What is the role of vigabatrin (VGB) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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In the 1970s, GABA was recognized as an important inhibitory neurotransmitter in the central nervous system (CNS). Favoring the balance toward the GABA system was a major target of drug research, and soon vigabatrin (VGB) was developed. The US Food and Drug Administration approved VGB in 2009. Although effective, it can cause vision loss, and because of this risk, it is not used as a first-line agent and is available only through a restricted access program.

VGB is indicated as adjunctive therapy for adults and pediatric patients aged 2 years or older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss.

Additionally, it is indicated as monotherapy for infantile spasms in pediatric patients aged 1 month to 2 years for whom the potential benefits outweigh the potential risk of vision loss.

VGB is a close structural analogue of GABA, binding irreversibly to the active site of GABA-T. Newly synthesized enzymes take 4-6 days to normalize the enzymatic activity. In vivo studies in human and animal subjects have shown that VGB significantly increases extracellular GABA concentrations in the brain. VGB has no other known action. [43, 44, 45, 46]

VGB is highly soluble in water but only slightly soluble in ethanol. It is absorbed rapidly after oral ingestion, with an oral bioavailability of 100%. Time to peak concentration is approximately 2 hours, and the volume of distribution of the drug is 0.8 L/kg. About 10% of the plasma concentration is found in cerebrospinal fluid (CSF). Only a small fraction crosses the placenta.

VGB is excreted in urine (up to 95%) with a half-life of 4-7 hours. In elderly patients, clearance is reduced and the half-life may double. VGB does not induce the activity of hepatic enzymes. Correlation between plasma levels and clinical effect is poor.

VGB can reduce the plasma concentration of phenytoin (PHT) by 25%. This reduction probably is mediated by decreased absorption; however, the exact mechanism is unknown. No other pharmacokinetic or pharmacodynamic interactions are present.

VGB has been studied exhaustively in 9 double-blind controlled trials. These trials reported that 40-50% patients with refractory partial seizures had a reduction in seizure frequency of more than 50%, and as many as 10% of patients became seizure free. Many patients continued the drug after completion of the trial. The dose of VGB ranged from 1000-4000 mg/d.

VGB is less effective against primarily generalized tonic-clonic seizures and also may worsen myoclonic seizures or generalized absence seizures. Like tiagabine (TGB), VGB has been reported to cause absence status. Patients with myoclonus or Lennox-Gastaut syndrome do not respond well to VGB.

In placebo-controlled trials in patients with refractory epilepsy, 20% of children and 5% of adults showed an increase in seizures. VGB is very effective in the treatment of infantile spasms; therefore, it is the drug of choice for this indication in many countries.

The usual starting dose for adults is 500 mg twice daily, and this is increased by 250-500 mg every 1-2 weeks to a maximum dose of 4000 mg/d. In children, 40 mg/kg/d is the usual starting dose, with maintenance doses of 80-100 mg/kg.

The most common adverse effect of VGB is drowsiness. Other important adverse effects include neuropsychiatric symptoms, such as depression (5%), agitation (7%), confusion and, rarely, psychosis. Minor adverse effects, usually occurring at the onset of therapy, include fatigue, headache, dizziness, increase in weight, tremor, double vision, and abnormal vision. VGB has little effect on cognitive function. Acute hypersensitivity and idiosyncratic immunologic adverse effects are extremely rare.

VGB causes widespread intramyelinic vacuolization throughout the brains of rats and dogs; however, primate and human studies have not demonstrated such changes. VGB also affects the retina in some rodent species, and later human studies show visual field changes, characterized by nasal constriction and then concentric constriction, with preservation of central vision. In 1 series, visual field disturbances were found in more than 50% of cases. The mechanism of this effect is unknown and the risk factors are unclear. In some cases, it appears to be irreversible.

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