Brivaracetam, sold under the brand name Briviact among others, is a chemical analog of
levetiracetam, a
racetam derivative with
anticonvulsant (antiepileptic) properties.[5][6] It is marketed by the pharmaceutical company
UCB.[7][8]
Brivaracetam is used to treat
partial- onset seizures with or without secondary generalization, in combination with other antiepileptic drugs. No data are available for its effectiveness and safety in people younger than 16 years of age.[11][12][13]
Adverse effects
The most common adverse effects include sleepiness,
dizziness,
nausea and vomiting. More rarely, coordination problems and changes in behaviour (such as severe
depression,
aggression, hostility, impatience, rage,
suicidal ideation, etc.) can occur.[11][12]
No clinically relevant differences in adverse effects incidence for the starting doses were observed, except for a dose–response relationship for somnolence and fatigue.[14]
Interactions
Coadministration of brivaracetam with
carbamazepine may increase exposure to carbamazepine-epoxide, the
active metabolite of carbamazepine, and could theoretically lead to reduced tolerability. Coadministration of brivaracetam with
phenytoin may increase phenytoin levels. Coadministration of other antiseizure drugs are unlikely to affect brivaracetam exposure. Brivaracetam provides no added therapeutic benefit when administered in conjunction with levetiracetam that acts on the same protein.[15]
No pharmacokinetic interaction was observed between single-dose 200mg brivaracetam and 0.6g/L ethanol in healthy subjects. However, brivaracetam approximately doubled the effect of alcohol on
psychomotor function, attention and memory. Alcohol use while under brivaracetam treatment is not recommended.[12]
Pharmacology
Mechanism of action
Brivaracetam is believed to act by binding to the ubiquitous
synaptic vesicle glycoprotein 2A (SV2A), like levetiracetam, but with 20-fold greater affinity.[16][17] There is some evidence that racetams including levetiracetam and brivaracetam access the luminal side of recycling synaptic vesicles during vesicular
endocytosis. They may reduce excitatory
neurotransmitter release and enhance synaptic depression during trains of high-frequency activity, such as is believed to occur during epileptic activity.[18]
Pharmacokinetics
Brivaracetam exhibits linear pharmacokinetics over a wide dose range, is rapidly and completely absorbed after oral administration, has an
elimination half-life of seven to eight hours, and has
plasma protein binding of less than 20%. It is extensively
metabolized (>90%), primarily via
hydrolysis of the
acetamide group, and secondarily through hydroxylation mediated by the liver enzyme
CYP2C19. The three major metabolites (hydroxy, acid, and hydroxyacid) are pharmacologically inactive. Brivaracetam is eliminated as
urinary metabolites, with over 95% of a radioactive test dose recovered in the urine within 72 hours, including only 8.6% as unchanged brivaracetam.[19]
Pharmacogenetics
As noted above, brivaracetam is primarily metabolized by hydrolysis, via amidase enzymes, to an inactive metabolite. To a lesser extent, it is also metabolized by a minor metabolic pathway via CYP2C19-dependent hydroxylation. Individuals who have no CYP2C19 enzyme activity, "CYP2C19 poor metabolizers", will have a greater exposure to standard doses of brivaracetam. Because they are less able to metabolize the drug to its inactive form for excretion, they may have an increased risk of adverse effects. The most common adverse effects of brivaracetam therapy include sedation, fatigue, dizziness, and nausea.[20] The FDA-approved drug label for brivaracetam states that patients who are CYPC19 poor metabolizers, or are taking medicines that inhibit CYP2C19, may require a dose reduction.[4]
Chemical and physical properties
Brivaracetam is the 4R-propyl
analogue of the anticonvulsant levetiracetam.
History
Positive preliminary results from stage III trials were recorded in 2008,[21] along with evidence that it is around ten times more potent for the prevention of certain types of seizure in mouse models than its analogue levetiracetam.[22]
It is sold under the brand name Brivlera in Canada.[27] In Argentina, it is sold under the brand Brivaxon from Raffo Laboratories and Briviact from Biopas Argentina. [28][29]
^Sargentini-Maier ML, Espié P, Coquette A, Stockis A (January 2008). "Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects". Drug Metabolism and Disposition. 36 (1): 36–45.
doi:
10.1124/dmd.107.017129.
PMID17908923.
S2CID14972675.
^Drug Enforcement Administration Department of Justice (May 2016). "Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V. Interim final rule, with request for comments". Federal Register. 81 (92): 29487–29492.
PMID27192732.