THE CLINICAL PHARMACOKINETICS OF THE NEWER ANTIEPILEPTIC DRUGS - FOCUS ON TOPIRAMATE, ZONISAMIDE AND TIAGABINE

Following the introduction of felbamate, gabapentin, lamotrigine, oxca rbazepine and vigabatrin in the early L990s, other new antiepileptic d rugs have been advancing in clinical development, Those most extensive ly evaluated to date include topiramate, zonisamide and tiagabine. Top iramate, licensed recently in the UK, acts multifactorially through th e blockade of sodium channels and kainate/AMPA receptors, enhancement of gamma-aminobutyric acid (GABA)ergic transmission and inhibition of carbonic anhydrase, It is well absorbed from the gastrointestinal trac t and negligibly bound to plasma proteins. When used as a monotherapy, topiramate is eliminated primarily in the urine in an unchanged form with a half-life of 20 to 30 hours; elimination is faster in patients receiving concurrent medication with enzyme-inducing anticonvulsants, in whom the extent of biotransformation becomes more prominent. Zonisa mide, which has been commercially available in Japan for some years, a lso has a multifactorial mode of action, possibly involving the blocka de of sodium channels, T-type calcium channels and inhibition of carbo nic anhydrase. It is rapidly absorbed, 50% bound to plasma proteins an d is eliminated predominantly by biotransformation; zonisamide has a h alf-life of 50 to 70 hours in monotherapy patients, or 25 to 35 hours in patients comedicated with enzyme-inducing anticonvulsants. Tiagabin e, a nipecotic acid derivative which inhibits GABA reuptake, is rapidl y and completely absorbed after oral intake, It is highly (96%) bound to plasma proteins and it is eliminated primarily by cytochrome P450 3 A-mediated oxidation, with a half-life of about 7 hours in healthy vol unteers, Tiagabine metabolism is also enhanced by concurrent medicatio n with enzyme-inducing anticonvulsants, resulting in a need to use dos ages larger than those required in monotherapy or valproic acid (sodiu m valproate)-treated patients. Additional investigational antiepilepti c agents included in this article are rufinamide (CGP 33101), fospheny toin, levetiracetam, losigamone, remacemide and stiripentol, All these drugs have undergone early characterisation with respect to pharmacok inetic features and interaction potential.