Brexpiprazole

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug was approved by the U.S. Food and Drug Administration (FDA) on July 10, 2015, for the treatment of schizophrenia, and as an adjunctive treatment for depression.[4][5] It has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).[6]

Brexpiprazole
Clinical data
Pronunciation/brɛkˈspɪprəzoʊl/ brek-SPIP-rə-zohl
/rɛkˈsʌlti/ rek-SUL-tee
Trade namesRexulti, Rxulti
Other namesOPC-34712
AHFS/Drugs.comMonograph
MedlinePlusa615046
License data
Pregnancy
category
Routes of
administration		By mouth (tablets)
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [2]
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Bioavailability95% (Tmax = 4 hours)[3]
Protein binding>99%
MetabolismHepatic (mainly mediated by CYP3A4 and CYP2D6)
Elimination half-life91 hours (brexpiprazole), 86 hours (major metabolite)
ExcretionFeces (46%), urine (25%)
Identifiers
IUPAC name
  • 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)
SMILES
  • O=C5/C=C\c4ccc(OCCCCN3CCN(c1cccc2sccc12)CC3)cc4N5
InChI
  • 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 drug was developed by Otsuka and Lundbeck, and is considered to be a successor[7] of Otsuka's top-selling atypical antipsychotic aripiprazole (Abilify).

Medical uses

Brexpiprazole is approved for the indication of schizophrenia in Canada, United States, Australia, Japan and Europe. In 2019, it was also approved in Canada as adjunctive treatment in Major Depressive Disorder.[5][8] In 2020 it was approved in Brazil only as an adjunctive to the treatment of Major Depressive Disorder.[9][10] In the United States it was extended approval for schizophrenia in 2022 in the treatment of pediatric patients from age 13 to 17.[11]

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%).[12]

Interactions

Based on information given on the consent forms, it seems brexpiprazole is a substrate of CYP2D6 and CYP3A4, like its predecessor aripiprazole. Participants in the clinical trials are advised to avoid grapefruit, Seville oranges and related citruses.

Pharmacology

Pharmacodynamics
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Brexpiprazole[13][14][15]
SiteHuman Ki (nM)ActionRef
5-HT1A0.12Partial agonist[14]
5-HT1B32ND[14]
5-HT2A0.47Antagonist[14]
5-HT2B1.9Antagonist[14]
5-HT2C12–34Partial agonist[14]
5-HT5A140ND[14]
5-HT658Antagonist[14]
5-HT73.7Antagonist[14]
D1160ND[14]
D2L0.30Partial agonist[14]
D31.1Partial agonist[14]
D46.3ND[14]
D5NDNDND
α1A3.8Antagonist[14]
α1B0.17Antagonist[14]
α1D2.6Antagonist[14]
α2A15Antagonist[14]
α2B17Antagonist[14]
α2C0.59Antagonist[14]
β159Antagonist[14]
β267Antagonist[14]
β3>10,000ND[14]
H119Antagonist[14]
H2>10,000ND[14]
H3>10,000ND[14]
mACh52% at 10 μMND[14]
  M167% at 10 μMND[14]
  M2>10,000ND[14]
σ96% at 10 μMND[14]
SERT65% at 10 μMBlocker[14]
NET0% at 10 μMBlocker[14]
DAT90% at 10 μMBlocker[14]
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.[14] 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.[14] 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, whereas brexpiprazole is the opposite. By contrast, brexpiprazole has a much higher affinity for the 5-HT1A receptor, potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole.[16] 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.[14] The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects.[14] Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.[17]

History

Partnership with Lundbeck

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.[18] 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.

Clinical trials

Brexpiprazole was in clinical trials for adjunctive treatment of MDD, adult ADHD, bipolar disorder[19] and schizophrenia.[20]

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.[21]

Phase III

A new 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)".[22] 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.

ADHD
  • Attention Deficit/Hyperactivity Disorder (STEP-A)[23]
Phase I
  • Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder[24]
Phase II
  • A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia[25]
Phase III
  • Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)[26][27]
  • Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)[28]
  • A Long-term Trial of OPC-34712 in Patients With Schizophrenia[29]

Conferences
  • Phase II results were presented at the American Psychiatric Association's 2011 annual meeting in May 2011.[30]
  • The drug has been presented at the 2nd Congress of Asian College of Neuropsychopharmacology[31] in September 2011.
  • At the US Psychiatric and Mental Health Congress in November 2011 in Vegas, Robert McQuade presented the Phase II Trial results for Schizophrenia[32]

Society and culture

In January 2018, it was approved for the treatment of schizophrenia in Japan.[33]

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.[35][36][37] It reached phase 2 clinical trials for this use prior to discontinuation.[37]

References
  1. "Brexpiprazole (Rexulti) Use During Pregnancy". Drugs.com. 10 February 2020. Retrieved 18 August 2020.
  2. "Summary for ARTG Entry:273224 Rexulti brexpiprazole 4 mg film coated tablets blisters". Therapeutic Goods Administration (TGA). Retrieved 18 August 2020.
  3. "REXULTI® (brexpiprazole) Tablets, for Oral Use. Full Prescribing Information" (PDF). Rexulti (brexpiprazole) Patient Site. Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Retrieved 15 July 2015.
  4. "Rexulti (brexpiprazole) Tablets". U.S. Food and Drug Administration (FDA). 10 July 2015. Retrieved 18 August 2020.
  5. "FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat major depressive disorder". U.S. Food and Drug Administration (FDA) Newsroom (Press release). FDA. 2015-07-13. Archived from the original on 2015-07-15. Retrieved 14 July 2015.
  6. "Otsuka Pharmaceutical Development & Commercialization, Inc". Bloomberg Businessweek. Retrieved 10 February 2012.
  7. "Otsuka HD places top priority on development of OPC-34712". Chemical Business Newsbase. January 3, 2011. Retrieved 10 February 2012.
  8. 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.
  9. "Rexulti (Brexpiprazole): novo registro". Č Informações Técnicas - Anvisa. Retrieved 2022-09-25.
  10. "Rexulti (Brexpiprazole): novo registro". Agência Nacional de Vigilância Sanitária - Anvisa (in Brazilian Portuguese). Retrieved 2022-09-25.
  11. Ernst D (2021-12-29). "Rexulti Approval Expanded to Include Adolescents With Schizophrenia". MPR. Retrieved 2022-09-25.
  12. "Otsuka Pharmaceutical reports OPC-34712 Phase 2 trial results in major depressive disorder". News-Medical.Net. 2011-05-16. Retrieved 10 February 2012.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Stahl SM (February 2016). "Mechanism of action of brexpiprazole: comparison with aripiprazole". CNS Spectrums. 21 (1): 1–6. doi:10.1017/S1092852915000954. PMID 26899451.
  18. "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.
  19. "Otsuka, Lundbeck initiate phase 3 trials of Rexulti for bipolar I disorder". www.healio.com. Retrieved 2017-10-16.
  20. "OPC-34712 search results". Retrieved 10 February 2012.
  21. 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
  22. 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
  23. 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
  24. 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
  25. Clinical trial number NCT01451164 for "A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia" at ClinicalTrials.gov
  26. Clinical trial number NCT01393613 for "Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)" at ClinicalTrials.gov
  27. Clinical trial number NCT01397786 for "Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)" at ClinicalTrials.gov
  28. 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
  29. Clinical trial number NCT01456897 for "A Long-term Trial of OPC-34712 in Patients With Schizophrenia" at ClinicalTrials.gov
  30. "Otsuka Pharmaceutical Co., Ltd. Announces Results from a Phase 2 Study of Investigational Product OPC-34712 as Adjunctive Therapy in Adults with Major Depressive Disorder". 2011-05-16. Retrieved 16 February 2012.
  31. "Preclinical Pharmacology of Brexpiprazole (Opc-34712): A Novel Compound with Dopamine D2 Receptor Partial Agonist Activity". Archived from the original on 3 March 2016. Retrieved 16 February 2012.
  32. "2011 U.S. Psych Congress Poster Session Abstracts". Retrieved 16 February 2012.
  33. "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 2018-10-04.
  34. "Canadian Patents Database 2620688". Retrieved 16 February 2012.
  35. "Brexpiprazole - Lundbeck/Otsuka". AdisInsight. Springer Nature Switzerland AG.
  36. Howland RH (April 2015). "Brexpiprazole: another multipurpose antipsychotic drug?". Journal of Psychosocial Nursing and Mental Health Services. 53 (4): 23–25. doi:10.3928/02793695-20150323-01. PMID 25856810.
  37. 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

Further reading
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