carbamazepine levels were not reported. ... 

The topiramate plasma levels and AUC were found to be about 40% lower in the presence of carbamazepine in a study in 12 epileptic patients. A population pharmacokinetic study reported that patients taking carbamazepine had 32% lower morning topiramate level than patients not taking enzyme-inducing antiepileptics. In a study in healthy subjects carbamazepine 600 mg daily was found to cause a twofold increase the clearance of a single 200-mg dose of topiramate. The mean half-life of topiramate decreased from 29 to 19 hours. There was also a two- to threefold increase in the formation of the 2 major metabolites of topiramate (2,3-diol-TPM and 10-OH-TPM), although 41% of topiramate was excreted unchanged in the urine in the presence of carbamazepine. In contrast, an earlier study reported that carbamazepine did not have a major effect on the pharmacokinetics of topiramate. ... 

Sachdeo RC, Sachdeo SK, Walker SA, Kramer LD, Nayak RK, Doose DR. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant dierapy. Epilepsia (1996) 37, 774-80. 

Britzi M, Perucca E, Soback S, Levy RH, Fattore C, Crema F, Gatti G, Doose D Maryanoff BE, Bialer M Pharmacokinetic and metabolic investigation of topiramate disposition in healdiy subjects indie absence and in the presence of enzyme induction by carbamazepine. Epilepsia (2005) 46,378-84. 

Topiramate appears not to alter the pharmacokinetics of phenobarbital or primidone. Phenobarbital reduces topiramate levels. 

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