Brivaracetam

Absorption

Nearly 100% oral bioavailability .

Toxicity

No carcinogenesis or fertility impairment found. Overdose is associated with somnolence and dizziness .

Description

Brivaracetam, a novel oral antiepileptic drug with a high affinity for synaptic vesicle protein 2A (SV2A), was approved in Europe and the US as an adjunctive therapy for the treatment of partial onset seizures with or without secondary generalization in patients aged 16 or older.42 Brivaracetam is very closely related to levetiracetam, an antiepileptic treatment whose immediate release formulation has been available in the United States as a generic drug since 2008, but whose extended release formulation is under patent protection until 2028. The two drugs, which were both developed by UCB Pharma, are structurally similar with brivaracetam having an n-propyl group at the C-4 position of the pyrrolidinone ring and levetiracetam having a hydrogen at this same position. A systematic investigation of the various substitutions of levetiracetam resulted in the identification of more potent and selective SV2A ligands and ultimately culminated in the discovery of brivaracetam, which has greater affinity for SV2A, improved selectivity, more rapid brain penetration, and faster onset of action against seizures than levetiracetam.

The Uses of Brivaracetam

Brivaracetam, is a 4-n-propyl analog of levetiracetam (L331500), and a racetam derivative with anticonvulsant properties.

The Uses of Brivaracetam

Treatment ofTreatment of epilepsy, neuropathic pain and essential tremor.

Background

Brivaracetam is a racetam derivative of levetiracetam used in the treatment of partial-onset seizures. Brivaracetam binds SV2A with 20 times higher affinity than levetiracetam . It is available under the brand name Briviact made by UCB. Briviact received FDA approval on February 19, 2016 .

Indications

Used as adjunctive therapy for partial-onset seizures in patients 16 years of age or older.

Definition

ChEBI: A non-proteinogenic amino acid derivative that is butanamide in which the pro-S hydrogen at position 2 is replaced by a (4R)-2-oxo-4-propylpyrrolidin-1-yl. Used for treatment of partial onset seizures related to epilepsy.

Pharmacokinetics

Brivaracetam binds SV2A with high affinity . SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release . It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action .

Clinical Use

Antiepileptic agent

Side Effects

Common side effects of brivaracetam include: constipation, nausea, vomiting, extreme tiredness or low energy. Serious side effects that may be caused include: swelling of the face, throat, tongue, lips, and eyes; difficulty swallowing or breathing; hoarseness, hallucinations (seeing things or hearing sounds that are not there), and delusions (strange thoughts or beliefs that have no basis in reality). An overdose may cause: drowsiness, extreme tiredness, dizziness, difficulty maintaining balance, blurred or double vision, slowed heartbeat, nausea, and feeling anxious.

Synthesis

Two enantioselective routes have been reported, one employing an enzymatic resolution and the other utilizing (R)- (-)-epichlorohydrin as a chiral starting material. The route involves an enzymatic resolution, is the only kilogram-scale route disclosed in the literature to date and reportedly permits the production of brivaracetam within the required commercial quality specifications. However, the authors note that the development of this route for commercial purposes has been stopped. Commercial dimethyl n-propylmalonate 108 was first alkylated with tertbutyl- 2-bromoacetate. The resulting product underwent Krapcho decarboxylation to afford racemic succinate derivative 109 in 94% yield over the two steps. Optimized conditions for the key enzymatic resolution employed protease C from Bacillus subtilis type 2 at 30 ??C for 18 h to resolve ester 109 and provide the acid enantiomer 110. This biocatalytic process allowed for residual unreacted diester 109 to be washed away with cyclohexane at pH 9 (adjusted with 0.5 M NaOH), and the desired acid 110 could be isolated upon lowering the pH (??1) and extracting with isopropyl acetate (42% yield, 97% ee). The transformation of acid 110 into propyllactone 111 proceeded in nearly quantitative yield by a three-step sequence: activation of the acid with ethyl chloroformate, reduction to the alcohol with sodium borohydride, and cyclization upon acidic workup with TFA. Exposure of 111 to HBr in acetic acid followed by esterification of the resulting acid-generated bromoester 112. Finally, TBAI-catalyzed alkylation of 112 with commercial (S)-2-aminobutanamide (113) in refluxing isopropyl acetate introduced the n-butylamide moiety while facilitating lactamization. Addition of MTBE followed by filtration and recrystallization from isopropyl acetate afforded brivaracetam (IX) in 32% yield and 96% ee.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin.
Antidepressants: antagonism of anticonvulsant effect (convulsive threshold lowered).
Antimalarials: mefloquine antagonises anticonvulsant effect.
Antipsychotics: antagonism of anticonvulsant effect (convulsive threshold lowered).
Orlistat: possibly increased risk of convulsions.

Metabolism

Primarily metabolized by hydrolysis of the acetamide moeity to form a carboxylic acid metabolite . Another metabolite is created via oxidation of the propyl side chain by CYP2C8 as well as CYP3A4, CYP2C19, and CYP2B6. Some conjugation with glucuronic acid and taurine account for a small amount of metabolism.

Metabolism

Brivaracetam is mainly metabolised by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60% the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30% the elimination). The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34% of the dose in urine) is supported by hepatic and extra-hepatic amidase. The metabolites are inactive. Greater than 95% of the dose is excreted in the urine as brivaracetam and its metabolites.

Storage

Store at -20°C