Rexulti

Rexulti Mechanism of Action

brexpiprazole

Manufacturer:

Lundbeck

Distributor:

Zuellig Pharma
Full Prescribing Info
Action
Pharmacotherapeutic group: Psycholeptics, other antipsychotics. ATC code: N05AX16.
Pharmacodynamics: Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5-HT1A (0.12 nM), 5-HT2A (0.47 nM), 5-HT2B (1.9 nM), 5-HT7 (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α1A (3.8 nM), α1B (0.17 nM), α1D (2.6 nM), and α2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT1A, D2, and D3 receptors and as an antagonist at 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C receptors. Brexpiprazole also exhibits affinity for histamine H1 receptor (19 nM) and for muscarinic M1 receptor (67% inhibition at 10 μM).
Cardiac Electrophysiology: At a dose 3-times the MRHD for the treatment of schizophrenia and 4-times the MRHD for adjunctive therapy to antidepressants for the treatment of MDD, REXULTI does not prolong the QTc interval to any clinically relevant extent.
Mechanism of Action: The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.
Clinical Studies: Adjunctive Treatment of Major Depressive Disorder: The efficacy of brexpiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in three 6-week, placebo-controlled, fixed-dose trials, and one flexible dose clinical trial with an active reference in adult patients meeting DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, who had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine delayed release, or venlafaxine extended release). Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of treatment.
The primary endpoint was change from baseline to Week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive symptomatology (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts). The key secondary endpoint was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life, and family life) with each item scored from 0 (not at all) to 10 (extreme).
At randomization, the mean MADRS total score was 27. In the three 6-week, placebo-controlled trials, brexpiprazole +ADT 2 mg/day and 3 mg/day demonstrated efficacy over placebo +ADT in reducing mean MADRS total scores. Brexpiprazole +ADT 2 mg/day and 3 mg/day also demonstrated efficacy over placebo +ADT in improving functioning as measured by the SDS mean score. Brexpiprazole 2 to 3 mg/day +ADT also showed statistically significantly greater improvement on the MADRS total score than placebo+ADT in the flexible-dose trial. Results from the primary and key secondary efficacy parameters for both fixed dose and flexible dose trials are shown as follows. In the three, fixed-dose clinical trials, pooled analysis of response rate provided support for the efficacy of brexpiprazole+ADT 2 mg/day and 3 mg/day. The response rate was higher in the brexpiprazole+ADT 2 and 3 mg/day group (28.0%) compared to placebo+ADT (21.1%).
An examination of population subgroups did not reveal evidence of differential response based on age, gender, race or choice of prospective antidepressant. (See Table 2.)

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The long-term efficacy and safety of REXULTI were evaluated in a phase 3, 24 week placebo-controlled trial (Study 5 (Study 14570A)). The adult patients in this trial fulfilled the DSM-IV-TR criteria for MDD, and demonstrated an inadequate response to 1-3 prior antidepressant therapy(ies) in the current episode and an inadequate response throughout 8 weeks of prospective antidepressant treatment.
Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of the 8 weeks prospective treatment. The primary efficacy endpoint was full remission (defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment). This trial did not show efficacy of REXULTI over placebo.
Schizophrenia: The efficacy of REXULTI in adults with schizophrenia was demonstrated in four 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia who met DSM-IV-TR criteria for schizophrenia.
The primary efficacy endpoint of all trials was change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score using MMRM analysis. The primary instrument for evaluating efficacy was the Positive and Negative Syndrome Scale, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. PANSS total score may range from 30 (absent symptoms) to 210 (extreme).
Efficacy was demonstrated in Study 6 (Study 231) for both brexpiprazole 2 mg/day and 4 mg/day and replicated in Study 7 (Study 230) only for brexpiprazole 4 mg/day and in Study 8 (Study 002) only for brexpiprazole 2 mg/day. The key secondary endpoint of both trials was change from baseline to Week 6 in Clinical Global Impression Severity of Illness Scale (CGI-S) total score, a validated clinician-related scale that measures the patient's current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale.
In two fixed-dose clinical trials, REXULTI 4 mg/day demonstrated efficacy over placebo in the PANSS total score and showed greater improvement in CGI-S score compared to placebo. In two trials, REXULTI 2 mg/day demonstrated efficacy over placebo in the PANSS total score. Results from the primary and key secondary efficacy parameters for the fixed dose trials are shown as follows. In the three, fixed-dose clinical trials, pooled analysis of response rate provided support for the efficacy of REXULTI 2 mg/day and 4 mg/day. The response rate was higher in the REXULTI 4 mg/day group (42.5%) and 2 mg/day group (39.0%) compared to placebo (28.5%). In the flexible-dose Study 9 (Study 14644A), at week 6, subjects in the REXULTI group had numerically greater improvements on PANSS total score than the subjects in the placebo group, although, the difference at week 6 did not reach statistical significance for the primary efficacy analysis (p = 0.0560) (see Table 3). In the same study the active reference, quetiapine XR added for assay sensitivity only, separated from placebo.
The effects of REXULTI were evaluated across a number of pre-specified secondary endpoints; specific aspects of symptoms of schizophrenia (PANSS Positive Subscale score, PANSS Negative Subscale score, PANSS Excited Component (PEC) score, PANSS Marder factors Positive, Negative, Disorganized Thoughts, Uncontrolled Hostility/Excitement and Anxiety/Depression), improvement in Global Clinical Impression (CGI-I) and functioning (Personal and Social Performance scale and the Global Assessment of Functioning (GAF, maintenance Study 11 (Study 232) only)). Analyses of response (defined as 30 % improvement in PANSS total score compared to baseline and a CGI-I score of 1 (very much improved) or 2 (much improved)) and discontinuation for lack of efficacy were also performed. In Study 6 (Study 231), improvement in the change from baseline to week 6 for REXULTI compared to placebo was observed PANSS Positive (2 mg and 4 mg) and PANSS Negative Subscale scores (2 mg and 4 mg), PEC score (2 mg and 4 mg), PANSS Marder factors Positive, Negative, Disorganized Thought, and Uncontrolled Hostility/Excitement ( 2 mg and 4 mg); CGI-I score (2 mg and 4 mg) and in PSP score (2 mg); response rate for REXULTI at week 6 (2 mg and 4 mg) was larger, and discontinuation for lack of efficacy (4 mg/day) lower than for placebo. In Study 7 (Study 230), improvement in the change from baseline to week 6 for REXULTI compared to placebo in PANSS Positive and PANSS Negative Subscale scores, PEC score, PANSS Marder factors Negative, Disorganized Thought, and Uncontrolled Hostility/Excitement at 4 mg dose and PANSS Marder factor Anxiety/Depression at 2 mg and 4 mg doses; CGI-I (2 mg and 4 mg) and PSP score (4 mg); the response rate at week 6 was larger for REXULTI than for placebo for the 4 mg dose. In trial 3, improvement in the change from baseline at week 6 for REXULTI compared to placebo for the PANSS Negative Subscale score (2 mg and 4 mg), the PEC score (2 mg), the PANSS Marder Factors Negative Symptoms (2 mg and 4 mg), Disorganized Thought, and Anxiety/Depression scores (both 2 mg).
Examination of population subgroups based on age, gender and race did not show any statistical evidence of differential responsiveness. (See Table 3.)

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Maintenance: The safety and efficacy of REXULTI as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in a 52-week maintenance phase of a randomized withdrawal trial (Study 232). A pre-specified interim analysis demonstrated a statistically significantly longer time to impending relapse in patients randomized to the REXULTI group (1 mg/day to 4 mg/day) compared to placebo-treated patients and the trial was subsequently terminated early because maintenance of efficacy had been demonstrated. The final analysis demonstrated a longer time to impending relapse in patients randomized to the REXULTI group compared to placebo. The key secondary endpoint, the proportion of patients who met the criteria for impending relapse, was lower in REXULTI -treated patients (13.5%) compared with placebo group (38.5%). REXULTI reduced the risk of impending relapse by 71% compared to placebo. REXULTI improved clinical symptomology (as assessed by PANSS, CGI-S and GGI-I [LOCF]) and functioning (as assessed by GAF [LOCF]) during the stabilization phase. These improvements were maintained during the 52-week double-blind maintenance phase in patients on REXULTI whereas patients randomized to placebo showed deterioration in PANSS, CGI-S and GGI-I, and GAF scores [LOCF]). REXULTI maintained symptom control and functioning compared to placebo.
Pharmacokinetics: Absorption: After single dose administration of REXULTI tablets, the peak plasma brexpiprazole concentrations occurred within 4 hours after administration; and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10-12 days of dosing.
REXULTI can be administered with or without food. Administration of a 4 mg REXULTI tablet with a standard high fat meal did not significantly affect the Cmax or AUC of brexpiprazole. After single and multiple once daily dose administration, brexpiprazole exposure (Cmax and AUC) increased in proportion to the dose administered. In vitro studies of brexpiprazole did not indicate that brexpiprazole is a substrate of efflux transporters such as MDRI (P-gp) and BCRP.
Distribution: The volume of distribution of brexpiprazole following intravenous administration is high (1.56±0.42 L/kg), indicating extravascular distribution. Brexpiprazole is highly protein bound in plasma (greater than 99%) to serum albumin and α1-acid glycoprotein, and its protein binding is not affected by renal or hepatic impairment. Based on results of in vitro studies, brexpiprazole protein binding is not affected by warfarin, diazepam, or digitoxin.
Elimination: Metabolism: Based on in vitro metabolism studies of brexpiprazole using recombinant human cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6.
In vivo brexpiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes. After single- and multiple-dose administrations, brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole.
Based on in vitro data, brexpiprazole showed little to no inhibition of CYP450 isozymes.
Excretion: Following a single oral dose of [14C]-labeled brexpiprazole, approximately 25% and 46% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the feces. Apparent oral clearance of a REXULTI oral tablet after once daily administration is 19.8 (±11.4) mL/h/kg. After multiple once daily administration of REXULTI, the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 hours, respectively.
Studies In Specific Populations: Exposures of brexpiprazole in specific populations are summarized in Figure 1. Population PK analysis indicated exposure of brexpiprazole in patients with moderate renal impairment was higher compared to patients with normal renal function. (See Figure 1.)

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Drug Interaction Studies: Effects of other drugs on the exposures of brexpiprazole are summarized in Figure 2. Based on simulation, a 5.1-fold increase in AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 4.8-fold increase in mean AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors [see Interactions]. (See Figure 2.)

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The effects of REXULTI on the exposures of other drugs are summarized in Figure 3. (See Figure 3.)

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Special Population: Age/Gender: After single dose administration of brexpiprazole (2 mg), elderly subjects (older than 65 years old) exhibited similar brexpiprazole systemic exposure (Cmax and AUC) in comparison with the adult subjects (18-45 years old) and female subjects exhibited approximately 40-50% higher brexpiprazole systemic exposure (Cmax and AUC) in comparison to the male subjects. Population pharmacokinetic evaluation identified age and female sex as statistically significant covariates affecting brexpiprazole PK but the effects on PK were not considered clinically relevant.
Race: Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of brexpiprazole, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of brexpiprazole.
CYP2D6 Poor Metabolisers: Approximately 8% of whites and 3-8% of blacks/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). Population pharmacokinetic evaluation shows that CYP2D6 PMs have 47% higher exposure to brexpiprazole compared to EMs.
Smoking: Based on studies utilizing human liver enzymes in vitro, brexpiprazole is not a substrate for CYP1A2. Smoking should, therefore, not have an effect on the pharmacokinetics of brexpiprazole.
Non-Clinical Safety: Abuse/liability: Brexpiprazole showed neither a potential to produce physical dependence in rats nor a reinforcing effect in rhesus monkeys. In a drug abuse liability study in rats, no withdrawal signs suggestive of physical dependence were evident. Brexpiprazole is not considered to have potential to produce physical dependence.
Carcinogenicity, mutagenesis, and impairment of fertility: The lifetime carcinogenic potential of brexpiprazole was evaluated in a two year study in ICR mice and Sprague-Dawley rats. Brexpiprazole was administered orally (gavage) for two years to mice at doses of 0.75, 2 and 5 mg/kg/day (0.9 to 6.1-fold the 4 mg oral maximum recommended human dose [MRHD] for a 60 kg patient based on body surface area). There was no increase in the incidence of tumors in males at any dose group. In female mice, there was an increased incidence of mammary gland adenocarcinoma and adenosquamous carcinoma, and pars distalis adenoma of the pituitary gland. Brexpiprazole was administered orally (gavage) for two years to rats at doses of 1, 3 and 10 mg/kg/day in male rats or 3, 10 and 30 mg/kg/day in female rats (for males 2.4 to 24.3-fold and for females 7.3 to 72.9-fold the 4 mg oral MRHD for a 60 kg patient based on body surface area). Long-term administration of brexpiprazole to rats did not induce neoplastic lesions.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.
The mutagenic potential of brexpiprazole was tested in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells, the in vivo micronucleus assay in rats, and the unscheduled DNA synthesis assay in rats. In vitro with mammalian cells brexpiprazole was mutagenic and clastogenic but occurred at doses that induced cytotoxicity. No mutagenicity or genotoxicity was observed in other studies. Based on a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans at therapeutic doses and exposures.
Brexpiprazole was given once daily by oral gavage to female rats at doses of 0, 0.3, 3 or 30 mg/kg/day prior to mating with untreated males and continuing through conception and implantation. Prolonged diestrus and decreased fertility were observed at 3 and 30 mg/kg/day. At 30 mg/kg/day a slight prolongation of the mating phase was observed and significantly increased preimplantation losses were seen. The no observed adverse effect level in brexpiprazole was 0.3 mg/kg/day (0.7-fold the 4 mg oral MRHD for a 60 kg patient based on body surface area).
Brexpiprazole was given once daily by oral gavage to male rats at 0, 3, 10 or 100 mg/kg/day. Following 63 days of dosing, treated males were cohabited with untreated females for a maximum of 14 days. No noticeable differences were noted in the duration of mating or fertility indices in any brexpiprazole treated group.
Teratogenic effects: Brexpiprazole was not teratogenic and did not cause adverse developmental effects in developmental toxicity studies in which pregnant rats and rabbits were given brexpiprazole during the period of organogenesis at doses up to 30 mg/kg/day (73-fold and 146-fold for rats and rabbits, respectively of the 4 mg/day oral MRHD for a 60 kg patient based on body surface area, with respective rat and rabbit exposures (plasma AUC) 3.3-fold and 5.9-fold the clinical exposure at the 4mg/day MRHD).
In a rabbit embryo-fetal development study (at 150 mg/kg/day, a dose that induced maternal toxicity), decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses.
Cardiovascular Toxicity: Decreased blood pressure and prolonged QT interval and QTc were noted in the conscious dog in the safety pharmacology study in the 13-week repeat-dose toxicity study with monkeys and in the juvenile toxicity study with dogs. The effect of brexpiprazole on decreased blood pressure was suggested to be due to a blockade of α1- adrenoceptors in peripheral blood vessels, which is consistent with the pharmacological profile for this compound.
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