Topamax Clinical Pharmacology

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Topamax - Clinical Pharmacology [Topiramate]

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/ day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topiramate is 13-17% bound to human plasma proteins over the concentration range of 1-250 痢/ mL.

Metabolism and Excretion

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose).

Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/ F) is approximately 20 to 30 mL/ min in humans following oral administration.

Pharmacokinetic Interactions (see also Drug Interactions)

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effect of these interactions on mean plasma AUCs are summarized under PRECAUTIONS (Table 3).

Special Populations

Renal Impairment

The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30-69 mL/ min/ 1.73m 2 ) and by 54% in severely renally impaired subjects (creatinine clearance <30 mL/ min/ 1.73m 2 ) compared to normal renal function subjects (creatinine clearance >70 mL/ min/ 1.73m 2 ). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment (see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).