vigabatrin: a comprehensive review of drug properties including clinical updates following recent...

1. Introduction

2. Overview

3. Regulatory history of

vigabatrin

4. The GABA System

5. Chemistry and pharmacology

of vigabatrin

6. Pharmacokinetics of vigabatrin

7. Clinical efficacy

8. Risk evaluation and mitigation

strategies for vigabatrin

9. Conclusion

10. Expert opinion

Drug Evaluation

Vigabatrin: a comprehensivereview of drug propertiesincluding clinical updatesfollowing recent FDA approvalJustin A Tolman† & Michele A FaulknerCreighton University School of Pharmacy and Health Professions, 2500 California Plaza, Omaha,

NE 68178, USA

Background: Vigabatrin (Sabril�) was approved in the USA in mid-2009 for the

adjunctive treatment of refractory complex partial seizures and as treatment

of infantile spasms. Vigabatrin’s more than 30-year history of research and

development is condensed into a clinically relevant review pertaining to this

2009 approval. Methods/discussion: A review of the scientific literature was

conducted with special focus given to the drug molecule, its mechanism of

action, its effects on living systems (e.g., pharmacokinetic, pharmacologic and

toxicologic), and its anticipated role among antiepileptic drugs in the USA.

Conclusions: The recent approval of vigabatrin makes a significant addition to

antiepileptic drug options. The FDA implemented a Risk Evaluation and

Mitigation Strategy to control for the possibility of severe adverse drug events.

Keywords: complex partial seizures, epilepsy, GABA, GABA-transaminase, infantile spasms,

REMS, Sabril, seizure, vigabatrin

Expert Opin. Pharmacother. (2009) 10(18):3077-3089

1. Introduction

In August 2009, vigabatrin (Sabril�; Box 1) was approved by the FDA as adjunctivetherapy for the treatment of refractory complex partial seizures (CPS) in adults andfor the treatment of infantile spasms (IS) [1]. This approval included a RiskEvaluation and Mitigation Strategy (REMS) to manage the risk of serious visionloss while still allowing access to this important antiepileptic drug (AED). Thisreview synthesizes and integrate the body of data for vigabatrin and provides expertopinions pursuant to the recent FDA approval.

2. Overview

Vigabatrin was approved for two very difficult to treat epileptic conditions, CPSand IS. Briefly, these epileptic conditions result from the disruption of normalelectrical signal generation, transduction or termination in large populations ofcortical neurons. CPS typically initiate in a focal area in the frontal or temporal lobesand rapidly propagate to other regions to precipitate a partial or complete alterationof consciousness with or without automatisms (including motor, sensory orsomatosensory, and/or psychic symptoms) [2]. The frequency with which CPSoccurs in the USA in persons aged 60 years or younger is approximately 20 per100,000. In those over the age of 60 years, the incidence increases to 80 per100,000 [3]. When seizures are difficult to control, the results can be devastating. Inthe most severe cases, uncontrolled CPS can lead to death from various causesincluding accidents or SUDEP (sudden unexplained death in someone withepilepsy), a condition where no underlying cause other than epilepsy can be

10.1517/14656560903451690 © 2009 Informa UK Ltd ISSN 1465-6566 3077All rights reserved: reproduction in whole or in part not permitted

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identified [4]. Partial seizures are the seizure type most likely tobe refractory to treatment [5]. Several drugs are approved forthe initiation of treatment of CPS in the USA, includingcarbamazepine, phenytoin and valproic acid/divalproexsodium, and many others have been employed as adjunctivetherapy. However, owing to the refractory nature of CPS,therapeutic failure often occurs following treatment withseveral AEDs.In contrast to CPS, IS are primarily generalized seizures that

lack a focal area of onset. Typical diagnostic criteria for ISinclude neonatal or infantile myoclonic-type extensions orflexions involving the whole body and characteristically dis-organized electroencephalogram (EEG) wave patterns (i.e.,hypsarrhythmia) [6]. IS are rare, can be catastrophic in nature,and are associated with a wide variety of neuropathologicalabnormalities [7]. Prevalence in the USA is 0.6 per 1000 livebirths and limited by the patient age [8]. IS tends to be amongthe most treatment-resistant pediatric epilepsy syndromes [9].Adrenocorticotropic hormone (ACTH), prednisone, sodiumvalproate and benzodiazepines have been used in patientswith IS, but are often unsuccessful. Dozens of drugs forthe treatment of IS have been studied, but treatment successesremain elusive because of variable availability of the drugs,significant adverse effect profiles and unpredictable long-termprognoses [10]. Vigabatrin is the only approved drug for thetreatment of IS in the USA.

3. Regulatory history of vigabatrin

Vigabatrin was first created in 1977 as a rationally designedanalog to GABA [11]. Specifically, vigabatrin was synthesized tobind irreversibly toGABA-transaminase (GABA-T) and elevateGABA concentrations in the CNS, producing prolongedGABA-ergic effects [12]. In 1980, the sponsor filed an investi-gational new drug application (IND) with the FDA and soonbegan human drug testing under several protocols [13]. Duringthe mid-1980s, the identification of intramyelinic edema and

the possibility of irreversible neuronal injury in numerousanimal species occurred during continued preclinical testingand led to interruptions in patient enrollment in human trials.In 1994,MarionMerrell Dow (now Sanofi-Aventis) submitteda new drug application (NDA) following the collection ofsufficient efficacy information based in patients with CPS.However, this NDA was delayed as a result of insufficientand structurally deficient safety data within the submission.By1998, additional safetydata hadbeenprovided to theFDAtoallow the drug approval process to proceed [13]. During thattime, additional testing identified permanent peripheral visionloss as a possible adverse event associated with vigabatrintherapy and again derailed vigabatrin’s approval with theFDA. By 2007, additional studies had been conducted to allowthe Peripheral and Central Nervous System Drugs AdvisoryCommittee of the FDA in January 2009 to reconsidervigabatrin’s application. Following two advisory committeehearings, drug approval was recommendedwhich led directlyto vigabatrin’s approval in August 2009 as adjunctive therapyfor the treatment in refractory CPS. The Committee’s rec-ommendation for the inclusion of a REMS (including pre-scriber and patient registries, restricted drug access andrequirements for regularmonitoring for drug-related adverseevents) to minimize and evaluate the risk of peripheral visualfield loss while still providing drug access was also mandatedas part of vigabatrin’s approval [14-17]. At present, Lundbeck,Inc. holds the rights to vigabatrin in the USA following theacquisition of Ovation Pharmaceuticals, Inc. in March 2009and is now managing the REMS requirements through aspecial SHARE� (Support, Help, and Resources for Epilepsy)program [18].

Before these regulatory discussions with the FDA, vigaba-trin was approved in 50 countries (first approved by the UK in1989) with approximately 1.5 million patients having receivedthe medication [15]. Over the past 30 years, numerous basicscience and clinical data have been gathered for vigabatrinwith numerous scientific reviews already having been pub-lished [4,19-41]. The approval of vigabatrin warrants an updatedreview of the drug with expert opinions regarding its place inAED therapy. In addition, details of the REMS will beelucidated to allow physicians, pharmacists, patients, andcaregivers to use vigabatrin effectively.

4. The GABA System

Vigabatrin affects abnormal electrical signal activity throughmodulation of the g-aminobutyric acid (GABA, 4-aminobu-tyric acid) system (Figure 1). Extensive research continues toelucidate components of this system, and has been reviewedelsewhere [42-50]. Briefly, GABA synthesis occurs by the trans-amination of a-ketoglutarate, an intermediary in the citratecycle, to glutamate, which is then converted to GABA viaglutamate decarboxylase (Figure 2). Vesicularized GABA isthen released into the synapse after neuronal depolarization bya propagated action potential. Free GABA diffuses to the

Box 1. Drug summary.

Drug name Vigabatrin

Phase Launched

Indication Epilepsy

Pharmacologydescription

GABA aminotransferase inhibitor

Route of administration Alimentary, p.o.

Chemical structure

HO

O

N

Pivotal trial(s) [4,5,7,9,84-89]

Pharmaprojects - Copyright to Citeline Drug Intelligence (an Informa

business). Readers are referred to Informa-Pipeline (http://informa-

pipeline.citeline.com) and Citeline (http://informa.citeline.com).

Vigabatrin

3078 Expert Opin. Pharmacother. (2009) 10(18)

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postsynaptic membrane, binds and activates various GABAreceptors, including both ionotropic and metabotropic recep-tors, to produce inhibition of the postsynaptic neuron throughdirect or indirect regulation of ion-flux or subsequent neuro-transmitter release [51-53]. Unbound GABA is then rapidlyremoved from the synaptic cleft by glial, post-synaptic, andpre-synaptic cells to be catabolized by GABA-transaminase(GABA-T) to succinic semialdehyde, which can then re-enterthe citrate cycle [39]. Vigabatrin specifically affects the GABAsystem through inhibition of GABA-T to elevate GABAconcentrations and increase functional pools of GABA [38,41].The elevation in GABA concentrations is then thought tosuppress abnormal electrical activity, but this elevation hasnot been directly correlated with seizure control [54,55]. Vigaba-trin is highly selective and specific for GABA-T and does notdirectlyaffectother enzymaticpathways in theGABAsystem[25].

5. Chemistry and pharmacology of vigabatrin

5.1 Physicochemical properties and formulationsVigabatrin is a very lowmolecular weight compound (129MW)that is freely soluble in water, slightly soluble in alcohols (e.g.,methanol) and practically insoluble in halogenated solvents (e.g.,chloroform). The freely flowing white crystalline powder has amelting point of 209�C. The acidic and basic functional groupsimpart pKa values of 4.02 and 9.72, respectively [23]. Thehydrophilic functional groups balance with the lipohilicity ofthe molecule to give a partition coefficient (log P value) of-0.1 [23,56]. Despite this favorable partition coefficient to drugdiffusion, the impermeable nature of the blood–brain barrierprevents diffusion of vigabatrin into the CNS. However, vigaba-trinusesactive transportmechanisms forGABAtodistribute intocortical fluid and tissues [49,57-59]. Although vigabatrin is synthe-sized and currently formulated as a mixture of both the (R) and(S) racemates, only the S(+)-enantiomer of vigabatrin is

pharmacologically active owing to target site steric restric-tions [38,60]. Current formulations of vigabatrin include a500-mg sachet (containing povidone K30 as a binder to formgranulesof the active ingredient) and a500-mgtablet (containingpovidone K30, microcrystalline cellulose, magnesium stearateand sodium starch glycollate with the active ingredient in thetablet core andwith a hypromellose film coating). The tablets arescored and can be cut, crushed or compounded for patient orclinician preference or to allow for flexibility in dosage regimens.Vigabatrin has no discernable smell or taste.

5.2 Pharmacology and pharmacodynamics ofvigabatrinVigabatrin is an irreversible inhibitor of GABA-T. GABA-T isa homodimer composed of 472 amino acid sequence mono-mers that each contain an active site with a pyridoxal5¢-phosphate (PLP) cofactor covalently bound to Lys-329via a Schiff base (Figure 3A) [61]. Although there are disagree-ments in the literature regarding the exact mechanistic crea-tion of vigabatrin-transaminase intermediates, vigabatrinirreversibly inhibits GABA-T through the formation of acovalent link at the active site (Figures 3B and 4). Owing tostereoselectivity in the active site, only the (S)+ enantiomer ofvigabatrin is capable of forming this covalent linkage with theLys-329 residue [19,25]. This suicide inhibition then preventsGABA from entering the active site and effectively decreasesthe enzymatically active pool of GABA-T available for neu-rotransmitter inactivation [38,39,41]. Thus, the pharmacologicaction of vigabatrin lasts until inactivated enzymes can beturned over and can typically last for 4 – 6 days [19]. No dose ofvigabatrin has been shown to cause complete inhibition of allGABA-T activity, which is probably due to competitivebinding with GABA [19,62]. GABA concentrations in theCSF and blood have been reported to increase followingadministration of vigabatrin, but do not always correlatewith the drug doses or with seizure control [19,25,55,63,64].The pharmacodynamic profile of vigabatrin is complexbecause of the inactivation of GABA-T in both GABA-ergicneurons and glial cells. The dose required to achieve 50%inhibition of GABA-T activity has been reported to be30 mg/kg when administered twice daily [19].

6. Pharmacokinetics of vigabatrin

Vigabatrin has optimal properties for oral drug delivery and asubstantially different pharmacokinetic profile from manyother AED. The pharmacokinetic parameters of vigabatrinare unaffected by food [65] and are consistent followingmultiple doses [23,62]. The pharmacokinetic profile of vigabatrinalso demonstrates linear dose relationships over therapeutic andsupratherapeutic dose ranges [62,66]. The molecule’s high aque-ous solubility and membrane permeability result in rapid andthorough absorption of the dose, with maximal plasma drugconcentrations for both the (R) and (S) enantiomers observedwithin 1 – 2 h following oral administration, andmaximal drug

Vigabatrin(γ-vinyl GABA, 4-amino-5-ene-

hexanic acid

OH

O

H2N

γ-aminobutyric acid(GABA, 4-aminobutyric acid)

OH

O

H2N

Figure 1. Chemical structures of GABA and vigabatrin*.*Vigabatrin has a chiral center with stereoselective activity.

Tolman & Faulkner

Expert Opin. Pharmacother. (2009) 10(18) 3079

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concentrations observed in the CNS within 3 h [54,67-69]. Drugconcentrations in theCNS are approximately 10–15%of thosein plasma [70]. The sachet and tablet formulations are bioequiva-lent with an absolute bioavailability of 60 – 70% [23,71]. Vigaba-trin readily distributes in the blood with an apparent volume ofdistribution of 0.8 – 1.0 liters/kg with no appreciable plasmaprotein binding [23,41,66,72]. Vigabatrin’s simple pharmaco-phore, lowmolecular weight and high aqueous solubility prob-ably contribute to the almost complete renal elimination of thedrug [73-75]. Approximately 80% of the dose is eliminatedunchanged in the urine within 24 h, with less than 5% ofthe dose accounted for bymetabolites [25,67]. Drug elimination

is not dose dependent, and the plasma elimination half-life isapproximately 7 h in humans [19,21,76].

6.1 Special populationsAlthough data are limited, vigabatrin use in pediatrics hasresulted in a large increase in apparent oral drug clearance,with a 40% increase in neonates specifically, and requires arelative dose increase to achieve doses equipotent to those usedin adults [19,23,69,71]. Patients with altered gastric function,including elderly patients, can experience lower plasmavigabatrin concentrations as a result of delayed gastricemptying [23]. Patients with renal impairment are at increased

Citrate

Acetyl CoA

α-ketoglutarate

Succinate

Succinic semialdehydeGABA-T

GABA

Glutamate

Glutamatedehydrogenase

Glutamatedecarboxylase

Oxaloacetate

Figure 2. Biochemical synthesis of GABA from glutamate by glutamate decarboxylase and deactivation to succinicsemialdehyde and inactivation to succininc semialdehyde by GABA-transaminase.The circular pathway in the figure is a schematic of the citrate cycle with pertinent chemical intermediates indicated that relate to the GABA system. Selected enzyme

names are italicized.

GABA: g-Aminobutyric acid; GABA-T: g-Aminobutyric acid transferase.

A. B.

Figure 3. The GABA-T active site: the unoccupied active site containing Lys-329 with a covalently bound pyridoxal5¢-phosphate (PLP) cofactor (A); and the inactivated enzyme active site containing a covalently linked sequence ofLys-329, vigabatrin and PLP (B).These images were created from published crystal structures using the Molecular Operating Environment 2009 (MOE) software package (Chemical Computing Group,

Inc., Montreal, Canada) [61,100-102]. The protein backbone is indicated by the red ribbon and water was eliminated from the image for clarity.

Vigabatrin


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risk for development of vigabatrin toxicity because ofdecreased vigabatrin clearance [23,71,73].

6.2 Drug interactionsInteractions between AEDs are concerns for the clinical man-agement of seizure disorders. Vigabatrin has a lower potentialfor interactions due to minimal hepatic drug metabolism andnegligible protein binding [32]. Although relativelyminor, somedrug interactions have been reported and require clinicaljudgment in monitoring therapeutic regimens. Specifically,vigabatrin has been reported to decrease both pentobarbitaland phenytoin drug concentrations [20,23]. Vigabatrin has alsobeen reported to increase carbamazepine clearance [77].

7. Clinical efficacy

The medical literature is replete with efficacy studies involvingvigabatrin owing to extended market availability in numerouscountries. Therefore, the review of clinical efficacy that follows

focuses on those studies that have been submitted to the FDAto support vigabatrin’s approval in the USA. Although long-term studies have shown sustained drug efficacy over time,there are limited data to indicate that tolerance to vigabatrin’seffects may develop in some initial responders [78-82]. Drugtolerance could possibly be due to decreased GABA synthesisin response to extended elevations in levels of GABAassociated with vigabatrin use [83].

7.1 Use in uncontrolled complex partial seizuresTwo studies evaluating the efficacy of vigabatrin in refractoryCPS were submitted to the FDA to support the drug’santicipated approval for this purpose. The first of these studiesconducted by French et al. was a double-blind, placebo-controlled study, during which patients received 3 g ofvigabatrin (the most commonly studied dose in Europeantrials) in addition to other anti-seizure medications (two onaverage) [84]. Patients were between the ages of 18 and 60 yearsand had CPS with or without secondary generalization.

N

OH

OPHO

O

O

NH

OH

ONH

HN

O

N

OH

OPHO

O

O

NH

OH

ONH

HN

O

N

OH

OPHO

O

O

NH

OH

ONH

HN

O

N

OH

OP

HOO

O

NH OH

O

O

HN

NH2

H2N

OH

O

:

:VIG

+ +

+

N

OPHO

O

OH

NH

HN

PLP

Lys 329

+ +

O

O

Figure 4. The proposed mechanism of action for vigabatrin inactivation of GABA-transaminase (GABA-T).Lys-329 is the primary lysine residue in the active site. These structures were re-created from Storicci et al. [61].

VIG: Vigabatrin; PLP: Pyridoxal 5¢-phosphate.

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Previous therapy with either phenytoin or carbamazepine wasa requirement for enrollment. The first of the three trialsegments was a 12-week evaluation period, during which abaseline was established. The second segment was a drugtitration phase, during which patients were randomized toreceive either vigabatrin (n = 92) or placebo (n = 90). Duringthis 4-week phase, vigabatin was titrated to a dose of 2.5 g/dayin two divided doses. Over the first week of the final 12-weeksegment, the vigabatrin dose was increased to 3 g/day. Theprimary efficacy parameter was the number of seizures expe-rienced per month during the final 8 weeks of the study. Thedecrease in seizure frequency for those taking vigabatrin wasthree per 28 days versus 0.8 per 28 days for those givenplacebo (p = 0.0002). Overall, the median seizure reductionwas 39.5 versus 7.5% for vigabatrin and placebo respectively(p > 0.001). The mean number of seizure-free days in thevigabatrin group was 2.2 versus 0.5 for the placebo group(p = 0.0024). A 50% reduction in mean monthly seizurefrequency was achieved in 40 persons receiving vigabatrin,thus resulting in what the authors defined as therapeuticsuccess. At study end, five vigabatrin patients remainedseizure-free.The second submitted study, a placebo-controlled trial

conducted by Dean and colleagues, was a dose-response studyof vigabatrin for patients with uncontrolled CPS taking one ortwo additional anti-seizure medications [85]. This study wasalso divided in to three separate segments, the first of whichincluded 12 weeks of pretreatment evaluation. The secondsegment was a 6-week titration phase, and the third segmentwas a maintenance phase of 12 additional weeks. Doses ofvigabatrin included 1, 3 or 6 g/day (in divided doses) given topersons between the ages of 18 and 60 years with CPS (with orwithout secondary generalization; n = 149). As with theprevious trial, phenytoin or carbamazepine therapy had tohave been used and failed. The number of seizures occurringin an individual during the final 8 weeks of segment 1 wascompared with 28-day seizure frequency during the final8 weeks of the study as the primary measure of efficacy.The group receiving 1 g of vigabatrin experienced meandecrease in seizure frequency of 0.8 (p = 0.2 versus placebo).Those receiving 3 or 6 g of vigabatrin had a decrease of 4.3 and4.5 seizures respectively (p < 0.0001 vs placebo for both).Therapeutic success (again defined as at least a 50% reductionin seizure frequency) was achieved in 51 persons taking 3 gand 54 taking 6 g of vigabatrin (p < 0.0001 vs placebo). In thegroup receiving 1 g/day, 24 persons were considered to haveexperienced therapeutic success versus seven in the placebogroup (p = 0.0248). These results are consistent withEuropean studies concluding that optimal doses of vigabatrinare ‡ 2 g daily [86].A Cochrane review of the use of vigabatrin in patients with

refractory partial epilepsy (which included the two trialsdetailed above) evaluated 11 randomized, double-blind,placebo-controlled, add-on trials [5]. The total number ofincluded patients was 755. The evaluated studies consistently

indicated that vigabatrin was capable of decreasing the overallfrequency of seizures, but long-term efficacy was not evaluablewith the studies used for comparison. Of note, quality oflife outcomes between placebo and vigabatrin were not foundto differ.

7.2 Use in infantile spasmsThree studies submitted to the FDA address the use ofvigabatrin in children with IS. One of these studies, conductedby Appleton and colleagues, evaluated vigabatrin as initialmonotherapy and was the first to look at the efficacy ofvigabatrin in newly diagnosed IS [87]. Study participantswere randomized to receive either placebo (n = 18) or activetreatment with vigabatrin (n = 16) at a dose of50 – 150 mg/kg/day. The baseline period lasted 2 or3 days depending on whether the participant had clustersof IS or isolated spasms. After the following 5 days, duringwhich subjects received study medication in a blinded fashion,an open-label trial phase of 24 weeks ensued. The primaryoutcome measure was the average percentage change in dailyIS frequency from baseline to the final day of the blindedtreatment phase. The reduction in IS frequency was 77.9% forvigabatrin users and 25.9% for those receiving placebo(p = 0.020). Fifteen of 36 subjects on vigabatrin monotherapyduring the open-label phase remained seizure-free, while aremaining four achieved seizure-free status with vigabatrin inaddition to a second medication.

In a second study of randomized, single-blind design,Elterman et al. evaluated the use of vigabatrin in childrenunder the age of 2 years who had been diagnosed with ISwithin the previous 3 months and were treatment naive [88].Participantswere given either high-dose (100– 148mg/kg/day)or low-dose (18 – 36 mg/kg/day) therapy for 14 days. Theprimary outcome measure was the number of subjects whowere spasm-free for 1 week beginning with the initial 2 weeksof therapy. If after 2 weeks IS was still present, doses wereincreased (the low-dose group was switched to high-dosetherapy). If spasms were still present 7 days later, doses couldbe titrated up to 200 mg/kg/day. Seventy-five and 67 subjectsreceived low- and high-dose vigabatrin respectively. Theprimary efficacy variable was met by eight subjects receivinglow-dose therapy. By contrast, the higher-dose group con-tained 24 subjects that met this criteria (p < 0.001). Responserates increased after the initial 2 weeks of therapy (8 versus65% at 3 months). Those receiving the higher-dose regimenresponded more quickly overall (p = 0.04). Sixteen per cent ofstudy subjects relapsed. The best responses were seen inpatients with tuberous sclerosis as the underlying cause ofIS (23 of 25 subjects who were spasm-free at 3 months).

The final study submitted to the FDA was completed insubjects with tuberous sclerosis, and was designed to comparevigabatrin to hydrocortisone [7]. Chiron and colleagues ran-domized 22 subjects to either vigabatrin 150 mg/kg/day orhydrocortisone 15 mg/kg/day for 1 month [9]. The primaryoutcome measure was spasm-free status. Nonresponders were

Vigabatrin


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crossed over to the alternative treatment for an additionalmonth. Vigabatrin proved to be more efficacious, with 100%of subjects achieving the primary outcome. Of the 11subjects initially randomized to hydrocortisone therapy,five were spasm-free after the initial month (p < 0.01).The remaining six subjects all responded to therapy afterbeing crossed over to vigabatrin. The mean response time tovigabatrin therapy was 4 days compared with 12.8 days withhydrocortisone (p = 0.058). It is possible that statisticalsignificance would have been achieved if the treatmentgroups had been larger.

A Cochrane review of the treatment of IS found that moststudies had been open-label regardless of whether they wereprospective or retrospective [89]. It was noted that, overall,hormonal treatments (including corticosteroids and cosyntro-pin) tend to control spasms more quickly than doesvigabatrin – although some open-label prospective studies(including the study by Chiron et al.) indicate that vigabatrinactually acts more quickly than steroids. However, which drugsresult in the best long-term outcomes remains unknown. Itshould be noted that evidence of vigabatrin efficacy in patientswith tuberous sclerosis was particularly robust, suggesting thatthe drug should probably be considered the drug of choice inpatients with this condition.

7.3 Safety and tolerabilityIn the adult studies previously summarized, the most com-monly reported adverse effects were CNS in nature, partic-ularly drowsiness, dizziness and fatigue. The Cochrane reviewof vigabatrin use in partial epilepsy noted that these adverseeffects were significantly associated with vigabatrin throughoutthe medical literature, and ataxia was marginally associatedwith use [5]. Insomnia and irritability have been documentedin infants being given vigabatrin, and less frequently there havebeen reports of psychomotor agitation, hyperexcitability andaxial hypertonia [9,88]. No significant laboratory abnormalitieshave been routinely linked to vigabatrin [4]. Abnormal MRIresults have been reported in limited preclinical and clinicalreports [90-92]. A recent study evaluating MRI results inpatients before, during and after vigabatrin use was completedby Pearl et al. and found that 8 of 22 patients developed MRIabnormalities consistent with reversible cytotoxic edema [92].The MRI changes abated with medication withdrawal. All ofthe patients with abnormalities were being treated for IS,suggesting that infants are at higher risk. These data indicatethat vigabatrin should be ruled out as the cause of new-onsetMRI abnormalities.

Some time after the approval of vigabatrin outside the USA,reports of visual field defects (VFD) associated with its usebegan to surface. This led to vigabatrin’s designation asunapproveable by the FDA at that time [93]. It is likely thatthe delay in recognizing this link between the drug and visualfield changes was related to the asymptomatic nature of theproblem in up to 90% of patients [4]. The exact mechanism ofinjury leading to the defect is unknown. Slow progressive

changes in the function of the retinal ganglia are noted inpatients who develop the VFD [4]. Changes are bilateral, andevolve as concentric constriction of the peripheral visual field.Central visual acuity is nearly always unaffected [22]. Severitycan be mild to severe, and patients frequently use eye move-ment and head turning to compensate for the changes thatoccur [4,2]. Data indicate that VFDs are irreversible innature [10,22].

During drug development, fewer than one in 1000 patientswere reported to have VFDs [93]. Prevalence from efficacy trialsis reported to be much higher, with approximately 25 – 50%of adults affected [22]. The frequency with which VFDs occurin children and infants is lower, with about 15% of childrenaffected and 15 – 30% of infants developing the condition.Detecting the defect can be challenging. For patients aged9 years or older, kinetic perimeter assessment (the standardassessment method per the manufacturer of the drug) isreliable [93]. To diagnose VFDs in infants, abnormalitiesmust be detected with two consecutive confirmed electroret-inography readings [8]. With FDA approval, baseline VFDtesting is mandated for patients on vigabatrin and continuedtesting to be carried out at predetermined intervals.

It is difficult to predict which patients are likely to develop aVFD [7]. The earliest that changes have been noted in adultpatients is 9 months after treatment initiation [22]. In children,the earliest findings were found after 11 months. On average,changes have been noted in both adults and children betweenyears 5 and 6 of vigabatrin use [22]. Clinicians disagree onwhether a relationship between dose and/or duration oftherapy and VFDs exists [4,22]. In patients with IS, it isgenerally felt that the risk of the development of a VFDdoes not outweigh the risk of allowing continuation of thespasms, which frequently lead to severe learning disabil-ities [4,10]. In addition, many patients with IS already havesevere visual impairment, thus making the development of aVFD less concerning [87]. Vigabatrin remains a drug of choicefor the treatment of IS according to many pediatric epileptol-ogists [4]. However, in adults with CPS a more conservativeapproach is probably warranted. Multiple drug failures, andsome would argue surgical ineligibility, should be consideredcriteria for use [4]. A 12-week trial of vigabatrin is unlikelyto result in development of a VFD. If the drug has notbeen efficacious within this time frame, it should bediscontinued [22].

Another safety concern with vigabatrin has been an apparentassociationwithpsychiatricdisturbances.Thesignificanceof theassociation is complicatedby the fact that in the faceof refractoryCPS, many patients experience neuropsychiatric symptomsrelated to both the seizure disorder itself as well as commontherapeutic interventions [94]. A higher incidence of depressionhas been linked to seizure disorders in general [95]. Virtually allanti-epileptic medications have been associated with mentalstatus changes and psychiatric disturbances [96]. There are nostudies comparing the incidence of psychiatric events withvigabatrin and other anti-epileptic agents.

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Using manufacturer databases, Levinson and Devinskyevaluated the overall prevalence of various psychiatric disor-ders in patients exposed to vigabatrin therapy [95]. From asample of 1942 enrollees in 10 trials included in the analysis,the most commonly noted adverse events in patients with CPSwere agitation (9.9%), depression (8.7%) and anxiety (7.7%).Other conditions encountered (in order of frequency ofoccurrence) include aggression, emotional lability, psychosis,mania and suicide attempt (all with a prevalence < 5%).Vigabatrin-treated patients tended to have more serious events(study withdrawal due to symptoms, hospitalization, psychosisassociated with depression and suicide attempt) than didplacebo-treated patients (p < 0.001). However, the withdrawalrate in patients experiencing symptoms of depression was only1.5%. The difference in the incidence of psychiatric symptomswas also significant for those taking vigabatrin (p = 0.028),though 40% of patients with symptoms had a history positivefor psychosis. One theory as to why psychotic symptoms mayemerge is one of ‘forced normalization’ [96,97]. According tothis theory, the psychosis is related to an abrupt cessation ofseizure activity rather than the medication. It has been notedthat in patients known to have schizophrenia, vigabatrin usedoes not tend to exacerbate symptoms leading to the conclu-sion that a biochemical relationship alone is unlikely to beresponsible [95]. Possibly, changes in GABA associated withvigabatrin use produce excitement in some neuronal systemsleading to symptoms [96].A retrospective study of 133 patients was completed to assess

psychiatric symptoms in patients using vigabatrin [98]. Of the22 that discontinued therapy, nine did so because of changes inmood, seven because of agitation or irritability, and six becauseof symptoms of aggression. Psychotic symptoms were noted intwo patients when vigabatrin was stopped. Overall, the relativerisk of developing symptoms in patients with a positivepsychiatric history was 1.23 (p = 0.61). Therefore, the authorsfound no support for the argument that patients with a historyof psychiatric disturbances are predisposed to exacerbationwhen given vigabatrin. In addition, there seemed to be nocorrelation with starting the drug at a higher dose versus alower dose with slower titration. The authors hypothesizedthat patients in their population were highly resistant totreatment and were therefore more susceptible to adverseevents, including psychiatric symptoms [98].Though some symptoms (such as delusions and hallucina-

tions) are easily recognized, other symptoms are not, or theymay overlap. Confusion, aggression, agitation, changes inmood and emotional lability are significantly more subjective.Investigators may define symptoms with terms different fromother investigators. Furthermore, studies are usually unclearabout whether the symptoms occurred when the patient wascognitively clear or had a diminished sensorium [96]. There-fore, the true incidence of psychiatric events, and morespecifically the type of events, in persons using vigabatrin isdifficult to ascertain.

8. Risk evaluation andmitigation strategies forvigabatrin

Vigabatrin’s demonstrated efficacy and potential for improve-ment to the therapeutic management of CPS and IS will bebalanced by specific approaches to reduce, control or avoidadverse events. The FDA mandated risk evaluation andmitigation strategies (REMS) imposed numerous require-ments for providers and patients in the USA using vigabatrin.These requirements include a provision that patients andproviders taking or prescribing vigabatrin be enrolled inand comply with the guidelines of the SHARE� programbefore the initiation of vigabatrin therapy [99]. Of note, thoughthey must acknowledge their understanding of the risksassociated with vigabatrin use by signing an enrollment andagreement form, there are no specific requirements for addi-tional training and prescribers need not be neurologists orepilepsy specialists. Separate agreement forms must be com-pleted by the patient or the patients’ legal guardian beforeaccess to vigabatrin is granted. The required forms necessitatesignatures at the time of treatment initiation and again when adecision is made to continue therapy based on a positivepatient response such that the risks associated with medicationuse are felt to be overridden by the observed benefit. A separatetreatment maintenance form signed by the prescriber alsoneeds to be submitted when the decision to continue therapyis made.

The treatment initiation form contains several sectionsincluding the prescription. The first section requests detailsabout the patient including demographic information, thephysical location of the patient at the time of drug admin-istration (i.e., home, hospital or other facility), and requiresthe patient’s signature for the release of protected healthinformation. The second section details the patient’s insuranceinformation. Section 3 requires signatures from the prescriberand a representative of TheraCom, LLC (acting on behalf ofthe drug company) authorizing the business relationshipbetween the parties, and authorizing the release of informationto the patient’s insurance company. The fourth section is themedication-specific information that will serve as the prescrip-tion. As of the time of FDA approval, only four pharmacycompanies in the USA (all mail-order pharmacies) are autho-rized to dispense vigabatrin. Once a request for medication issubmitted via the SHARE program, coordination with one ofthe authorized pharmacies will occur according to the patient’sinsurance status. Neither the patient nor the prescriber hasinput into which pharmacy company will undertake thedispensing role. The final part of the form requests additionalpatient information, including which medications have beenused for the attempted control of seizures or spasms and howmany multidrug regimens were employed before the initiationof vigabatrin therapy.

Periodic visual assessment must be completed for therapy tobe ongoing as part of the REMS. The baseline assessment

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must be undertaken and reviewed within 4 weeks of therapyinitiation. Thereafter, visual assessments must occur no lessoften than every 3 months and within 6 months of drugdiscontinuation. Therapy will be discontinued if the prescrib-ing physician fails to fax a completed ophthalmologic assess-ment form to the SHARE program. Official reminders will besent before the form due dates, and written warnings will besent to prescribers and patients alike if the forms are notreceived. Local pharmaceutical representatives will also benotified in the event of late reporting in order that they maymakedirect contactwith the prescriber to facilitate the receipt ofthe information to ensure uninterrupted therapy.

9. Conclusion

Vigabatrin has a substantial body of scientific and clinicalstudy with a long history of regulatory discussion beforeapproval in the USA. The medication has optimal propertiesfor oral drug delivery with low potential for the pharmaco-kinetic complications experienced with many of the otherAEDs. It has a clinically unique mechanism of action with thepossibility for adjunctive or sole use in seizure conditions.Vigabatrin has demonstrated efficacy in both CPS and ISpatient populations and represents a significant improvementin the therapeutic management of these conditions. The side-effect profile of vigabatrin has raised numerous concernsnecessitating the implementation of a REMS in the USA.

10. Expert opinion

The approval of vigabatrin in the USA should serve to providean alternative therapy to two groups of patients with seizuredisorders that in some cases have devastating consequences.

In the adult population, patients with CPS often findthemselves on multidrug treatment regimens without achiev-ing therapeutic success. Through decades of data collection,vigabatrin has been shown to be a viable addition to theregimens of those patients who have failed alternative thera-pies, often resulting in decreases in seizure frequency of 50%or more. However, the drug’s side-effect profile remains aconcern, particularly in the adult patient. As such, it is unlikelythat vigabatrin will find a place in therapy other than for use inthe most refractory patients.

In the case of IS, vigabatrin is likely to play a moresubstantial role, particularly in infants who have tuberoussclerosis as the underlying cause of their spasms. Despiteconcerns about side effects, many clinicians with expertisein treating pediatric epilepsies consider vigabatrin an appro-priate choice for first-line therapy in the face of IS. In addition,many of the agents historically used in the treatment of IS,such as systemic corticosteroids, are not without their ownrisks and consequences with long-term use.

In most cases, the side-effect profile of vigabatrin is notunlike that of other antiepileptic agents. Among adults, themost commonly experienced adverse events affect the CNS,

and include drowsiness, dizziness, fatigue and ataxia. Ininfants, insomnia and irritability occur with frequency, andpsychomotor agitation, hyperexcitability and axial hypertoniahave been noted. The psychiatric effects that have beendocumented in vigabatrin patients are more difficult to quantify.There is insufficient evidence in most cases to gauge whethervigabatrin use is the reason for the emergence of psychiatricsymptoms, which have included aggressive behavior, altera-tions in mood (including emergence of major depression),mania and, in extreme cases, suicidality. There seems to be norelationship to dose or duration of drug titration, and patientswith pre-existing psychiatric disorders seem to be no moresusceptible to symptom exacerbation. In addition, seizurecontrol has been correlated with the emergence of psychiatricsymptoms. The antiepileptic drugs as a group have beenassociated with psychiatric disturbances, and there is noevidence at present that symptoms are more frequent withvigabatrin as head-to-head trials have not been done. Cautionand monitoring for adverse psychiatric events are warrantedany time an antiepileptic agent is initiated.

More concerning is the discovery of visual field defectsassociated with vigabatrin use. Visual changes are apparentlyirreversible and because these events occur with relativefrequency, there was a substantial delay in the approval ofthe drug in the USA. There have been no specific patientcharacteristics identified so far to indicate which individualsmight be more or less susceptible to development of thedefects. These events have not been documented in any patientearlier than a minimum of 9 months of exposure to vigabatrintherapy. Because infants experiencing IS typically experiencedevelopmental delays if the spasms are allowed to continue,and because changes in vision are a frequent occurrence withthe spasms themselves, clinicians are likely to be less appre-hensive about early prescribing of vigabatrin in these patients.The approach in adults is likely to be substantially moreconservative, however, with virtually all drugs available for thetreatment of CPS having been used and determined to besubstandard with regard to seizure control before the initiationof vigabatrin therapy. Initiation of treatment in both adultsand infants should be undertaken with caution, and should anadequate response not be noted before 12 weeks of therapy,the drug should be discontinued.

The REMS that has been implemented for vigabatrinpatients should help to prevent unchecked vision loss withquarterly mandated ophthalmologic exams and reporting tothe SHARE program. Although regular vision testing ismandated (with allowable exceptions for blindness andother medical reasons), the clinical decisions regarding themaintenance of vigabatrin therapy reside with the prescriberand rely on recurrent monitoring and communicationbetween healthcare professionals. There is no informationavailable detailing the amount of leeway or flexibility thatexists with regard to late reporting. In addition, the REMShas no provision for allowing hospital or other institutionalpharmacy access to the medication for patients admitted with

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acute medical conditions. This may cause a delay in treat-ment or prevent medication continuation depending on theindividual policies of the institution. It is also concerningthat the FDA has disallowed community pharmacies theability to carry and dispense the medication. The use of fourspecialty pharmacies under the structure of the REMSassures that patients on multiple medications will be acquir-ing them from different pharmacies making the monitoringof a patient’s entire medication profile impossible unless thepatient transfers all of their prescriptions to the mail-orderpharmacy chosen by the SHARE program for vigabatrindispensing. The inclusion of trained and registered com-munity or institutional pharmacists with knowledge of apatient’s entire medication history would be logical, moreconvenient for the prescriber and arguably safer as thepatient could discuss medication-related concerns with ahealth care professional familiar with their medical historyand concurrent therapies. The use of trained pharmacists ina specialized dispensing model has been employed before(e.g., monitoring of the white blood cell and absolute

neutrophil counts in patients using the antipsychotic clozapine)and proven to be safe and successful.

In conclusion, vigabatrin is slated to be an important newaddition to the antiepileptic drug arsenal available to patientsin the USA. With appropriate monitoring, the benefit ofcontrolling refractory CPS and IS in previously uncontrolledpatients is likely to outweigh associated risks.

Acknowledgements

The authors thank BS Henriksen for assistance with theMolecular Operating Environment 2009 (MOE) softwarepackage (Chemical Computing Group, Inc., Montreal,Canada) and the creation of chemical structures andGABA-T images.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

Bibliography1. Walsh S. Sabril approved by FDA to treat

spasms in infants and epileptic seizures.

2009. Available from: http://www.fda.gov/

NewsEvents/Newsroom/

PressAnnouncements/ucm179855.htm

[Last accessed 25 August 2009]

2. Gidal BE, Garnett WR. Epilepsy.

In: DiPiro JT, Talbert RL, Yee GC,

et al., editors, Pharmacotherapy: a

pathophysiological approach. 6th edition.

Chicago, IL: McGraw–Hill; 2005. pp.

1023-1048

3. Murro AM. Complex partial seizures.

2006. Available from: www.emedicine.

com/neuro/topic74.htm

[Last accessed 24 July 2009]

4. Wheless JW, Ramsay RE, Collins SD.

Vigabatrin. Neurother 2007;4:163-72

5. Hemming K, Maguire MJ, Hutton JL,

Marson AG. Vigabatrin for refractory

partial epilepsy. Cochrane Database

Syst Rev 2008;3:CD007302

6. Gaily E, Liukkonen E, Paetau R, et al.

Infantile spasms: diagnosis and assessment

of treatment response by video-EEG.

Dev Med Child Neurol 2001;43:658-67

7. Parisi P, Bombardieri R, Curatolo P.

Current role of vigabatrin in infantile

spasms. Eur J Paediatr Neurol

2007;11:331-6

8. MackayMT,Weiss SK, Adams-Webber T,

et al. Practice parameter: medical

treatment of infantile spasms. Report of

the American academy of neurology and

the child neurology society. Neurology

2004;62:1668-81

9. Chiron C, Dumas C, Jambaque I, et al.

Randomized trial comparing vigabatrin

and hydrocortisone in infantile spasms due

to tuberous sclerosis. Epilepsy Res

1997;26:389-95

10. Hancock EC, Osborne JP, Edwards SW.

Treatment of infantile spasms.

Cochrane Database Syst Rev

2008;4:CD001770

11. Lippert B, Metcalf BW, Jung MJ,

Casara P. 4-Amino-hex-5-enoic acid, a

selective catalytic inhibitor of

4-aminobutyric-acid aminotransferase in

mammalian brain. Eur J Biochem

1977;74:441-5

12. Schechter PJ, Tranier Y. The

pharmacology of enzyme-activated

inhibitors of GABA-transaminase.

Enzyme-act irreversible inhibitors.

Proc Int Symp 1978:149-62

13. NDAs 20-427 & 22-006: Sabril

Advisory Committee Backgrounder. 2008.

Available from: http://www.fda.gov/

AdvisoryCommittees/

CommitteesMeetingMaterials/

Drugs/PeripheralandCentralNervous

SystemDrugsAdvisoryCommittee/

ucm153750.htm


14. Young SB. Sabril� now available

in US for patients with two

difficult-to-treat epilepsies. 2009. Available

from: http://www.lundbeckinc.com/USA/

media/press-releases/2009/

09_Sept21_SabrilLaunch.asp

[Last accessed 25 September 2009]

15. Ovation Pharmaceuticals, Inc. Sabril

(vigabatrin) Advisory Committee briefing

document. Peripheral and Central Nervous

System Advisory Committee, 2008:197

16. Ngo D-KH, Goldstein LB. Summary

Minutes of the Peripheral and Central

Nervous System Drugs Advisory

Committee Meeting, 7 January 2009.

Peripheral and Central Nervous System

Drugs Advisory Committee. Rockville,

MD: US Food and Drug

Administration, 2009

17. Ngo D-KH, Goldstein LB. Summary

Minutes of the Peripheral and Central

Nervous System Drugs Advisory

Committee Meeting 8 January 2009.

Peripheral and Central Nervous System

Drugs Advisory Committee.

Rockville, MD: US Food and Drug

Administration, 2009

18. Lundbeck, Inc. Lundbeck’s acquisition of

Ovation Pharmaceuticals cleared by US

Federal Trade Commission. 2009.

Available from: http://www.lundbeckinc.

com/USA/media/press-releases/2009/

09_March16_FTCclose.asp

[Last accessed 29July 2009]

Vigabatrin


Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

2/04

/14

For

pers

onal

use

onl

y.

19. Grant SM, Heel RC. Vigabatrin:

a review of its pharmacodynamic and

pharmacokinetic properties, and

therapeutic potential in epilepsy and

disorders of motor control. Drugs

1991;41:889-926

20. Gidal BE, Privitera MD, Sheth RD,

Gilman JT. Vigabatrin: a novel therapy for

seizure disorders. Ann Pharmacother

1999;33:1277-86

21. Mumford J, Dulac O. Vigabatrin: a new

antiepileptic medication. J Child Neurol

1991;6(Suppl 2):S3-6

22. Willmore LJ, Abelson MB,

Ben-Menachem E, et al. Vigabatrin:

2008 update. Epilepsia 2009;50:163-73

23. Rey E, Pons G, Olive G. Vigabatrin.

Clinical pharmacokinetics.

Clin Pharmacokinet 1992;23:267-78

24. Shields WD, Sankar R. Vigabatrin.

Semin Pediatr Neurol 1997;4:43-50

25. Schechter PJ. Vigabatrin.

Curr Probl Epilepsy 1986;4:265-75

26. Sankar R, Derdiarian AT. Vigabatrin.

CNS Drug Rev 1998;4:260-74

27. Reynolds EH. Vigabatrin. BMJ

1990;300:277-8

28. Mumford JP, Lewis PJ. Vigabatrin.

Epilepsy Res Suppl 1991;3:161-8

29. Mumford JP, Cannon DJ. Vigabatrin.

Epilepsia 1994;35:(Suppl 5):S25-8

30. Lewis H, Wallace SJ. Vigabatrin.

Developmental medicine and

child neurology 2001;43:833-5

31. French JA. Vigabatrin. Epilepsia

1999;40:(Suppl 5):S11-16

32. Connelly JF. Vigabatrin.

Ann Pharmacother 1993;27:197-204

33. Calli J, Farrington E. Vigabatrin.

Pediatr Nurs 1998;24:357-61

34. Ben-Menachem E. Vigabatrin.

Handb Exp Pharmacol

1999;138:375-94

35. Ben-Menachem E. Vigabatrin. Epilepsia

1995;36:(Suppl 2):S95-104

36. Vigabatrin. Lancet 1989;1:532-3

37. Sabers A, Gram L. Pharmacology of

vigabatrin. Pharmacol Toxicol

1992;70:237-43

38. Patsalos PN, Duncan JS. The

pharmacology and pharmacokinetics of

vigabatrin. Rev Contemp Pharmacother

1995;6:447-56

39. Richens A. Pharmacology and clinical

pharmacology of vigabatrin.

J Child Neurol 1991;6(Suppl 2):S7-10

40. Monaco F. Cognitive effects of vigabatrin:

a review. Neurology

1996;47:(Suppl 1):S6-11

41. Schechter PJ. Clinical pharmacology

of vigabatrin. Br J Clin Pharmacol

1989;27:(Suppl 1):19-22S

42. Yogeeswari P, Sriram D,

Vaigundaragavendran J. The GABA shunt:

an attractive and potential therapeutic

target in the treatment of epileptic

disorders. Curr Drug Metab

2005;6:127-39

43. Jakobs C, Jaeken J, Gibson KM. Inherited

disorders of GABA metabolism. J Inherit

Metab Dis 1993;16:704-15

44. Meldrum BS. GABAergic mechanisms

in the pathogenesis and treatment of

epilepsy. Br J Clin Pharmacol

1989;27:(Suppl 1):3-11S

45. Gale K. GABA and epilepsy: basic

concepts from preclinical research.

Epilepsia 1992;33:(Suppl 5):S3-12

46. Tillakaratne NJK, Medina-Kauwe L,

Gibson KM. Gamma-aminobutyric acid

(GABA) metabolism in mammalian

neural and non-neural tissues.

Comp Biochem Physiol A Physiol

1995;112A:247-63

47. Czuczwar SJ, Patsalos PN. The new

generation of GABA enhancers: potential

in the treatment of epilepsy. CNS Drugs

2001;15:339-50

48. Treiman DM. GABAergic

mechanisms in epilepsy. Epilepsia

2001;42:(Suppl 3):8-12

49. Sarup A, Larsson OM, Schousboe A.

GABA transporters and

GABA-transaminase as drug targets.

Curr Drug Targets CNS Neurol Disord

2003;2:269-77

50. Madsen KK, Larsson OM, Schousboe A.

Regulation of excitation by GABA

neurotransmission: focus on metabolism

and transport. Results Probl Cell Differ

2008;44:201-21

51. Landmark CJ. Targets for antiepileptic

drugs in the synapse. Med Sci Monit

2007;13:RA1-7

52. Draguhn A, Axmacher N, Kolbaev S.

Presynaptic lonotropic GABA receptors.

Results Probl Cell Differ

2008;44:69-85

53. Richerson GB. Looking for GABA in all

the wrong places: the relevance of

extrasynaptic GABA(A) receptors to

epilepsy. Epilepsy Curr

2004;4:239-42

54. Sheean G, Schramm T, Anderson DS,

Eadie MJ. Vigabatrin–plasma enantiomer

concentrations and clinical effects.

Clin Exp Neurol 1992;29:107-16

55. Riekkinen PJ, Ylinen A, Halonen T,

et al. Cerebrospinal fluid GABA and

seizure control with vigabatrin.

Br J Clin Pharmacol

1989;27:(Suppl 1):87-94S

56. Henczi M, Nagy J, Weaver DF.

Determination of octanol-water partition

coefficients by an HPLC method for

anticonvulsant structure-activity studies.

J Pharm Pharmacol 1995;47:345-7

57. Petroff OA, Rothman DL. Measuring

human brain GABA in vivo: effects of

GABA-transaminase inhibition with

vigabatrin. Mol Neurobiol

1998;16:97-121

58. Pow DV, Baldridge W, Crook DK.

Activity-dependent transport of GABA

analogs into specific cell types

demonstrated at high resolution using a

novel immunocytochemical strategy.

Neuroscience 1996;73:1129-43

59. Espie P, Whomsley R, Benedetti MS, et al.

Antiepileptic drugs as substrates, inhibitors

and inducers of the multidrug

resistance-associated proteins (MRPs):

implications for endo- and xenobiotic

interactions. New Res Epilepsy Behav

2007:33-55

60. Jacqz-Aigrain E, Guillonneau M, Rey E,

et al. Pharmacokinetics of the S(+) and R(-)

enantiomers of vigabatrin during chronic

dosing in a patient with renal failure.

Br J Clin Pharmacol 1997;44:183-5

61. Storici P, De Biase D, Bossa F, et al.

Structures of I3-aminobutyric acid

(GABA) aminotransferase, a pyridoxal

5¢-phosphate, and [2Fe-2S]

cluster-containing enzyme, complexed

with I3-ethynyl-GABA and with the

antiepilepsy drug vigabatrin. J Biol Chem

2004;279:363-73

62. Valdizan EM, Armijo JA. Effects of single

and multiple increasing doses of vigabatrin

on brain GABA metabolism and

correlation with vigabatrin plasma

concentration. Biochem Pharmacol

1992;43:2143-50

Tolman & Faulkner


Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

2/04

/14

For

pers

onal

use

onl

y.

63. Ben-Menachem E, Persson LI, Mumford J,

et al. Effect of long-term vigabatrin therapy

on selected neurotransmitter

concentrations in cerebrospinal fluid.

J Child Neurol 1991;6(Suppl 2):S11-6

64. Ben-Menachem E, Persson LI,

Schechter PJ, et al. The effect of different

vigabatrin treatment regimens on CSF

biochemistry and seizure control in

epileptic patients. Br J Clin Pharmacol

1989;27:(Suppl 1):79-85S

65. Frisk-Holmberg M, Kerth P, Meyer P.

Effect of food on the absorption of

vigabatrin. Br J Clin Pharmacol

1989;27:(Suppl 1):23-5S

66. Hoke JF, Yuh L, Antony KK, et al.

Pharmacokinetics of vigabatrin following

single and multiple oral doses in normal

volunteers. J Clin Pharmacol

1993;33:458-62

67. Durham SL, Hoke JF, Chen TM.

Pharmacokinetics and metabolism of

vigabatrin following a single oral dose of

[14C]vigabatrin in healthy male

volunteers. Drug Metab Dispos

1993;21:480-4

68. Haegele KD, Schechter PJ. Kinetics

of the enantiomers of vigabatrin after an

oral dose of the racemate or the active

S-enantiomer. Clin Pharmacol Ther

1986;40:581-6

69. Rey E, Pons G, Richard MO, et al.

Pharmacokinetics of the individual

enantiomers of vigabatrin (gamma-vinyl

GABA) in epileptic children.

Br J Clin Pharmacol 1990;30:253-7

70. Bialer M. Comparative pharmacokinetics

of the newer antiepileptic drugs.

Clin Pharmacokinet 1993;24:441-52

71. Perucca E. Pharmacokinetic variability of

new antiepileptic drugs at different ages.

Ther Drug Monit 2005;27:714-17

72. Bourgeois BF. Important pharmacokinetic

properties of antiepileptic drugs. Epilepsia

1995;36:(Suppl 5):S1-7

73. Haegele KD, Huebert ND, Ebel M, et al.

Pharmacokinetics of vigabatrin:

implications of creatinine clearance.

Clin Pharmacol Ther 1988;44:558-65

74. Yu DK, Hutcheson SJ, Wei G, et al. A

comparison of population and standard

two-stage pharmacokinetic analyses of

vigabatrin data. Biopharm Drug Dispos

1994;15:473-84

75. Lacerda G, Krummel T, Sabourdy C, et al.

Optimizing therapy of seizures in patients

with renal or hepatic dysfunction.

Neurology 2006;67:(Suppl 4):S28-33

76. Tong X, Ratnaraj N, Patsalos PN. The

pharmacokinetics of vigabatrin in rat blood

and cerebrospinal fluid. Seizure

2007;16:43-9

77. Sanchez-Alcaraz A, Quintana MB,

Lopez E, et al. Effect of vigabatrin on the

pharmacokinetics of carbamazepine. J Clin

Pharm Ther 2002;27:427-30

78. Browne TR, Mattson RH, Penry JK, et al.

Vigabatrin for refractory complex partial

seizures: multicenter single-blind study

with long-term follow-up. Neurology

1987;37:184-9

79. Tartara A, Manni R, Galimberti CA, et al.

Vigabatrin in the treatment of epilepsy: a

long-term follow-up study. J Neurol

Neurosurg Psychiatry 1989;52:467-71

80. Loscher W, Schmidt D. Experimental and

clinical evidence for loss of effect

(tolerance) during prolonged treatment

with antiepileptic drugs. Epilepsia

2006;47:1253-84

81. Browne TR, Mattson RH, Penry JK,

et al. A multicentre study of vigabatrin

for drug-resistant epilepsy.

Br J Clin Pharmacol

1989;27:(Suppl 1):95-100S

82. Remy C, Beaumont D. Efficacy and safety

of vigabatrin in the long-term treatment of

refractory epilepsy. Br J Clin Pharmacol

1989;27:(Suppl 1):125-9S

83. Petroff OA, Rothman DL, Behar KL,

Mattson RH. Human brain GABA levels

rise after initiation of vigabatrin therapy

but fail to rise further with increasing dose.

Neurology 1996;46:1459-63

84. French JA, Mosier M, Walker S, et al.

A double-blind, placebo-controlled study

of vigabatrin three g/day in patients

with uncontrolled complex partial

seizures. Vigabatrin Protocol 024

Investigative Cohort. Neurology

1996;46:54-61

85. Dean C, Mosier M, Penry K.

Dose-response study of vigabatrin as

add-on therapy in patients with

uncontrolled complex partial seizures.

Epilepsia 1999;40:74-82

86. Mumford JP, Dam M. Meta-analysis

of European placebo controlled studies

of vigabatrin in drug resistant epilepsy.

Br J Clin Pharmacol

1989;27:(Suppl 1):101-7S

87. Appleton RE, Peters ACB, Mumford JP,

Shaw DE. Randomized,

placebo-controlled study of vigabatrin as

first-line treatment of infantile spasms.

Epilepsia 1999;40:1627-33

88. Elterman RD, Shields WD, Mansfield KA,

et al. Randomized trial of vigabatrin in

patients with infantile spasms. Neurology

2001;57:1416-21

89. Hancock E, Osborne J, Milner P.

Treatment of infantile spasms.

Cochrane Database Syst Rev

2003;3:CD001770

90. Jackson GD, Grunewald RA, Connelly A,

Duncan JS. Quantitative MR relaxometry

study of effects of vigabatrin on the brains

of patients with epilepsy. Epilepsy Res

1994;18:127-37

91. Cohen JA, Fisher RS, Brigell MG, et al.

The potential for vigabatrin-induced

intramyelinic edema in humans. Epilepsia

2000;41:148-57

92. Pearl PL, Vezina LG, Saneto RP, et al.

Cerebral MRI abnormalities associated

with vigabatrin therapy. Epilepsia

2009;50:184-94

93. Kalviainen R, Nousiainen I. Visual field

defects with vigabatrin: epidemiology and

therapeutic implications. CNS Drugs

2001;15:217-30

94. Trimble MR. The psychosis of epilepsy.

New York: Raven Press; 1991

95. Levinson DF, Devinsky O. Psychiatric

adverse events during vigabatrin therapy.

Neurology 1999;53:1503-11

96. Ferrie CD, Robinson RO,

Panayiotopoulos CP. Psychotic and severe

behavioral reactions with vigabatrin: a

review. Acta Neurol Scand

1996;93:1-8

97. Thomas L, Trimble M. Schmitz B,

Ring H. Vigabatrin and behavior

disorders: A retrospective survey.

Epilepsy Res 1996;25(1):21-7

98. Wong ICK. Retrospective study of

vigabatrin and psychiatric behavioral

disturbances. Epilepsy Res

1995;21:227-30

99. Lundbeck, Inc. Support, help and

resources for epilepsy: a comprehensive

resource for healthcare professionals and

their patients with severe or

uncontrolled epilepsies. 2009. Available

Vigabatrin


Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

2/04

/14

For

pers

onal

use

onl

y.

from: http://www.lundbeckshare.com/

Default.aspx

[Last accessed 15 October 2009]

100. Storici P, Capitani G, De Biase D,

et al. Crystal structure of

GABA-aminotransferase, a target for

antiepileptic drug therapy. Biochemistry

1999;38:8628-34

101. Storici P, Capitani G, De Biase D, et al.

4-aminobutyrate-aminotransferase from

pig. 1999. Available from: http://www.

rcsb.org/pdb/explore.do?

structureId=1OHV [Last accessed

28 July 2009]

102. Storici P, De Biase D, Bossa F, et al.

4-aminobutyrate-aminotransferase

inactivated by gamma-vinyl GABA. 2004.

Available from: http://www.rcsb.org/pdb/

explore/explore.do?structureId=1OHW


AffiliationJustin A Tolman† PharmD PhD &

Michele A Faulkner PharmD†Author for correspondence

Creighton University School of Pharmacy and

Health Professions,

2500 California Plaza,

Omaha, NE 68178, USA

Tel: +1 402 280 2915; Fax: +1 402 280 1883;

E-mail: [email protected]

Tolman & Faulkner


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oade

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ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

2/04

/14

For

pers

onal

use

onl

y.

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