Chemistry:Brexpiprazole

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Short description: Atypical antipsychotic
Brexpiprazole
Brexpiprazole.svg
Brexpiprazole molecule ball.png
Clinical data
Pronunciation/brɛkˈspɪprəzoʊl/ brek-SPIP-rə-zohl
Trade namesRexulti, Rxulti, others
Other namesOPC-34712
AHFS/Drugs.comMonograph
MedlinePlusa615046
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability95% (Tmax = 4 hours)[7]
Protein binding>99%
MetabolismLiver (mainly mediated by CYP3A4 and CYP2D6)
Elimination half-life91 hours (brexpiprazole), 86 hours (major metabolite)
ExcretionFeces (46%), urine (25%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC25H27N3O2S
Molar mass433.57 g·mol−1
3D model (JSmol)

Brexpiprazole, sold under the brand name Rexulti among others, is a medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.[7][9][10] It is an atypical antipsychotic.[7]

The most common side effects include akathisia (a constant urge to move) and weight gain.[8] The most common side effects among people with agitation associated with dementia due to Alzheimer's disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia).[9]

Brexpiprazole was developed by Otsuka and Lundbeck, and is considered to be a successor to aripiprazole (Abilify).[11] It was approved for medical use in the United States in July 2015.[12][13] A generic version was approved in August 2022.[14] Brexpiprazole is the first treatment approved by the US Food and Drug Administration (FDA) for agitation associated with dementia due to Alzheimer's disease.[9]


Medical uses

In the United States and Canada, brexpiprazole is indicated as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia.[5][7][15][16] In May 2023, the indication for brexpiprazole was expanded in the US to include the treatment of agitation associated with dementia due to Alzheimer's disease.[9]

In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.[2][8]

In 2020, it was approved in Brazil only as an adjunctive to the treatment of major depressive disorder.[17][18]

Side effects

The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%).[19] Brexpiprazole can cause impulse control disorders.[20]

Pharmacology

Pharmacodynamics

Site Human Ki (nM) IA (%) Action Ref
5-HT1A 0.12 ~60% Partial agonist [21]
5-HT1B 32 ND [21]
5-HT2A 0.47 Antagonist [21]
5-HT2B 1.9 Antagonist [21]
5-HT2C 34 Antagonist [21]
5-HT5A 140 ND [21]
5-HT6 58 Antagonist [21]
5-HT7 3.7 Antagonist [21]
D1 160 ND [21]
D2L 0.30 ~45% Partial agonist [21]
D3 1.1 ~15% Partial agonist [21]
D4 6.3 ND [21]
D5 ND ND ND
α1A 3.8 Antagonist [21]
α1B 0.17 Antagonist [21]
α1D 2.6 Antagonist [21]
α2A 15 Antagonist [21]
α2B 17 Antagonist [21]
α2C 0.59 Antagonist [21]
β1 59 Antagonist [21]
β2 67 Antagonist [21]
β3 >10,000 ND [21]
H1 19 Antagonist [21]
H2 >10,000 ND [21]
H3 >10,000 ND [21]
mACh 52% at 10 μM ND [21]
  M1 67% at 10 μM ND [21]
  M2 >10,000 ND [21]
σ 96% at 10 μM ND [21]
SERT 65% at 10 μM Blocker [21]
NET 0% at 10 μM Blocker [21]
DAT 90% at 10 μM Blocker [21]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. Most or all data are for human cloned proteins.

IA = Intrinsic Activity

Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors.[21] Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor, aripiprazole, which may decrease its risk for agitation and restlessness.[21] Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D2 receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, while brexpiprazole has the inverse effect because a partial agonist competes with dopamine.[22][23][24][25] Brexpiprazole has a high affinity for the 5-HT1A receptor, acting as a potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole.[26] In vivo characterization of brexpiprazole shows that it may act as a near-full agonist of the 5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT1A receptor agonism. It is also an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the α1A-, α1B-, α1D-, and α2C-adrenergic receptors.[21] The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects.[21] Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.[27]

History

Clinical trials

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder,[28] schizophrenia,[29] and agitation associated with dementia due to Alzheimer's disease.[9]

Major depressive disorder

Phase II

The phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.[30]

Phase III

A phase III study was in the recruiting stage: "Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)".[31] Its goal is "to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with major depressive disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT". Estimated enrollment was 1250 volunteers.

Adult attention deficit hyperactivity disorder

  • Attention Deficit/Hyperactivity Disorder (STEP-A)[32]

Schizophrenia

Phase I
  • Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder[33]
Phase II
  • A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia[34]
Phase III
  • Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)[35][36]
  • Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)[37]
  • A Long-term Trial of OPC-34712 in Patients With Schizophrenia[38]

Agitation associated with dementia due to Alzheimer's disease

The effectiveness of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies.[9] In these studies, participants were required to have a probable diagnosis of Alzheimer's dementia; have a score between 5 and 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviors that require medication.[9] Trial participants ranged between 51 and 90 years of age.[9]

Society and culture

Legal status

In January 2018, it was approved for the treatment of schizophrenia in Japan.[39]

Economics

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.[40] Lundbeck gave Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion.[citation needed] Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.[citation needed]

Patents

Research

Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication.[42][43][44] It reached phase II clinical trials for this use prior to discontinuation.[44]

Brexpiprazole has shown promise in clinical trials for the treatment of borderline personality disorder.[45]

References

  1. ↑ "Brexpiprazole (Rexulti) Use During Pregnancy". 10 February 2020. https://www.drugs.com/pregnancy/brexpiprazole.html. 
  2. ↑ 2.0 2.1 2.2 "Rexulti brexpiprazole 4 mg film coated tablets blisters (273224)". https://www.tga.gov.au/resources/artg/273224. 
  3. ↑ AusPAR: Brexpiprazole
  4. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". 21 June 2022. https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017. 
  5. ↑ 5.0 5.1 "Rexulti Product information". https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=94955. 
  6. ↑ Rexulti monograph
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Rexulti- brexpiprazole tablet Rexulti- brexpiprazole kit". 21 February 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d301358-6291-4ec1-bd87-37b4ad9bd850. 
  8. ↑ 8.0 8.1 8.2 "Rxulti EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/rxulti.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 "FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia due to Alzheimer's Disease". U.S. Food and Drug Administration (FDA) (Press release). 11 May 2023. Retrieved 12 May 2023. This article incorporates text from this source, which is in the public domain.
  10. ↑ Lee, Daniel; Slomkowski, Mary; Hefting, Nanco; Chen, Dalei; Larsen, Klaus Groes; Kohegyi, Eva; Hobart, Mary; Cummings, Jeffrey L. et al. (1 December 2023). "Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial". JAMA Neurology 80 (12): 1307–1316. doi:10.1001/jamaneurol.2023.3810. PMID 37930669. 
  11. ↑ "Otsuka HD places top priority on development of OPC-34712.". Chemical Business Newsbase. 3 January 2011. http://www.accessmylibrary.com/article-1G1-247731102/otsuka-hd-places-top.html. 
  12. ↑ "Rexulti (brexpiprazole) Tablets". 10 July 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205422s000TOC.cfm. 
  13. ↑ "FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat ]" (Press release). U.S. Food and Drug Administration (FDA). 13 July 2015. Archived from the original on 15 July 2015. Retrieved 14 July 2015.
  14. ↑ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 3 March 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals. 
  15. ↑ "Regulatory Decision Summary for Rexulti". https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00222. 
  16. ↑ "Regulatory Decision Summary for Rexulti". https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00506. 
  17. ↑ "Rexulti (Brexpiprazole): novo registro". Č Informações Técnicas - Anvisa. http://antigo.anvisa.gov.br/informacoes-tecnicas13?p_p_id=101_INSTANCE_WvKKx2fhdjM2&p_p_col_id=column-2&p_p_col_pos=1&p_p_col_count=2&_101_INSTANCE_WvKKx2fhdjM2_groupId=219201&_101_INSTANCE_WvKKx2fhdjM2_urlTitle=rexulti-brexpiprazole-novo-registro&_101_INSTANCE_WvKKx2fhdjM2_struts_action=/asset_publisher/view_content&_101_INSTANCE_WvKKx2fhdjM2_assetEntryId=5876142&_101_INSTANCE_WvKKx2fhdjM2_type=content. 
  18. ↑ "Rexulti (Brexpiprazole): novo registro" (in pt-br). https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/novos-medicamentos-e-indicacoes/rexulti-brexpiprazole-novo-registro. 
  19. ↑ "Otsuka Pharmaceutical reports OPC-34712 Phase 2 trial results in major depressive disorder". News-Medical.Net. 16 May 2011. http://www.news-medical.net/news/20110516/Otsuka-Pharmaceutical-reports-OPC-34712-Phase-2-trial-results-in-major-depressive-disorder.aspx?page=2. 
  20. ↑ "Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System". The International Journal of Neuropsychopharmacology 25 (9): 727–736. September 2022. doi:10.1093/ijnp/pyac031. PMID 35639870. 
  21. ↑ 21.00 21.01 21.02 21.03 21.04 21.05 21.06 21.07 21.08 21.09 21.10 21.11 21.12 21.13 21.14 21.15 21.16 21.17 21.18 21.19 21.20 21.21 21.22 21.23 21.24 21.25 21.26 21.27 21.28 21.29 21.30 21.31 21.32 21.33 21.34 "Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator". The Journal of Pharmacology and Experimental Therapeutics 350 (3): 589–604. September 2014. doi:10.1124/jpet.114.213793. PMID 24947465. 
  22. ↑ "Glaxo Wellcome pharmacology guide". http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html#relative. 
  23. ↑ "The elusive nature of intrinsic efficacy". Trends in Pharmacological Sciences 19 (7): 270–276. July 1998. doi:10.1016/s0165-6147(97)01138-3. PMID 9703760. 
  24. ↑ "Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride". Neuropsychopharmacology 27 (2): 248–259. August 2002. doi:10.1016/S0893-133X(02)00304-4. PMID 12093598. 
  25. ↑ "Intrinsic Efficacy". Encyclopedia of Molecular Pharmacology. 2008. p. 652. doi:10.1007/978-3-540-38918-7_6001. ISBN 978-3-540-38916-3. 
  26. ↑ "Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole". Neuropsychopharmacology Reports 41 (2): 134–143. June 2021. doi:10.1002/npr2.12180. PMID 33960741. 
  27. ↑ "Mechanism of action of brexpiprazole: comparison with aripiprazole". CNS Spectrums 21 (1): 1–6. February 2016. doi:10.1017/S1092852915000954. PMID 26899451. 
  28. ↑ "Otsuka, Lundbeck initiate phase 3 trials of Rexulti for bipolar I disorder". https://www.healio.com/psychiatry/bipolar-disorder/news/online/%7B7281829f-0895-4785-88bc-9c76235e095c%7D/otsuka-lundbeck-initiate-phase-3-trials-of-rexulti-for-bipolar-i-disorder. 
  29. ↑ "OPC-34712 search results". http://clinicaltrials.gov/ct2/results?term=OPC-34712. 
  30. ↑ Clinical trial number NCT00797966 for "Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder" at ClinicalTrials.gov
  31. ↑ Clinical trial number NCT01360632 for "Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)" at ClinicalTrials.gov
  32. ↑ Clinical trial number NCT01074294 for "Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)" at ClinicalTrials.gov
  33. ↑ Clinical trial number NCT01423916 for "Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder" at ClinicalTrials.gov
  34. ↑ Clinical trial number NCT01451164 for "A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia" at ClinicalTrials.gov
  35. ↑ Clinical trial number NCT01393613 for "Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)" at ClinicalTrials.gov
  36. ↑ Clinical trial number NCT01397786 for "Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)" at ClinicalTrials.gov
  37. ↑ Clinical trial number NCT01396421 for "Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)" at ClinicalTrials.gov
  38. ↑ Clinical trial number NCT01456897 for "A Long-term Trial of OPC-34712 in Patients With Schizophrenia" at ClinicalTrials.gov
  39. ↑ "Otsuka Receives Approval in Japan for the Manufacture and Sale of New Antipsychotic Drug Rexulti Tablets for Schizophrenia｜News Releases". Otsuka Pharmaceutical Co., Ltd.. https://www.otsuka.co.jp/en/company/newsreleases/2018/20180119_1.html. 
  40. ↑ "Lundbeck and Otsuka Pharmaceutical sign historic agreement to deliver innovative medicines targeting psychiatric disorders worldwide". Lundbeck. http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=622993. 
  41. ↑ "Canadian Patents Database 2620688". http://brevets-patents.ic.gc.ca/opic-cipo/cpd/eng/patent/2620688/summary.html. 
  42. ↑ "Brexpiprazole - Lundbeck/Otsuka". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800029282. 
  43. ↑ "Brexpiprazole: another multipurpose antipsychotic drug?". Journal of Psychosocial Nursing and Mental Health Services 53 (4): 23–25. April 2015. doi:10.3928/02793695-20150323-01. PMID 25856810. 
  44. ↑ 44.0 44.1 Clinical trial number NCT01074294 for "A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder" at ClinicalTrials.gov
  45. ↑ Grant, Jon E.; Valle, Stephanie; Chesivoir, Eve; Ehsan, Dustin; Chamberlain, Samuel R. (February 2022). "A Double-Blind, Placebo-Controlled Study of Brexpiprazole in the Treatment of Borderline Personality Disorder". The British Journal of Psychiatry : The Journal of Mental Science 220 (2): 58–63. doi:10.1192/bjp.2021.159. PMID 35049469. 

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