Brexpiprazole

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.[8][10] It is an atypical antipsychotic.[8]

Brexpiprazole
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)[8]
Protein binding>99%
MetabolismLiver (mainly mediated by CYP3A4 and CYP2D6)
Elimination half-life91 hours (brexpiprazole), 86 hours (major metabolite)
ExcretionFeces (46%), urine (25%)
Identifiers
  • 7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]quinolin-2(1H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.242.305
Chemical and physical data
FormulaC25H27N3O2S
Molar mass433.57 g·mol−1
3D model (JSmol)
  • O=C5/C=C\c4ccc(OCCCCN3CCN(c1cccc2sccc12)CC3)cc4N5
  • InChI=1S/C25H27N3O2S/c29-25-9-7-19-6-8-20(18-22(19)26-25)30-16-2-1-11-27-12-14-28(15-13-27)23-4-3-5-24-21(23)10-17-31-24/h3-10,17-18H,1-2,11-16H2,(H,26,29)
  • Key:ZKIAIYBUSXZPLP-UHFFFAOYSA-N

The most common side effects include akathisia (a constant urge to move) and weight gain.[9] 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).[10]

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.[10]

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.[6][8][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.[10]

In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.[2][9]

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
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Brexpiprazole[21][22][23]
SiteHuman Ki (nM)ActionRef
5-HT1A0.12Partial agonist[22]
5-HT1B32ND[22]
5-HT2A0.47Antagonist[22]
5-HT2B1.9Antagonist[22]
5-HT2C12–34Partial agonist[22]
5-HT5A140ND[22]
5-HT658Antagonist[22]
5-HT73.7Antagonist[22]
D1160ND[22]
D2L0.30Partial agonist[22]
D31.1Partial agonist[22]
D46.3ND[22]
D5NDNDND
α1A3.8Antagonist[22]
α1B0.17Antagonist[22]
α1D2.6Antagonist[22]
α2A15Antagonist[22]
α2B17Antagonist[22]
α2C0.59Antagonist[22]
β159Antagonist[22]
β267Antagonist[22]
β3>10,000ND[22]
H119Antagonist[22]
H2>10,000ND[22]
H3>10,000ND[22]
mAChTooltip Muscarinic acetylcholine receptor52% at 10 μMND[22]
  M167% at 10 μMND[22]
  M2>10,000ND[22]
σ96% at 10 μMND[22]
SERTTooltip Serotonin transporter65% at 10 μMBlocker[22]
NETTooltip Norepinephrine transporter0% at 10 μMBlocker[22]
DATTooltip Dopamine transporter90% at 10 μMBlocker[22]
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.

Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors.[22] 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.[22] 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.[24][25][26][27] 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.[28] 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.[22] The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects.[22] Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.[29]

History

Clinical trials

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder,[30] schizophrenia,[31] and agitation associated with dementia due to Alzheimer's disease.[10]

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.[32]

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)".[33] 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)[34]
Phase I
  • Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder[35]
Phase II
  • A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia[36]
Phase III
  • Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)[37][38]
  • Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)[39]
  • A Long-term Trial of OPC-34712 in Patients With Schizophrenia[40]

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.[10] 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.[10] Trial participants ranged between 51 and 90 years of age.[10]

Society and culture

In January 2018, it was approved for the treatment of schizophrenia in Japan.[41]

Economics

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.[42] 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. 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.

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.[44][45][46] It reached phase II clinical trials for this use prior to discontinuation.[46]

References
  1. "Brexpiprazole (Rexulti) Use During Pregnancy". Drugs.com. 10 February 2020. Retrieved 18 August 2020.
  2. "Rexulti brexpiprazole 4 mg film coated tablets blisters (273224)". Therapeutic Goods Administration (TGA). Retrieved 26 February 2023.
  3. AusPAR: Brexpiprazole
  4. "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  5. 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.
  6. "Rexulti Product information". Health Canada. Retrieved 26 February 2023.
  7. Rexulti monograph
  8. "Rexulti- brexpiprazole tablet Rexulti- brexpiprazole kit". DailyMed. 21 February 2023. Retrieved 26 February 2023.
  9. "Rxulti EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 26 February 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. "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. Public Domain This article incorporates text from this source, which is in the public domain.
  11. "Otsuka HD places top priority on development of OPC-34712". Chemical Business Newsbase. 3 January 2011. Retrieved 10 February 2012.
  12. "Rexulti (brexpiprazole) Tablets". U.S. Food and Drug Administration (FDA). 10 July 2015. Retrieved 18 August 2020.
  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. Retrieved 30 April 2023.
  15. "Regulatory Decision Summary for Rexulti".
  16. "Regulatory Decision Summary for Rexulti".
  17. "Rexulti (Brexpiprazole): novo registro". Č Informações Técnicas - Anvisa. Retrieved 25 September 2022.
  18. "Rexulti (Brexpiprazole): novo registro". Agência Nacional de Vigilância Sanitária - Anvisa (in Brazilian Portuguese). Retrieved 25 September 2022.
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  21. Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  22. Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futamura T, et al. (September 2014). "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. doi:10.1124/jpet.114.213793. PMID 24947465. S2CID 10768032.
  23. Das S, Barnwal P, Winston AB, Mondal S, Saha I (February 2016). "Brexpiprazole: so far so good". Therapeutic Advances in Psychopharmacology. 6 (1): 39–54. doi:10.1177/2045125315614739. PMC 4749739. PMID 26913177.
  24. "Glaxo Wellcome pharmacology guide".
  25. Clarke WP, Bond RA (July 1998). "The elusive nature of intrinsic efficacy". Trends in Pharmacological Sciences. 19 (7): 270–276. doi:10.1016/s0165-6147(97)01138-3. PMID 9703760.
  26. Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, et al. (August 2002). "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. doi:10.1016/S0893-133X(02)00304-4. PMID 12093598. S2CID 26101524.
  27. "Intrinsic Efficacy". Encyclopedia of Molecular Pharmacology. 2008. p. 652. doi:10.1007/978-3-540-38918-7_6001. ISBN 978-3-540-38916-3.
  28. Kikuchi T, Maeda K, Suzuki M, Hirose T, Futamura T, McQuade RD (June 2021). "Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole". Neuropsychopharmacology Reports. 41 (2): 134–143. doi:10.1002/npr2.12180. PMC 8340839. PMID 33960741.
  29. Stahl SM (February 2016). "Mechanism of action of brexpiprazole: comparison with aripiprazole". CNS Spectrums. 21 (1): 1–6. doi:10.1017/S1092852915000954. PMID 26899451.
  30. "Otsuka, Lundbeck initiate phase 3 trials of Rexulti for bipolar I disorder". www.healio.com. Retrieved 16 October 2017.
  31. "OPC-34712 search results". Retrieved 10 February 2012.
  32. 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
  33. 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
  34. 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
  35. 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
  36. Clinical trial number NCT01451164 for "A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia" at ClinicalTrials.gov
  37. Clinical trial number NCT01393613 for "Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)" at ClinicalTrials.gov
  38. Clinical trial number NCT01397786 for "Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)" at ClinicalTrials.gov
  39. 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
  40. Clinical trial number NCT01456897 for "A Long-term Trial of OPC-34712 in Patients With Schizophrenia" at ClinicalTrials.gov
  41. "Otsuka Receives Approval in Japan for the Manufacture and Sale of New Antipsychotic Drug Rexulti Tablets for Schizophrenia｜News Releases". Otsuka Pharmaceutical Co., Ltd. Retrieved 4 October 2018.
  42. "Lundbeck and Otsuka Pharmaceutical sign historic agreement to deliver innovative medicines targeting psychiatric disorders worldwide". Lundbeck. Archived from the original on 1 April 2012. Retrieved 10 February 2012.
  43. "Canadian Patents Database 2620688". Retrieved 16 February 2012.
  44. "Brexpiprazole - Lundbeck/Otsuka". AdisInsight. Springer Nature Switzerland AG.
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  46. 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
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