Chemistry:Brivaracetam

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Short description: Medication used to treat seizures
Brivaracetam
Brivaracetam.svg
Clinical data
Pronunciation/ˌbrɪvəˈræsətəm/ BRIV-ə-RASS-ə-təm
Trade namesBriviact, Nubriveo, Brivajoy
AHFS/Drugs.comMonograph
MedlinePlusa616027
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNearly 100%
Protein binding≤20%
MetabolismHydrolysis by amidase, CYP2C19-mediated hydroxylation
Metabolites3 inactive metabolites
Elimination half-life≈9 hours
ExcretionKidneys (>95%)[2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC11H20N2O2
Molar mass212.293 g·mol−1
3D model (JSmol)
Specific rotation[α]D −60°
Melting point72 to 77 °C (162 to 171 °F)

Brivaracetam, sold under the brand name Briviact among others, is a chemical analog of levetiracetam, is a racetam derivative with anticonvulsant (antiepileptic) properties.[3][4] It is marketed by the pharmaceutical company UCB.[5][6]

It is available as a generic medication.[7][8]

Medical uses

Brivaracetam is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. No data are available for its effectiveness and safety in people younger than 16 years of age.[9][10][11]

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.[9][10]

No clinically relevant differences in adverse effects incidence for the starting doses were observed, except for a dose–response relationship for somnolence and fatigue.[12]

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.[13]

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.[10]

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.[14][15] 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.[16]

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.[17]

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.[18] 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.[2]

Chemical and physical properties

Levetiracetam, for comparison

Brivaracetam is the 4R-propyl analogue of the anticonvulsant levetiracetam.

History

Positive preliminary results from stage III trials were recorded in 2008,[19] 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.[20]

On 14 January 2016, the European Commission,[10] and on 18 February 2016, the U.S. Food and Drug Administration (FDA)[21] approved brivaracetam under the trade name Briviact. The Drug Enforcement Administration (DEA) issued an interim final rule[clarification needed] placing brivaracetam into schedule V of the Controlled Substances Act (CSA) effective 9 March 2017.[22] (As of May 2016), brivaracetam is not approved in some other countries. It was approved in Australia in August 2016.[23] In Canada it was approved on 9 March 2016 under the trade name Brivlera.[24]

Society and culture

Brand names

It is sold under the brand name Brivlera in Canada.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". 21 June 2022. https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016. 
  2. ↑ 2.0 2.1 2.2 "Briviact- brivaracetam tablet, film coated Briviact- brivaracetam solution Briviact- brivaracetam injection, suspension". DailyMed. U.S. National Library of Medicine. 15 May 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3cf2f439-0e97-443e-8e33-25ecef616f6c. 
  3. ↑ "Brivaracetam (UCB 34714)". Neurotherapeutics 4 (1): 84–87. January 2007. doi:10.1016/j.nurt.2006.11.004. PMID 17199019. 
  4. ↑ "Brivaracetam UCB". Current Opinion in Investigational Drugs 6 (7): 740–746. July 2005. PMID 16044671. 
  5. ↑ "Briviact Product Page". UCB. https://www.ucb.com/our-products/Products/briviact%c2%ae-epilepsy. 
  6. ↑ "Brivaracetam". DrugBank. https://www.drugbank.ca/drugs/DB05541. 
  7. ↑ "2022 First Generic Drug Approvals". 3 March 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals. 
  8. ↑ "Competitive Generic Therapy Approvals". 29 June 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  9. ↑ 9.0 9.1 Briviact Drugs.com
  10. ↑ 10.0 10.1 10.2 10.3 "Briviact". European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003898/human_med_001945.jsp&mid=WC0b01ac058001d124. 
  11. ↑ "Brivaracetam add-on therapy for drug-resistant epilepsy". The Cochrane Database of Systematic Reviews 2022 (3): CD011501. March 2022. doi:10.1002/14651858.CD011501.pub3. PMID 35285519. 
  12. ↑ "A review of the pharmacology and clinical efficacy of brivaracetam". Clinical Pharmacology 10: 1–22. 31 December 2018. doi:10.2147/CPAA.S114072. PMID 29403319. 
  13. ↑ "The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men". British Journal of Clinical Pharmacology 66 (1): 71–75. July 2008. doi:10.1111/j.1365-2125.2008.03158.x. PMID 18341673. 
  14. ↑ "New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels". Current Neurology and Neuroscience Reports 8 (4): 345–352. July 2008. doi:10.1007/s11910-008-0053-7. PMID 18590620. 
  15. ↑ (in de) Austria-Codex. Vienna: Österreichischer Apothekerverlag. 2015. 
  16. ↑ "A New SV2A Ligand for Epilepsy". Cell 167 (3): 587. October 2016. doi:10.1016/j.cell.2016.09.057. PMID 27768878. 
  17. ↑ "Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects". Drug Metabolism and Disposition 36 (1): 36–45. January 2008. doi:10.1124/dmd.107.017129. PMID 17908923. 
  18. ↑ "Brivaracetam Therapy and CYP2C19 Genotype". Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). 2018. Bookshelf ID: NBK500036. https://www.ncbi.nlm.nih.gov/books/NBK500036/. Retrieved 7 February 2020. 
  19. ↑ "Brivaracetam: a rational drug discovery success story". British Journal of Pharmacology 154 (8): 1555–1557. August 2008. doi:10.1038/bjp.2008.221. PMID 18552880. 
  20. ↑ "Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A". British Journal of Pharmacology 154 (8): 1662–1671. August 2008. doi:10.1038/bjp.2008.198. PMID 18500360. 
  21. ↑ "FDA approves Briviact to treat partial onset seizures". U.S. Food and Drug Administration (FDA). 19 February 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486827.htm. 
  22. ↑ 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. PMID 27192732. 
  23. ↑ "Australian Public Assessment Report for brivaracetam". Therapeutic Goods Administration. 2017. https://www.tga.gov.au/sites/default/files/auspar-brivaracetam-170307.pdf. 
  24. ↑ UCB Canada Inc. (29 July 2020). "Health Canada Approves BRIVLERA® (brivaracetam) to treat partial-onset seizures in pediatric epilepsy patients". Cision Canada. https://www.newswire.ca/news-releases/health-canada-approves-brivlera-r-brivaracetam-to-treat-partial-onset-seizures-in-pediatric-epilepsy-patients-868605074.html. 

Further reading



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