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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Revised guideline for prescribing vigabatrin in children - Letter to the Editor
From British Medical Journal, 1/27/01 by Andrew L Lux

Guideline's claim about infantile spasms is not based on appropriate evidence

EDITOR--The Vigabatrin Paediatric Advisory Group, which in 1998 produced a guideline to "help clinicians when prescribing vigabatrin in children," has now revised it.[1 2] We, the steering committee of the United Kingdom infantile spasm study (UKISS), responded to the original guideline.[3] Our opinion was that there is no evidence that vigabatrin is a better treatment of infantile spasms than hormonal treatments, such as prednisolone and synthetic adrenocorticotrophic hormone preparations.

When we challenged the claim that vigabatrin is the drug of choice, the advisory group offered no rebuttal. Now the claim is stated again, without any appropriate new evidence being produced. Indeed, the finding that visual field losses attributable to vigabatrin occur in children as well as adults strengthens any challenge to the guideline's claim.

We stand by our argument that no one has yet determined the best first line treatment for infantile spasms. To back our challenge we cited the one randomised trial that has compared vigabatrin and adrenocorticotrophic hormone; confidence intervals for this suggest that vigabatrin is unlikely to have a superior treatment effect.[4] Also, we pointed to a lack of studies using neurodevelopmental outcome measures and to new and emerging information about the safety of vigabatrin.

Our desire to gather reliable data is shared by many paediatricians and paediatric neurologists: consultants in over 140 health districts are helping our study to collect evidence about these treatments. Before clinicians can decide if any of the first line treatments for infantile spasms might reasonably be described as the drug of choice they will need to examine (when they become available) the results of studies such as the United Kingdom infantile spasm study.

Andrew L Lux clinical research fellow andrew@lux@ruh-bath.swest.nhs.uk

Stuart W Edwards UKISS research coordinator Bath Unit for Research in Paediatrics, Children's Centre, Royal United Hospital, Bath BA1 3NG

John P Osborne professor of paediatrics and child health

Royal United Hospital, Bath BA1 3NG

Eleanor Hancock specialist registrar in paediatric neurology.

Chelsea and Westminster Hospital, London SW 10 9NH

Anthony L Johnson statistician

MRC Biostatistics Unit, Institute of Public Health, Cambridge CB2 2SR

Colin R Kennedy consultant paediatric neurologist

Finbar J K O'Callaghan specialist registrar in paediatric neurolog),

Southampton General Hospital, Southampton SO9 4XY

Richard W Newton consultant paediatric neurologist Royal Manchester Children's Hospital, Manchester M27 1HA

Christopher M Verity consultant paediatric neurologist

Addenbrooke's Hospital, Cambridge CB2 2QQ

[1] Appleton RE. Guideline may help in prescribing vigabatrin. BMJ 1998;317:1322.

[2] Vigabatrin Paediatric Advisory Group. Guideline tot prescribing vigabatrin in children has been revised. BM] 2000;320:1404-5. (20 May.)

[3] Osborne JP, Edwards SW, Hancock E, Lux AL, O'Callaghan F. Johnson T, et al. Infantile spasms and vigabatrin. BMJ 1999;318:56-7.

[4] Vigevano F, Cilio MR. Vigabatrin vs ACTH as first-line treatment for infantile spasms: a randomized prospective stud),. Epilepsia 1997;38:12704.

Advisory group's reply

EDITOR--Both of Lux et al's letters (this one and that in 1999) have largely, and understandably, promoted the United Kingdom infantile spasm study; their comments have been of little relevance to both the initial[1] and revised[2] pragmatic clinical guideline. At the time that we wrote both guidelines, vigabatrin was the drug of first choice, on the basis of efficacy and safety evidence, in treating infantile spasms; it still remains the drug of choice.

We agree with Lux et al that there is no convincing evidence that vigabatrin shows superior efficacy to adrenocorticotrophic hormone or prednisolone either in controlling spasms or in long term neurodevelopmental outcome. It is disingenuous, though, to ignore the recognised benefits of using vigabatrin in treating infantile spasms--namely, that the drug seems to be effective in at least half of patients[3]; that its effect is rapid (usually less than seven days in patients responsive to vigabatrin[3 4]); and that, unlike adrenocorticotrophic hormone and prednisolone, it does not cause severe side effects.[5] The information currently available on visual field constriction does not alter this opinion, the reasons for which have been discussed recently in more detail.[6] With these issues in mind, the justification for the content of the pragmatic guideline should be obvious.

Although we support Lux et al's call for large and well designed comparative studies, methodological and ethical concerns about their study have precluded universal participation in it. Roughly 300 British children develop infantile spasms each year. For these children, their parents and carers, and their clinicians, treatment cannot be deferred pending the findings of the United Kingdom study, whose results will not be available for many years. In addition, because infants who have infantile spasms (and West's syndrome) do not constitute a homogeneous population, the study findings may prove inconclusive. In the interim the guideline simply provides clinicians with pragmatic advice about how and when to use vigabatrin in the paediatric epilepsies, including infantile spasms.[2]

We should emphasise that our opinion is shared by many paediatric neurologists outside the United Kingdom,[3 4 7] including paediatric neurologists in the United States (personal communication).

Vigabatrin Paediatric Advisory Group Members of the group are: Richard Appleton, consultant paediatric neurologist, Liverpool (to whom correspondence should be addressed at the Roald Dahl EEG Unit, Alder Hey Children's Hospital, Liverpool L12 2AP); Peter Baxter, consultant paediatric neurologist, Sheffield; David Calver, consultant ophthalmologist, London; Celia Cramp, consultant paediatrician, Shrewsbury; John Gibbs, consultant paediatrician, Chester; Graham Harding, consultant clinical neurophysiologist, Birmingham; John Livingston, consultant paediatric neurologist, Leeds; Richard Robinson, consultant paediatric neurologist, London; Isabelle Russell-Eggitt, consultant paediatric ophthalmologist, London; Sheila Wallace, consultant paediatric neurologist, Cardiff; and John Wild, senior lecturer in vision sciences, Birmingham.

[1] Appleton RE. Guideline for prescribing vigabatrin. BMJ 1998;317:1322.

[2] Vigabatrin Paediatric Advisory Group. Guideline for prescribing vigabatrin in children has been revised. BMJ 2000;320:1404-5. (20 May.)

[3] Aicardi J, Mumford JP, Dumas C, Wood S. (With Sabril IS, investigator, and peer review groups.) Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Epilepsia 1996;37:638-42.

[4] Chiron C, Dumas C, Jambaque 1, Mumford J, Dulac O. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Research 1997;26:389-95.

[5] Riikonen, Donner M. ACTH therapy in infantile spasms: side effects. Arch Dis Child 1980;55:664-72.

[6] Appleton RE, Peters ACB, Mumford JP, Shaw DE. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia 1999;40:1627-33.

[7] Fejerman N, Cersosimo R, Caraballo R, et al. Vigabatrin as a first-choice drug in the treatment of West syndrome. J Child Neurol 2000;15:161-5.

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