Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of GABA, which increases the level of GABA in the synapses.

Vigabatrin is a racemic compound, and its -enantiomer is pharmacologically active.^,

Pharmacokinetics

With most drugs, elimination half-life is a useful predictor of dosing schedules and the time needed to reach steady state concentrations. In the case of vigabatrin, however, it has been found that the half-life of biologic activity is far longer than the elimination half-life.

For vigabatrin, there is no range of target concentrations because researchers found no difference between the serum concentration levels of responders and those of non-responders. Instead, the duration of action is believed to be more a function of the GABA-T resynthesis rate; levels of GABA-T do not usually return to their normal state until six days after stopping the medication.

Uses

Approved/clinically proven

Canada

In Canada, vigabatrin is approved for use as an adjunctive treatment (with other drugs) in treatment resistant epilepsy,complex partial seizures, secondary generalized seizures, and for monotherapy use in infantile spasms in West syndrome.

Mexico

As of 2003, vigabatrin is approved in Mexico for the treatment of epilepsy that is not satisfactorily controlled by conventional therapy (adjunctive or monotherapy) or in recently diagnosed patients who have not tried other agents (monotherapy).

Vigabatrin is also indicated for monotherapy use in secondarily generalized tonic-clonic seizures, partial seizures, and in infantile spasms due to West syndrome.

Unapproved/Investigational

In November of 2001, a team of scientists lead by Peter Zwanzger of the University of Munich reported that vigabatrin reduced cholecystokinin tetrapeptide-induced symptoms of panic disorder, in addition to elevated cortisol and ACTH levels, in healthy volunteers.

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How Does Vigabatrin Compare with Carbamazepine for Epilepsy?
From American Family Physician, 10/15/99 by Anne D. Walling

Vigabatrin reduces seizure activity primarily by increasing gamma aminobutyric acid (GABA) concentrations in the brain. Limited information is available concerning the role of this new drug as monotherapy for partial seizures.

All double-blind controlled studies of vigabatrin in the treatment of epilepsy have been placebo-controlled and have evaluated vigabatrin as an add-on drug in uncontrolled epilepsy. Only two studies of vigabatrin as monotherapy have been published. Chadwick and colleagues conducted a study of the safety and efficacy of vigabatrin compared with that of carbamazepine in the treatment of newly diagnosed partial seizures.

The double-blind randomized study began with 459 patients 12 to 65 years of age with previously untreated partial seizures. The study was completed by 130 patients assigned to receive vigabatrin and 132 patients assigned to receive carbamazepine. The study was conducted at 44 centers in 15 countries.

Vigabatrin was initiated in a daily dosage of 1 g, which was increased to an initial maintenance dosage of 2 g daily. Carbamazepine was initiated in a daily dosage of 200 mg, which was increased to an initial maintenance dosage of 600 mg daily. Dosages were adjusted upward or downward depending on the occurrence of seizures or adverse effects. Daily dosages ranged from 1 to 4 g of vigabatrin and 200 to 1,600 mg of carbamazepine to achieve seizure control with minimum toxicity. The primary outcome measure was the time to treatment failure because of adverse effects or lack of seizure control. Secondary outcomes included time to achieve remission lasting at least six months, time to the first seizure and the incidence and severity of adverse events.

In the intention-to-treat group, lack of therapeutic effect was the reason for withdrawal in 23 patients receiving vigabatrin and in nine patients receiving carbamazepine. Patients taking carbamazepine were more likely to withdraw before patients receiving vigabatrin, particularly during the first four to six months. After 12 months, remission for at least six months was achieved in 107 patients who received vigabatrin and in 116 patients who received carbamazepine.

The number of patients experiencing adverse events was similar in each group. At least one adverse event occurred in 195 (85 percent) of 229 patients who received carbamazepine and in 191 (84 percent) of 228 patients who received vigabatrin. Psychiatric symptoms were more common with vigabatrin (25 percent versus 15 percent), as was weight gain (11 percent versus 5 percent). Rash was reported by 22 (10 percent) patients taking carbamazepine, compared with seven (3 percent) patients taking vigabatrin. The most common reason for withdrawal from the medication was an adverse event, which was the reason for withdrawal in 43 patients who received vigabatrin and 61 patients who received carbamazepine.

The authors conclude that vigabatrin appears to be less effective but better tolerated than carbamazepine as monotherapy for newly diagnosed partial seizures. In view of the findings, plus new information that links long-term vigabatrin therapy to visual field loss, the authors do not recommend vigabatrin as first-line monotherapy.

Chadwick D, et al. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Lancet July 3, 1999; 354:13-9.

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