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Keywords:

  • antiepileptic drugs;
  • γ-aminobutyric acid;
  • mechanism of action;
  • review;
  • vigabatrin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand: 2011: 124 (Suppl. 192): 5–15. © 2011 John Wiley & Sons A/S.

Discovered more than three decades ago, vigabatrin is approved in more than 50 countries as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with infantile spasms. Contrary to a fairly common misperception, the compound’s mechanism of action is very well-characterized in animal models and cell cultures. γ-Aminobutyric acid (GABA)-ergic synapses comprise approximately 30% of all synapses within the central nervous system, and therein underlies the primary mode of synaptic inhibition. Vigabatrin was rationally designed to have a specific effect on brain chemistry by inhibiting the GABA-degrading enzyme, GABA transaminase, resulting in a widespread increase in GABA concentrations in the brain. The increase in GABA functions as a brake on the excitatory processes that can initiate seizure activity. Despite the short half-life of vigabatrin in the body (5–7 h) and its relatively low concentration in cerebrospinal fluid (10% of the concentration observed in plasma), it has the profound effect of increasing GABA concentration in the brain for more than a week after a single dose in humans. This effect persists steadily over years of vigabatrin administration and results in significant and persistent decreases in seizure activity. Vigabatrin can be effective with once-daily dosing. Because of its specificity, vigabatrin has helped researchers explore the specific mechanisms within the brain that underlie seizure activity.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

Vigabatrin has been available for more than three decades. First approved in the United Kingdom in 1989, vigabatrin is now approved in more than 50 countries worldwide for the treatment of epilepsy (1, 2). The development of vigabatrin in the United States was delayed based on safety concerns, including intramyelinic edema and peripheral visual field defects (pVFDs) (3, 4). Clinical trials were temporarily suspended in 1983 after intramyelinic edema was observed in animal studies, but trials resumed in 1990 after such toxicity was not demonstrated in humans. Reports of pVFDs associated with vigabatrin were first published in 1997 (5) and resulted in a second regulatory delay. Vigabatrin was approved in the United States in 2009 as adjunctive therapy for adult patients with refractory complex partial seizures (rCPS) who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with infantile spasms (6, 7). The approval of vigabatrin by the US Food and Drug Administration was accompanied by the implementation of a comprehensive Risk Evaluation and Mitigation Strategy (REMS), which is administered through the Lundbeck Inc. Support, Help And Resources for Epilepsy (SHARE) program.

More than three decades after the development of vigabatrin, there appears still to be some misunderstanding regarding vigabatrin’s known mechanism of action (MOA) (8, 9). However, vigabatrin’s activity has been well-characterized, as the compound was actually developed as a designer drug with one specific MOA in mind: the irreversible inhibition of γ-aminobutyric acid (GABA) transaminase (1, 10–15). In fact, vigabatrin is among the few antiepileptic drugs (AEDs) for which the MOA is well-understood (14–16).

The aim of this review is to provide a better understanding of vigabatrin’s MOA and dispel any misperceptions about what vigabatrin does and does not do. The discovery of GABA and its actions in the brain will be discussed, including how GABA relates to epilepsy, how vigabatrin affects GABA activity in decreasing seizure activity, and how vigabatrin has helped promote the acquisition of fundamental knowledge about brain function.

GABA

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

γ-Aminobutyric acid is an amino acid neurotransmitter first described in 1883 (17). It was later discovered to be a substance resulting from bacterial activity in putrefying mixtures (18, 19). GABA is synthesized in neurons by the decarboxylation of glutamate via glutamic acid decarboxylase (GAD) (2) (Fig. 1).

image

Figure 1.  Production and degradation of GABA via GABA-T. CoA, coenzyme A; GABA, γ-aminobutyric acid; GABA-T, GABA transaminase. Tolman JA, Faulkner MA (2). Expert Opin Pharmacother 2009;10(18):3077–3089. copyright © 2009, Informa Healthcare. Reproduced with permission of Informa Healthcare.

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The first discovery of GABA in the brain was made in 1950 by Eugene Roberts (20) who examined mouse brain extracts using a novel chromatographic technique. The assay revealed a novel ninhydrin-reactive material, which was isolated and confirmed to be GABA. The presence of GABA in brain was subsequently confirmed by concurrent efforts in multiple laboratories (21, 22). Aside from its presence in the brain, GABA has more recently been found to be rather ubiquitous throughout the body and present in a number of other organ systems. These include the pancreas, adrenal gland, intestine, stomach, Fallopian tube, uterus, ovary, testis, kidney, urinary bladder, lung, liver, and blood (especially platelets) (23–25).

γ-Aminobutyric acid serves as the primary inhibitory neurotransmitter in the central nervous system (CNS), with approximately 30% of all synapses utilizing GABA (26, 27). Upon activation of a GABAergic neuron, the neurotransmitter is released into synapses either by calcium (Ca++)-dependent vesicular release or by reversal of active GABA-transport mechanisms (28). Once GABA is in the synapse, its action is mediated through GABA-specific receptors on postsynaptic membranes (29–31) (Fig. 2). There are currently three known GABA receptors: GABAA, GABAB, and GABAC (32). GABAA and GABAC receptors are ligand-gated ion channels that facilitate neuronal inhibition by permitting the influx of chloride ions (Cl) into cell, resulting in neuronal hyperpolarization (32). GABAB receptors, on the other hand, are 7-transmembrane, G-protein-coupled metabotropic receptors that initiate intracellular signaling cascades. Signaling through this pathway ultimately results in either the opening of potassium (K+) channels, leading to neuronal hyperpolarization (32), or a reduction in the activity of the voltage-dependent Ca++ channels that mediate glutamate release at axon terminals (33). Because of their widespread presence and action within the CNS, GABAA and GABAB receptors have been attractive targets for drug discovery efforts (34), whereas GABAC receptors are mainly found in the retina (35).

image

Figure 2.  Diagram of a GABAergic synapse and proposed mechanisms of action of various AEDs. Vigabatrin inhibits GABA-T, whereas tiagabine inhibits GAT1. Benzodiazepines, barbiturates, felbamate, topiramate, and zonisamide exert effects on GABAA receptors through allosteric modification, leading to an increase in chloride ion conductance. AEDs, antiepileptic drugs; Cl, chloride ions; GABA, γ-aminobutyric acid; GABA-T, GABA transaminase; GAD, glutamic acid decarboxylase; GAT1, GABA transporter 1. Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Drug Discov. Bialer M, White HS (31). Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 2010;9:68–82. Copyright 2010.

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γ-Aminobutyric acid–mediated synaptic activity is inactivated by two primary mechanisms: diffusion away from the synapse and reuptake into neuronal and glial cellular processes (33). The reuptake process is mediated by specialized molecules known as GABA transporters (GATs) (27). The amount of GABA transported into neuronal processes is approximately four- to five-fold greater than the amount taken into glial cells (28). There are currently five known GATs, which all function via active transport driven by ion gradients. The first is the vesicular GAT, which transports GABA into synaptic vesicles in preparation for exocytotic synaptic release. The remaining four, cloned from mouse and rat — GAT1, GAT2, GAT3, and GAT4 — are associated with plasma membranes and involved in GABA reuptake after synaptic release (28).

The GABA that is returned directly into neurons can be used unchanged to refill synaptic vesicles and be reutilized as neurotransmitter. However, GABA transported into glial cells is degraded and reprocessed by the enzyme GABA transaminase (GABA-T) (28). In addition to GABA degradation, GABA-T is also actually involved in the synthesis of the neurotransmitter, occurring when α-ketoglutarate is transaminated to form glutamate, which is subsequently decarboxylated by GAD to form GABA (Fig. 1). GABA degradation by the enzyme occurs in mitochondria, where GABA is converted to succinic semialdehyde if α-ketoglutarate is present (28, 36).

Physiological roles of GABA

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

In the 1950s, GABA was first suggested to play an inhibitory role in the CNS when impulse generation in crayfish stretch receptor neurons was experimentally inhibited by mammalian brain and spinal cord extracts (37). Soon thereafter, evidence from animal models began to mount that epilepsy stemmed, at least in part, from GABA-related dysfunction, including reductions in GABA receptors (38), changes in the number or density of GABAergic neurons (39–41), and a myriad of other changes within the GABAergic system (42–46). Similar results have been observed in humans, as changes in GABA synthesis and overall concentrations (47); GABA receptor density (48–50); GAD activity; GATs (51, 52); and other related genetic alterations (53, 54) were found to be related to seizure disorders.

Despite GABA serving an inhibitory role, its overall effect is somewhat complex, because of brain circuit intricacies, with GABA able to facilitate either excitation or inhibition, depending on neuronal interconnections. One example of this is a neural pathway in the midbrain involving the substantia nigra (SN) (Fig. 3). Originating in the striatum, neurons extend axons to form synapses within the SN, which contains neurons that extend axons to the superior colliculus. As GABAergic neurons are located in both the striatum and the SN (55), an increase in GABA from the striatum will inhibit GABAergic neurons in the SN, ultimately resulting in less inhibition in the superior colliculus (55). Therefore, the net result of the initial GABAergic transmission in this circuit is excitation. These complexities result in specific areas of the brain being influenced by GABA in different ways, with corresponding differential effects on seizure propagation, sensitivity, or initiation of specific seizure types (55).

image

Figure 3.  The net effects of GABA are influenced by neuronal circuitry. When GABA inhibition is the predominant influence on the SN by the striatum, inhibition of the superior colliculus (SC) is relieved, resulting in excitation. Accordingly, glutamate-induced excitation from the striatum to the SN will result in inhibition in the SC. GABA, γ-aminobutyric acid; SC, superior colliculus; SN, substantia nigra. GABA and epilepsy: basic concepts from preclinical research, Gale K (55). Copyright © 1992 Epilepsia. Reproduced with permission of John Wiley & Sons, Inc.

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GABA and the development of AEDs

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

Antiepileptic drug development has a long and rich history dating back nearly 150 years. The first compound discovered to alleviate seizure activity was potassium bromide, which was first used as a sedative agent (56). However, in 1857, Sir Charles Locock made the unexpected discovery that this compound also reduced seizure activity (57). Despite the apparent promise of this initial breakthrough, however, development of epilepsy treatments did not achieve much progress for the next 100+ years (58).

In consideration of GABA’s role in epilepsy, components of the GABAergic system have been targeted in attempts to develop treatments for seizure disorders. Initial efforts to increase GABA concentrations in brain by presenting GABA directly were unsuccessful, because the blood–brain barrier is impermeable to the neurotransmitter (59). Therefore, more creative strategies for increasing GABA concentrations in the CNS have been required.

In 1975, with the opening of the National Institute of Neurological Disorders and Stroke, the modern era of AED development began, ushering in a rapid acceleration of drug discoveries to treat seizure disorders (58) (Fig. 4). During this time, research on the pathophysiology of epilepsy made great initial strides (60), leading to the development of novel drugs with varied MOAs, which centered on both excitatory and inhibitory neurotransmitter systems. These included specific neurotransmitter agonists (e.g., progabide), receptor agonists (e.g., clobazam), Ca++ channel inhibitors (e.g., flunarizine), excitatory amino acid receptor antagonists (e.g., MK 801), and GABA analogs (e.g., pregabalin and gabapentin). An overview of currently available GABAergic AEDs and their putative functions is provided in Table 1 and Fig. 2.

image

Figure 4.  One hundred and fifty years of AED development. AED, antiepileptic drug. Reprinted from Seizure, Vol. 19, Brodie MJ (58), Antiepileptic drug therapy the story so far, p650-655, Copyright 2010, with permission from Elsevier.

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Table 1.   Known or possible mechanisms of action of antiepileptic drugs
Decreased Na+ channel activityDecreased Ca++ channel activityIncreased GABA transmissionDecreased glutamate transmissionGABA-receptor agonism
  1. Possible mechanisms are in italics. Reprinted from Seizure, Vol. 19, Issue 10, Brodie MJ (58), Antiepileptic drug therapy the story so far, p650-655. Copyright (2010), with permission from Elsevier. Adapted from Future Medicinal Chemistry, Mula M (61), GABAergic drugs in the treatment of epilepsy: modern or outmoded?, Future Medicinal Chemistry Vol. 3, Issue 2, p177-182 (2011) with permission of Future Science Ltd.

  2. GABA, γ-aminobutyric acid

CarbamazepineCarbamazepineBenzodiazepineCarbamazepineBenzodiazepine
EthosuximideEthosuximideFelbamateFelbamateFelbamate
FelbamateFelbamateGabapentinLamotrigineLevetiracetam
LacosamideGabapentinLamotrigineOxcarbazepinePhenobarbital
LamotrigineLamotriginePhenobarbitalTopiramateTopiramate
OxcarbazepineLevetiracetamTiagabineValproic acid 
PhenytoinOxcarbazepineTopiramate Valproic acid
RufinamidePhenobarbitalValproic acidPhenobarbital 
TopiramatePregabalinVigabatrinLevetiracetam 
EslicarbazepineTopiramate Phenytoin 
ZonisamideZonisamideCarbamazepineZonisamide 
  Levetiracetam  
Valproic acidValproic acidOxcarbazepine  
Gabapentin Zonisamide  

Vigabatrin and its MOA

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

Vigabatrin was first synthesized in 1974, and its development for approval as a therapeutic drug was initiated in the late 1970s (12, 62, 63). Vigabatrin is classified as a neuromodulatory agent, because its net effect is to influence the activity of neurons. The compound was designed to be structurally identical to GABA except for the addition of a vinyl group (Fig. 5).

image

Figure 5.  The structure of γ-aminobutyric acid (GABA; top) and vinyl-γ-aminobutyric acid (vigabatrin). The vinyl group is in blue.

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Unlike many CNS-related drugs that have been discovered through serendipity (57, 64), vigabatrin was rationally constructed to have a precise effect on brain chemistry. Specifically, vigabatrin was designed to be an enzyme-activated, irreversible, selective suicide inhibitor of GABA-T (65, 66). The effect of vigabatrin is the inhibition of GABA catabolism by GABA-T, leading to an increase in GABA available in the synaptic cleft, thereby resulting in enhanced GABAergic transmission (62, 67, 68). In addition, some evidence suggests that vigabatrin may inhibit glial uptake of GABA (69) and may also stimulate GABA release (11). Moreover, Yang et al. showed that vigabatrin reduces glutamate/glutamine cycling between astrocytes and neurons. These findings suggest a glutamatergic effect, which could also be related to the anticonvulsant effect of vigabatrin (70). However, these findings have never been replicated, and, therefore, GABA-T inhibition is still considered the primary function of vigabatrin.

Pharmacokinetics of vigabatrin in humans

Vigabatrin is available in oral formulations and exists as a racemic mixture of the S(+) and R(−) enantiomers (71, 72). The S(+) enantiomer is solely responsible for drug activity. Vigabatrin is rapidly absorbed after administration. Concentrations in plasma peak within 2 h (71, 73, 74), possibly as rapidly as 1 h (75). The absorption half-life ranges from 10 to 35 min (71, 73, 74), and the mean terminal half-life is between 5 and 7 h (70), with small amounts detected at 72 h after dosing (75). Vigabatrin does not bind to plasma proteins (76), and a total of 60–80% of the drug is recovered unchanged in the urine, suggesting a bioavailability of at least 60–80% (77). The apparent volume of distribution is 0.8 l/kg (78) and the half-life of distribution is 1–2 h (76). The area-under-the-concentration–time curve (AUC) values have been shown to be decreased for S(+) enantiomer (30.1 μmol/ml per min) compared with the inactive R(−) enantiomer (39.2 μmol/ml per min), which is likely explained by some S(+) enantiomer irreversibly binding to GABA-T.

The pharmacokinetics of vigabatrin in cerebrospinal fluid (CSF) were evaluated in patients with epilepsy who received 50 mg of vigabatrin daily (75). In these patients, the concentration of vigabatrin in the CSF was approximately 10% of that observed in plasma. The greatest CSF concentrations were achieved after 6 h following a single dose, with only trace amounts remaining after 24 h and none being detectable by 72 h. After 3 years of receiving vigabatrin, patients’ CSF vigabatrin concentrations were not significantly increased compared with their concentrations at 6 months (78).

Plasma pharmacokinetics are affected by some individual variables, including age and renal clearance. In one study, when receiving a single 1,500-mg dose of vigabatrin, healthy adult volunteers aged 76–97 years had slower overall pharmacokinetics compared with volunteers aged 22–33 years. Specifically, there was a 3.3-fold increase in time to reach maximum plasma concentration, a 2.7-fold increase in the maximum concentration, a 9.8-fold increase in the AUC, a two-fold prolongation of the terminal half-life, and reduced urinary excretion of the S(+) enantiomer (73). These results were likely attributable to age-related decreases in both absorptive capacity and renal function. Children and infants also demonstrated lesser plasma AUC values compared with adults (72). As renal clearance in this particular study was comparable between adults and children, the findings may indicate that vigabatrin has lesser overall bioavailability in infants and children than adults. Therefore, greater dosages of the drug may be required for younger patients to achieve similar plasma concentrations to those seen in adults.

Activity of vigabatrin in the CNS

Vigabatrin has been predictably shown to increase GABA concentrations in the brain. This was first demonstrated in a study in mice in which a decrease in GABA-T activity resulted in a five-fold increase in whole-brain GABA concentration 4 h after a 1,500-mg/kg injection of vigabatrin (62). Interestingly, despite the rapid plasma pharmacokinetics of vigabatrin, the increase in GABA concentration in the CNS persisted much longer, revealing that the biologic half-life of the drug is measured in days, not hours. This timing aligns with the observed recovery time of GABA-T (5 days) after its elimination (62), providing further evidence of vigabatrin’s role as a GABA-T inhibitor.

Similar results have been observed in humans. In one study, vigabatrin and GABA concentrations in the CSF of patients with diverse neurologic conditions increased in a dosage-responsive manner following dosages of 1, 2, or 6 g/day for 3 days (65). In a study in which patients received 0.5 g of vigabatrin twice daily for 2 weeks, followed by 1 g twice daily for 2 weeks and then placebo for 2 weeks, a dosage-related increase in GABA was observed, followed by a decline to baseline concentrations by the end of the placebo period (79). In addition, at a dosage of 50 mg/kg (administered as a single dose, once every third day for 2 months, every other day for 2 months, and daily for 1 month), vigabatrin was shown to cause a 200–300% increase in GABA in CSF and brain tissues (80). Despite peak drug concentrations in serum within 1 h of administration and in the CSF within 6 h, GABA concentration remained elevated in the CSF for more than 1 week (75). When patients took vigabatrin continuously for 3 years, these effects were sustained in that GABA concentrations in CSF remained elevated (78, 80).

Clinical efficacy of vigabatrin

The GABA-increasing effect of vigabatrin has been demonstrated to be of therapeutic benefit in both animal models and humans. Vigabatrin has been effective in decreasing seizures in a number of experimentally induced seizure models in rats, including maximal electroshock (MES), bicuculline, and pentylenetetrazol, although seizure reductions were only observed if vigabatrin was directly injected into the midbrain (81). In these rats, vigabatrin-induced seizure protection after MES lasted up to 72 h after a single injection into the SN. The rats did not respond normally to MES until the fifth day after administration. Intravenous injection of vigabatrin was also demonstrated to be effective in decreasing seizures in models of bicuculline-induced myoclonic activity (82), strychnine-induced tonic seizures (83), isoniazid-induced generalized seizures (84), audiogenic seizures (79), light-induced seizures (84), and amygdala-kindled seizures (66, 85).

Vigabatrin is effective as adjunctive therapy for adult patients with refractory CPS (rCPS) who have responded inadequately to several alternative treatments. Well-controlled trials in Europe (86–92) and the United States (93–95) have demonstrated statistically significant decreases in seizure frequency with vigabatrin compared with placebo. These studies are reviewed by Ben-Menachem & Sander (96) and Faught (97), respectively, in this supplement. Vigabatrin is also effective as monotherapy in pediatric patients with infantile spasms (98–104). Well-controlled trials of vigabatrin for infantile spasms are reviewed in this supplement by Carmant (105). Decreases in seizure activity have been shown to directly relate to increased GABA concentrations in brain, as elevations in GABA concentrations exceeding 1.8 mmol/kg were shown to be associated with a two-fold decrease in seizure frequency (106). Plasma concentration of vigabatrin does not correlate with clinical effectiveness (1). In addition, vigabatrin catabolizes the reaction with GABA-T, acting as the substrate and depleting GABA-T in the process. Reconstitution of the enzyme takes several days (62). The effectiveness of vigabatrin on seizure control persists over time, as no loss of efficacy has been observed after usage of vigabatrin extending for 3 years and beyond (107–112).

The specificity of vigabatrin’s activity on the GABAergic system compared with other neurotransmitter systems has also been examined. In long-term studies, no consistent changes in acetylcholine, somatostatin, β-endorphins, prolactin, cyclic adenosine monophosphate, cyclic guanosine monophosphate in CSF, amino acids, or dopamine or serotonin metabolites have been observed (78, 113, 114). In a single-dose study, however, concentrations of metabolites of dopamine and serotonin increased up to 100% initially and then returned to baseline or slightly less than baseline after 1 month of treatment (75). Additional findings have suggested that striatal dopamine release was inhibited by vigabatrin treatment, but this was likely a result of an increase in GABA and not any direct effect of vigabatrin on dopamine release (115, 116).

Experimental uses of vigabatrin

Because of vigabatrin’s highly specific MOA, the compound has proven to be a useful experimental tool for examining the effects of the GABA throughout the brain, including identifying regions involved in seizure activity. For example, partial seizures induced by kindling in limbic or cortical structures were shown to respond to microinjections of vigabatrin in the amygdala or in the deep prepiriform cortex, which has neural projections into the amygdala (85, 117). In addition, when focal injections of vigabatrin were made in the SN of rats, seizure activity was reduced, revealing that this region is a key site of seizure initiation (81, 118, 119). It was also shown that in some brain areas, GABA may actually act as a proconvulsant. For example, petit mal seizures in animals have been shown to respond adversely to vigabatrin, likely owing to hyperfunction of GABAergic inhibitory pathways (60). These findings highlight the complexities of the GABAergic system as influenced by brain circuitry and also underscore the value of having a compound with such a specific MOA to provide insight into normal and pathologic functioning in the brain.

Dosage considerations

Based on vigabatrin’s effectiveness in decreasing seizure activity, the drug has been approved for use in specific seizure conditions in many countries (1, 2). For everyday use of the drug, several important considerations should be factored into achieving optimal dosages and scheduling of administration. For example, if patients are immediately initiated to a full therapeutic dosage, a dramatic decrease in seizures can lead to forced normalization, which has been described to cause psychosis (82). Moreover, adverse effects such as sedation and confusion may be experienced when initiating treatment (120). Therefore, for adults, vigabatrin should be titrated slowly from a relatively low starting dosage (typically 1 g/day) to a therapeutic dosage (typically between 2 and 4 g/day) (6). In pediatric patients with infantile spasms, a titration is also used during treatment initiation, with starting and target dosages adjusted for body weight (7).

In discontinuing treatment, rapid withdrawal can elicit an increase in rebound seizures (86, 88, 90, 121) and also lead to postictal psychosis (82). Therefore, gradual withdrawal of vigabatrin is recommended at a decrease of 500 mg/day to 1 g/day on a weekly basis for adults and 25–50 mg/kg every 3–4 days for children (6, 7).

Differential absorption of vigabatrin throughout the body also has the potential to be a complicating factor with regard to dosing. One adverse effect of particular concern is the development of pVFDs (4). In rats, the greatest dosage-related decrease in GABA-T activity (and subsequent increase in GABA concentrations) was observed in retina, resulting from an 18.5-fold greater concentration of vigabatrin in retina than brain (122). This is likely attributable to the differential permeabilities of the blood–retinal barrier vs the blood–brain barrier (123). Furthermore, the 9:1 plasma-to-CSF ratio of vigabatrin concentrations could also be an important consideration because GABA-T shows a 70% reduction in activity in platelets with vigabatrin dosage of 2 g/day (76). New GABA-T cannot be regenerated in platelets, requiring a replenishment of platelets themselves (124). Last, based on the findings that vigabatrin clearance is slowed in elderly and/or renally impaired patients (73), these factors should be identified and considered when initiating vigabatrin therapy in these individuals.

Once the proper dosage is established, vigabatrin dosing has traditionally been twice daily, primarily based on a demonstration that this schedule produced increases in CSF GABA concentrations in humans (65, 79). Although the effective dosage range in adults is typically between 2 and 4 g/day, this may vary based on individual patient characteristics (66, 91). Several dosage-ranging studies have demonstrated an increasing benefit as dosages were titrated upward (93, 107, 125). When vigabatrin dosages were decreased from 3 to 1.5 g/day, a deterioration of seizure control was observed for most patients, although seizure frequency did not return to baseline degrees (114). Dosages of at least 100 mg/kg/day appear to produce the best response in most infants, with optimal dosages ranging from 100 to 150 mg/kg/day (126).

An evaluation of different dosing schemes was conducted for patients with severe drug-resistant partial epilepsy (127). For these patients, a dosage of 50 mg/kg once daily appeared to be as effective as the common twice-daily dosing. Specifically, the increased CSF GABA concentrations resulting from the once-daily dosage schedule were sustained with the twice-daily dosing. The conclusions from this study suggested that once-daily dosing was as effective as twice-daily dosing (128). In contrast, seizure control was compromised when vigabatrin was administered at intervals >24 h.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

In conclusion, despite the fairly common misconception that vigabatrin has an unknown or non-specific MOA, vigabatrin was rationally designed to have one specific function: to reduce the activity of GABA-T, thereby increasing GABA concentrations in brain. This mechanism has been found to be effective for decreasing seizure frequency in adult patients with rCPS and in pediatric patients with infantile spasms. Moreover, the specificity of vigabatrin makes the compound a valuable tool in the search for seizure-inducing pathways and mechanisms in the brain. With vigilance and careful considerations with dosing, this drug is a valuable option for patients with intractable epilepsy.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

Elinor Ben-Menachem has received consultancy fees, research grants, or speaker fees from Bial, Cyberonics, Eisai, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Lundbeck Inc., and UCB Pharma.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References

Medical writing and editorial assistance were provided by Nathan C. Connors, PhD, and Robin L. Stromberg, PhD, of Arbor Communications, Inc. (Ann Arbor, MI, USA), as well as by Michael A. Nissen, ELS, of Lundbeck Inc. (Deerfield, IL, USA). This support was funded by Lundbeck.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. GABA
  5. Physiological roles of GABA
  6. GABA and the development of AEDs
  7. Vigabatrin and its MOA
  8. Conclusions
  9. Conflicts of interest
  10. Acknowledgments
  11. References