Molecular pharmacodynamics, clinical therapeutics, and pharmacokinetics of topiramate

Abstract

Topiramate (TPM; TOPAMAX) is a broad-spectrum antiepileptic drug (AED) that is approved in many world markets for preventing or reducing the frequency of epileptic seizures (as monotherapy or adjunctive therapy), and for the prophylaxis of migraine. TPM, a sulfamate derivative of the naturally occurring sugar D-fructose, possesses several pharmacodynamic properties that may contribute to its clinically useful attributes, and to its observed adverse effects. The sulfamate moiety is essential, but not sufficient, for its pharmacodynamic properties. In this review, we discuss the known pharmacodynamic and pharmacokinetic properties of TPM, as well as its various clinically beneficial and adverse effects.

Figure 1

Topiramate and its synthesis.

Figure 2

Log–log plot of the anticonvulsant potency (inverse of ED₅₀ obtained with mouse MES test) versus the inhibition of CA‐II (which is the most prevalent CA isozyme). The data are the results obtained for TPM and 26 structural analogues. Note that the slope of 0.25 indicates that for every 10‐fold difference in anticonvulsant potency, there is a 10,000‐fold difference in CA‐inhibition potency. Details of the assay procedures are described elsewhere (Shank et al. 1994, 2006; Dodgson et al. 2000).

Figure 3

Effect of long‐term dosing (102 weeks) of TPM on body weight of male and female Wistar rats. Topiramate was mixed into pulverized “lab chow,” which was provided ad libitum. To ensure that each rat received the intended dose (20, 45, or 120 mg/kg), the amount of TPM added to the chow was adjusted weekly based on the amount of chow each rat consumed during the previous week (n= 50 per group). Body weight was recorded every two weeks. The tendency for the relative decrease in the body weight of TPM‐treated rats to reverse reflects, in part, a plateau in the body weight of the control rats, and eventually actual weight loss in the control rats. Topiramate did not have an effect on food consumption in male rats; however, in females there was a dose‐related decrease that reached statistical significance at the highest dose (p < 0.05).