Brivaracetam

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Brivaracetam
Brivaracetam.svg
Clinical data
Pronunciation /ˌbrɪvəˈræsətəm/ BRIV-ə-RASS-ə-təm
Trade names Briviact, Nubriveo, Brivajoy
AHFS/Drugs.com Monograph
MedlinePlus a616027
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Nearly 100%
Protein binding ≤20%
Metabolism Hydrolysis by amidase, CYP2C19-mediated hydroxylation
Metabolites 3 inactive metabolites
Elimination half-life ≈9 hours
Excretion Kidneys (>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 InfoCard 100.118.642 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H20N2O2
Molar mass 212.293 g·mol−1
3D model (JSmol)
Specific rotation [α]D −60°
Melting point 72 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 Yes check.svgY
  • Key:MSYKRHVOOPPJKU-BDAKNGLRSA-N Yes check.svgY

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]

Contents

A generic version of brivaracetam has been approved by the Food and Drug Administration (FDA) in the United States, but it is not yet available as a generic medication. [9] [10]

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. [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

Levetiracetam, for comparison Levetiracetam.svg
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, [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, [12] 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

Brand names

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]

Related Research Articles

<span class="mw-page-title-main">Phenytoin</span> Anti-seizure medication

Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures and focal seizures, but not absence seizures. The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines. It may also be used for certain heart arrhythmias or neuropathic pain. It can be taken intravenously or by mouth. The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. Blood levels can be measured to determine the proper dose.

Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.

<span class="mw-page-title-main">Topiramate</span> Medication used to treat epilepsy and migraine

Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence and essential tremor. For epilepsy this includes treatment for generalized or focal seizures. It is taken orally.

<span class="mw-page-title-main">Lamotrigine</span> Medication used for bipolar disorder, epilepsy, & many seizure disorders

Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome. In bipolar disorder, lamotrigine has not been shown to reliably treat acute depression for all groups except in the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression.

<span class="mw-page-title-main">Oxcarbazepine</span> Anticonvulsant medication

Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.

<span class="mw-page-title-main">Levetiracetam</span> Medication

Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.

<span class="mw-page-title-main">Piracetam</span> Chemical compound

Piracetam is a drug that has efficacy in cognitive disorders, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia; sources differ on its usefulness for dementia. Piracetam is sold as a medication in many European countries. Sale of piracetam is not illegal in the United States, although it is not regulated nor approved by the FDA, so it is legally sold for research use only.

<span class="mw-page-title-main">Clonazepam</span> Benzodiazepine medication

Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, OCD and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.

<span class="mw-page-title-main">Tiagabine</span> Anticonvulsant medication

Tiagabine is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder.

<span class="mw-page-title-main">Primidone</span> Barbiturate medication used to treat seizures and tremors

Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures and essential tremors. It is taken by mouth.

<span class="mw-page-title-main">Clobazam</span> Benzodiazepine class medication

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

<span class="mw-page-title-main">Valnoctamide</span> Chemical compound

Valnoctamide has been used in France as a sedative-hypnotic since 1964. It is a structural isomer of valpromide, a valproic acid prodrug; unlike valpromide, however, valnoctamide is not transformed into its homologous acid, valnoctic acid, in vivo.

<span class="mw-page-title-main">Felbamate</span> Chemical compound

Felbamate is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drug's usage to severe refractory epilepsy.

<span class="mw-page-title-main">Rufinamide</span> Chemical compound

Rufinamide is an anticonvulsant medication. It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders. Rufinamide, a triazole derivative, was developed in 2004 by Novartis Pharma, AG, and is manufactured by Eisai.

<span class="mw-page-title-main">Seletracetam</span> Chemical compound

Seletracetam is a pyrrolidone-derived drug of the racetam family that is structurally related to levetiracetam. It was under development by UCB Pharmaceuticals as a more potent and effective anticonvulsant drug to replace levetiracetam but its development has been halted.

<span class="mw-page-title-main">Lacosamide</span> Anticonvulsant and analgesic medication

Lacosamide, sold under the brand name Vimpat among others, is a medication used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. It is used by mouth or intravenously.

<span class="mw-page-title-main">Retigabine</span> Anticonvulsant, which works as a potassium-channel opener

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017.

<span class="mw-page-title-main">Perampanel</span> Anti-epileptic medication

Perampanel, sold under the brand name Fycompa, is an anti-epileptic medication developed by Eisai Co. that is used in addition to other drugs to treat partial seizures and generalized tonic-clonic seizures for people older than twelve years. It was first approved in 2012, and as of 2016, its optimal role in the treatment of epilepsy relative to other drugs was not clear. It was the first antiepileptic drug in the class of selective non-competitive antagonist of AMPA receptors.

<span class="mw-page-title-main">Eslicarbazepine acetate</span> Anticonvulsant medication

Eslicarbazepine acetate (ESL), sold under the brand names Aptiom and Zebinix among others, is an anticonvulsant medication approved for use in Europe and the United States as monotherapy or as additional therapy for partial-onset seizures epilepsy.

<span class="mw-page-title-main">Cenobamate</span> Anticonvulsant drug

Cenobamate, sold under the brand names Xcopri (US) and Ontozry (EU), is a medication used for the treatment of partial-onset seizures, a kind of epilepsy, in adults. It is taken by mouth.

References

  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. 1 2 3 "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. ↑ "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.
  10. ↑ "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.
  11. 1 2 Briviact Drugs.com
  12. 1 2 3 4 "Briviact". European Medicines Agency. Archived from the original on 10 June 2016. Retrieved 30 May 2016.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  18. ↑ Rogawski MA (October 2016). "A New SV2A Ligand for Epilepsy". Cell. 167 (3): 587. doi: 10.1016/j.cell.2016.09.057 . PMID   27768878.
  19. ↑ 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.
  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. ↑ 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.
  28. ↑ "Brivaxon". Laboratorios Raffo. Retrieved 12 April 2024.
  29. ↑ "Biopas Portal para Médicos". Biopas Colombia. Retrieved 12 April 2024.

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