Vigabatrin for refractory complex partial seizures

Abstract

The irreversible GABA transaminase inhibitor vigabatrin (VGB) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. The median number of CPS per month decreased from 11.0 to 5.0 after addition of VGB, and 51% of patients had a 50% or greater decrease in CPS frequency (p less than 0.001). Side effects (principally drowsiness, ataxia, and headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on VGB, side effects significantly interfered with functioning in only 13% of patients, and the efficacy:toxicity ratio warranted continued administration in 74% of patients. Coadministration of VGB resulted in a mean decrease of 20% in phenytoin serum concentration (p less than 0.001). Sixty-six patients with a favorable response to VGB during the single-blind study have been followed for a median of 16.7 months on VGB. No serious systemic or neurologic toxicity has been detected, and most patients have retained their initial favorable CPS control.

Vigabatrin‐induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability

“…The first and the last of these possibilities have been excluded in this study, and a displacing effect of VGB on serum protein bound PHT had been ruled out previously [2,3].…”

“…Moreover, enzyme induction is rarely selective and VGB is known not to affect the serum concentrations of other oxidized anticonvulsants [1] with the exception of phenobarbitone, whose concentrations may be marginally decreased [3]. In a recent study designed to assess the effect of VGB on PHT kinetics and metabolism, addition of VGB for 8 weeks in 13 epileptic patients not on chronic PHT treatment failed to affect significantly the elimination of Table 1 Urinary recoveries (0-24 h) of PHT and its metabolites pHPPH and mHPPH (expressed as % of the administered dosage) and urinary PHT/metabolites molar ratios during oral and intravenous dosing at baseline (pre-VGB) and after at least 5 weeks of add-on VGB in the 21 patients who completed the study.…”

“…When given as add-on therapy, VGB has been found to lower the serum concentrations of concurrently taken phenytoin (PHT) by 20-30% [1,2]. This effect occurs after about 5 weeks [2] and in some cases the decrease in PHT concentration has been considered to compromise seizure control [3].…”

“…It has been shown that it does not involve displacement of PHT from plasma proteins [2,3], and increase of PHT metabolism by VGB is unlikely because there is no evidence that VGB induces hepatic monooxygenases [1].…”

New Antiepileptic Drugs

“…It is now established that the metabolism of vigabatrin (albeit small) is inducible. Furthermore, recent data from patients prescribed vigabatrin as monotherapy suggest that vigabatrin plasma concentrations increase linearly with dose.1 8,19 (b) It is now known that there is an upper dose limit of efficacy for vigabatrin, which may be different for different patients. Thus, when the plasma concentrations resulting in maximum inhibition of brain GABA-T are exceeded, no additional anticonvulsive effect would occur.…”