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Brivaracetam

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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 has been approved since 2016. It is marketed by the pharmaceutical company UCB.[7][8] It is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs.

Brivaracetam
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%)[4]
Identifiers
  • (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.118.642 Edit this at Wikidata
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)
  • O=C(N)[C@@H](N1C(=O)C[C@@H](CCC)C1)CC
  • InChI=1S/C11H20N2O2/c1-3-5-8-6-10(14)13(7-8)9(4-2)11(12)15/h8-9H,3-7H2,1-2H3,(H2,12,15)/t8-,9+/m1/s1 checkY
  • Key:MSYKRHVOOPPJKU-BDAKNGLRSA-N checkY

Medical uses

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Brivaracetam is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. Efficacy and tolerability is comparable in general and Intellectual Disability populations.[9] No data are available for its effectiveness and safety in people younger than 16 years of age.[10][11][12]

Adverse effects

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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.[10][11]

No clinically relevant differences in adverse effects incidence for the starting doses were observed, except for a dose–response relationship for somnolence and fatigue.[13]

Interactions

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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.[14]

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.[11]

Pharmacology

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Mechanism of action

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Brivaracetam is believed to act by binding to the ubiquitous synaptic vesicle glycoprotein 2A (SV2A), like levetiracetam, but with 20-fold greater affinity.[15][16] 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.[17]

Pharmacokinetics

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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.[18]

Brivaracetam can be interchanged with levetiracetam as follows: 50 mg Brivaracetam by 1,000 mg levetiracetam, 100 mg of brivaracetam by 2,000 mg levetiracetam, and 200 mg of brivaracetam by 3,000 mg levetiracetam.[19]

Pharmacogenetics

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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

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Levetiracetam, for comparison

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

History

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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]

On 14 January 2016, the European Commission,[11] and on 18 February 2016, the U.S. Food and Drug Administration (FDA)[23] 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.[24] As of May 2016, brivaracetam is not approved in some other countries. It was approved in Australia in August 2016.[25]

In Canada it was approved on 9 March 2016 under the trade name Brivlera.[26]

Society and culture

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As of 2022, the US Food and Drug Administration approved a generic drug version of brivaracetam, but as of 2023 it was not yet available as a generic medication.[27][28]

In Argentina, brivaracetam has been sold under the brand Brivaxon from Raffo Laboratories and Briviact from Biopas Argentina. [29] [30]

In Germany, UCB was unable to demonstrate an additional benefit in 2016,[31] 2018[32] and 2022[33] by adding brivaracetam. In Germany, newly approved drugs with new active ingredients have to be evaluated by the Federal Joint Committee (Germany)(Gemeinsamer Bundesausschuss) if the pharmaceutical manufacturer wishes to achieve a higher selling price than just the fixed amount. Only if there is an additional benefit, the pharmaceutical manufacturer can negotiate a price with the top association of statutory health insurance companies.

References

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  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ^ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada. 14 March 2017. Retrieved 7 April 2024.
  4. ^ a b c "Briviact- brivaracetam tablet, film coated Briviact- brivaracetam solution Briviact- brivaracetam injection, suspension". DailyMed. U.S. National Library of Medicine. 15 May 2018. Archived from the original on 21 March 2021. Retrieved 25 January 2019.
  5. ^ von Rosenstiel P (January 2007). "Brivaracetam (UCB 34714)". Neurotherapeutics. 4 (1): 84–87. doi:10.1016/j.nurt.2006.11.004. PMC 7479692. PMID 17199019.
  6. ^ Malawska B, Kulig K (July 2005). "Brivaracetam UCB". Current Opinion in Investigational Drugs. 6 (7): 740–746. PMID 16044671.
  7. ^ "Briviact Product Page". UCB. Archived from the original on 19 September 2020. Retrieved 1 January 2020.
  8. ^ "Brivaracetam". DrugBank. Archived from the original on 10 January 2020. Retrieved 1 January 2020.
  9. ^ Allard J, Henley W, Sellers A, O'Shaughnessy E, Thomson O, McLean B, et al. (September 2024). "Efficacy and tolerability of Brivaracetam in people with intellectual disability compared to those without intellectual disability". Epilepsy & Behavior. 158: 109906. doi:10.1016/j.yebeh.2024.109906. PMID 38936308.
  10. ^ a b Briviact Drugs.com
  11. ^ a b c d "Briviact". European Medicines Agency. Archived from the original on 10 June 2016. Retrieved 30 May 2016.
  12. ^ Bresnahan R, Panebianco M, Marson AG (March 2022). "Brivaracetam add-on therapy for drug-resistant epilepsy". The Cochrane Database of Systematic Reviews. 2022 (3): CD011501. doi:10.1002/14651858.CD011501.pub3. PMC 8919456. PMID 35285519.
  13. ^ Klein P, Diaz A, Gasalla T, Whitesides J (31 December 2018). "A review of the pharmacology and clinical efficacy of brivaracetam". Clinical Pharmacology. 10: 1–22. doi:10.2147/CPAA.S114072. PMC 5783144. PMID 29403319.
  14. ^ Rolan P, Sargentini-Maier ML, Pigeolet E, Stockis A (July 2008). "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. doi:10.1111/j.1365-2125.2008.03158.x. PMC 2485265. PMID 18341673.
  15. ^ Rogawski MA, Bazil CW (July 2008). "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. doi:10.1007/s11910-008-0053-7. PMC 2587091. PMID 18590620.
  16. ^ Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  17. ^ Rogawski MA (October 2016). "A New SV2A Ligand for Epilepsy". Cell. 167 (3): 587. doi:10.1016/j.cell.2016.09.057. PMID 27768878.
  18. ^ 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. PMID 17908923. S2CID 14972675.
  19. ^ Asadi-Pooya AA, Patel AA, Trinka E, Mazurkiewicz-Beldzinska M, Cross JH, Welty TE (October 2022). "Recommendations for treatment strategies in people with epilepsy during times of shortage of antiseizure medications". Epileptic Disorders. 24 (5): 751–764. doi:10.1684/epd.2022.1468. PMID 35894673.
  20. ^ Dean L (2018). "Brivaracetam Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 29763212. Bookshelf ID: NBK500036. Archived from the original on 26 October 2020. Retrieved 7 February 2020.
  21. ^ Rogawski MA (August 2008). "Brivaracetam: a rational drug discovery success story". British Journal of Pharmacology. 154 (8): 1555–1557. doi:10.1038/bjp.2008.221. PMC 2518467. PMID 18552880.
  22. ^ Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H (August 2008). "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. doi:10.1038/bjp.2008.198. PMC 2518465. PMID 18500360.
  23. ^ "FDA approves Briviact to treat partial onset seizures". U.S. Food and Drug Administration (FDA). 19 February 2016. Archived from the original on 23 April 2019. Retrieved 20 May 2023.
  24. ^ 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.
  25. ^ "Australian Public Assessment Report for brivaracetam" (PDF). Therapeutic Goods Administration. 2017. Archived (PDF) from the original on 14 August 2021. Retrieved 13 June 2020.
  26. ^ UCB Canada Inc. (29 July 2020). "Health Canada Approves BRIVLERA® (brivaracetam) to treat partial-onset seizures in pediatric epilepsy patients". Cision Canada. Archived from the original on 19 October 2021. Retrieved 16 October 2021.
  27. ^ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 3 March 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  28. ^ "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  29. ^ "Brivaxon". Laboratorios Raffo. Retrieved 12 April 2024.
  30. ^ "Biopas Portal para Médicos". Biopas Colombia. Retrieved 12 April 2024.
  31. ^ "Nutzenbewertungsverfahren zum Wirkstoff Brivaracetam (Fokale Anfälle bei Epilepsie, ≥ 16 Jahre) - Gemeinsamer Bundesausschuss". www.g-ba.de. Retrieved 16 June 2024.
  32. ^ "[A18-48] Brivaracetam (Epilepsie) - Nutzenbewertung gemäß § 35a SGB V". Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) (in German). 2 November 2018. Retrieved 16 June 2024.
  33. ^ "Brivaracetam (Epilepsie bei Kindern von ≥ 2 bis < 4 Jahren) – Nutzenbewertung gemäß § 35a SGB V" (PDF). 18 May 2022. Retrieved 16 June 2024.

Further reading

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