Vigabatrin

Vigabatrin is a selective irreversible inhibitor of GABA transaminase, the enzyme responsible for the breakdown of GABA (gamma aminobutyric acid). Vigabatrin increases the concentration of GABA, the major inhibitory neurotransmitter in the brain.

Controlled and long-term clinical trials have shown that vigabatrin is an effective anticonvulsant agent when given as first line treatment in patients with infantile spasms and as add-on therapy in patients with epilepsy not controlled satisfactorily by conventional therapy. This efficacy is particularly marked in patients with seizures of partial origin.

Adults

Absorption

Vigabatrin is a water soluble compound and it is rapidly and completely absorbed from the gastrointestinal tract. Food administration does not alter the extent of vigabatrin absorption. Time to reach maximum plasma concentrations (t_max) is approximately 1 hour.

Distribution

Vigabatrin is widely distributed with an apparent volume of distribution slightly greater than total body water. Binding to plasma proteins is negligible. Plasma and cerebrospinal fluid concentrations are linearly related to dose over the recommended dose range.

Biotransformation

Vigabatrin is not significantly metabolised. No metabolites have been identified in plasma.

Elimination

Vigabatrin is eliminated via renal excretion with a terminal half-life of 5-8 hours. Oral clearance (Cl/F) of vigabatrin is approximately 7 l/h (i.e. 0.10 l/h/kg). Approximately 70% of a single oral dose was recovered as unchanged drug in the urine in the first 24 hours post-dose.

Pharmacokinetic/pharmacodynamic relationship(s)

There is no direct correlation between plasma concentration and efficacy. The duration of the effect of the medicinal product is dependent on the GABA transaminase re-synthesis rate.

Paediatric population

Pharmacokinetic properties of vigabatrin have been investigated in groups of six neonates (age 15-26 days), six infants (age 5-22 months) and six children (age 4.6-14.2 years) with refractory epilepsy.

After administration of a single 37-50 mg/kg dose of an oral solution vigabatrin t_max was approximately 2.5 hours in neonates and infants, and 1 hour in children. Mean terminal half-life of vigabatrin was about 7.5 hours in neonates, 5.7 hours in infants and 5.5 hours in children. The mean Cl/F of active S-enantiomer of vigabatrin in infants and children was 0.591 l/h/kg and 0.446 l/h/kg respectively.

Animal safety studies carried out in the rat, mouse, dog and monkey have indicated that vigabatrin has no significant adverse reactions on the liver, kidney, lung, heart or gastrointestinal tract.

In the brain, microvacuolation due to intramyelinic oedema has been observed in white matter tracts of rat, mouse and dog at doses of 30-50 mg/kg/day. In the monkey these lesions are minimal or equivocal. In both rat and dog they were reversible on stopping vigabatrin treatment and even regressed with continued treatment.

Vigabatrin-associated retinotoxicity has been observed in 80-100% of albino rats at the dose of 300 mg/kg/day orally, but not in pigmented rats, dogs or monkeys. The retinal changes in albino rats were characterised as focal or multifocal disorganisation of the outer nuclear layer while the other layers of retina were not affected.

Animal experiments have shown that vigabatrin has no negative influence on fertility or pup development. No teratogenicity was seen in rats in doses up to 150 mg/kg (3 times the human dose) or in rabbits in doses up to 100 mg/kg. However, in rabbits, a slight increase in the incidence of cleft palate at doses of 150-200 mg/kg was seen.

Studies with vigabatrin revealed no evidence of mutagenic or carcinogenic effects.