|Bioavailability||95% (Tmax = 4 hours)|
|Metabolism||Hepatic (mainly mediated by CYP3A4 and CYP2D6)|
|Elimination half-life||91 hours (brexpiprazole), 86 hours (major metabolite)|
|Excretion||Feces (46%), urine (25%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||433.6 g/mol g·mol−1|
|3D model (JSmol)|
Brexpiprazole, sold under the brand name Rexulti, 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 received FDA approval on July 13, 2015 for the treatment of schizophrenia, and as an adjunctive treatment for depression. 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).
The drug was developed by Otsuka and Lundbeck, and is considered to be a successor of Otsuka's top-selling atypical antipsychotic aripiprazole (Abilify). Otsuka's U.S. patent on aripiprazole expired on October 20, 2014; and a generic was approved in April, 2015.
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%).
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.
|mACh||52% at 10 µM||ND|||
|M1||67% at 10 µM||ND|||
|σ||96% at 10 µM||ND|||
|SERT||65% at 10 µM||Blocker|||
|NET||0% at 10 µM||Blocker|||
|DAT||90% at 10 µM||Blocker|||
|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. 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. 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 than aripiprazole as well as a much higher intrinsic activity. 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. The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects. Although brexpiprazole has less affinity for H1 compared to aripiprazole weight gain can occur.
In November 2011, Otsuka and Lundbeck announced a global alliance. 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.
The Phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three 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.
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)". 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 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.