Brexpiprazole

Brexpiprazole is an atypical antipsychotic agent. The pharmacology of brexpiprazole is believed to be mediated by a modulatory activity at the serotonin and dopamine systems that combines partial agonist activity at serotonergic 5-HT_1A and at dopaminergic D₂ receptors with antagonist activity at serotonergic 5-HT_2A receptors, with similar high affinities at all of these receptors (Ki: 0.1 nM to 0.5 nM). Brexpiprazole also shows antagonist activity at noradrenergic α_1B/2C receptors with affinity in the same sub-nanomolar Ki range (Ki: 0.2 nM to 0.6 nM).

Pharmacodynamic effects

Influences of genetic variation on the pharmacodynamic responses to brexpiprazole have not been investigated.

Effects on QT

The effects of brexpiprazole on the QT interval were evaluated in patients with schizophrenia or schizoaffective disorder. In the overall analysis brexpiprazole did not prolong the QT_c interval to clinically relevant extent following therapeutic and supra-therapeutic doses (4 mg/day; n=62 or 12 mg/day; n=53) and no correlation has been observed between brexpiprazole concentrations and QT_c prolongation.

Subgroup analyses from the thorough QT_c trial suggested that the QT_c prolongation was larger in female subjects than in males. In the brexpiprazole 4 mg/day group, the maximum placebo-adjusted mean change from baseline in the QT_cI interval was 5.2 ms (90% CI: 1.5, 8.9) in males (n=48) and 15.0 ms (90% CI: 7.7., 22.3) in females (n=14) at 6 hours post-dosing. In the brexpiprazole 12 mg/day group, the maximum placebo-adjusted mean change from baseline in the QT_cI interval was 2.9 ms (90% CI: −1.2, 6.9) in males (n=40) at 12 hours post-dosing and 10.4 ms (90% CI: 2.7, 18.2) in females (n=13) at 24 hours post-dosing. The smaller number of female than male subjects enrolled in the study does not allow to draw definitive conclusions.

Absorption

Brexpiprazole is absorbed after administration of the tablet, with peak plasma concentrations occurring within 4.0 hours after single dose administrations; the absolute oral bioavailability of the tablet formulation is 95.1%. Brexpiprazole steady-state concentrations are attained within 10 days to 12 days of dosing. Administration of a 4 mg brexpiprazole tablet with a standard high fat meal did not significantly affect the C_max or AUC of brexpiprazole. After single and multiple once daily dose administration, brexpiprazole exposure (C_max and AUC) increase in proportion to the dose administered. Based on in vivo studies, brexpiprazole is neither a substrate nor an inhibitor of efflux transporters, such as Multi Drug Resistance (MDR) 1 (P-gp) and BCRP.

Distribution

The volume of distribution of brexpiprazole following intravenous administration is high (1.56 L/kg ± 0.418 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, and digitoxin.

Biotransformation

Based on in vitro metabolism studies using recombinant human cytochrome P450, the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6 leading to formation of oxidative metabolites. Based on in vitro data brexpiprazole showed little to no inhibition of other CYP450 isozymes. In vivo, the metabolism of brexpiprazole is mainly mediated by CYP3A4 and CYP2D6 leading to formation of oxidative metabolites with only one metabolite, DM-3411, present in plasma with more than 10% of plasma exposure.

At steady-state, DM-3411 represents 23.1% to 47.7% of brexpiprazole exposure (AUC) in plasma. It should be noted that in vivo preclinical studies have shown that at clinically relevant plasma exposures of brexpiprazole, DM-3411 brain exposures were below the detection limit. Thus, DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole.

Elimination

Following a single oral dose of [¹⁴C]-labelled brexpiprazole, approximately 24.6% and 46% of the administered radioactivity was recovered in the urine and faeces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the faeces. Apparent oral clearance of brexpiprazole tablet after once daily administration is 19.8 (± 11.4) mL/h/kg. After multiple once daily administration of brexpiprazole, the terminal elimination half-life of brexpiprazole and its major metabolite, DM-3411, is 91.4 hours and 85.7 hours, respectively.

Linearity/non-linearity

The pharmacokinetic of brexpiprazole is dose proportional and time-invariant after single-dose (0.2 mg to 8 mg) and multiple-dose (0.5 mg to 4 mg) using once-daily administration.

Pharmacokinetics in special populations

Age

After single dose administration of brexpiprazole (2 mg), elderly subjects (older than 65 years) exhibited similar brexpiprazole systemic exposure (C_max and AUC) in comparison with the adult subjects (18 years to 45 years old).

Gender

Population PK evaluation identified gender as statistically significant covariate. The exposure (AUC) of brexpiprazole in women was estimated to be 25% higher than in men.

Race

Although no specific pharmacokinetic study was conducted, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of brexpiprazole.

CYP2D6 genotype

Population pharmacokinetic evaluation shows that CYP2D6 poor metabolisers have 47% higher exposure to brexpiprazole compared to extensive metabolisers.

Smoking

Based on studies utilising human liver enzymes in vitro, brexpiprazole is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of brexpiprazole.

Renal impairment

In subjects (n=10) with severe renal impairment (CLcr <30 mL/min), AUC of oral brexpiprazole (3 mg single dose) compared to matched healthy subjects was increased by 68% while its C_max was not changed. For patients with moderate to severe renal impairment (creatinine clearance CLcr <60 mL/minute), the maximum recommended dose is reduced to 3 mg once daily.

Hepatic impairment

In subjects (n=22) with varying degrees of hepatic impairment (Child-Pugh Classes A, B, and C), the AUC of oral brexpiprazole (2 mg single dose), compared to matched healthy subjects, increased 24% in mild hepatic impairment, increased 60% in moderate hepatic impairment, and did not change in severe hepatic impairment. For patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C), the maximum recommended dose is reduced to 3 mg once daily.

Paediatric population

The safety and efficacy of brexpiprazole in children and adolescents aged less than 18 years have not been established.

Effects observed in repeated-dose toxicity studies in rats and monkeys were mainly related to the exaggerated pharmacological activity of brexpiprazole. No safety margins based on AUC_0-24h at the Maximum Recommended Human Dose (MRHD) of 4 mg/day could be derived in both female and male rats and monkey.

Cardiovascular toxicity

Following oral administration, brexpiprazole decreased blood pressure and prolonged QT interval in safety pharmacology study in conscious male dog, in repeated-dose toxicity studies in male and female monkeys and in juvenile toxicity study in male and female dogs. The effect of brexpiprazole on blood pressure reduction is attributed to the expected blockade of α₁-adrenoceptors in peripheral blood vessels.

Genotoxicity, carcinogenicity

Brexpiprazole did not show any genotoxic potential in both in vitro and in vivo studies using clinically relevant exposures. Brexpiprazole administered orally did not increase in the incidence of tumours in 2-year carcinogenicity study in both male and female rats and in male mice at exposures up to 4.4-fold and 3.1-fold the MRHD. In female mice, an increased incidence of mammary gland adenocarcinoma and adeno-squamous carcinoma, and pars distalis adenoma of the pituitary gland, was observed at similar or even lower clinically relevant exposures: these prolactin-mediated endocrine tumours were also observed in rodents with other antipsychotics and their clinical relevance is unknown.

Reproductive toxicity

Following oral administration, brexpiprazole did not affect male fertility in rats but prolonged diestrus and decreased fertility in female rats at similar or even lower exposure levels than those clinically achieved at MRHD. Significant increased pre-implantation losses were observed at 4.1-fold the clinical exposure at MRHD. In embryo-foetal developmental toxicity studies, brexpiprazole was not teratogen in orally treated rats up to exposure levels (based on data in non-pregnant rats) clinically achieved at MRHD. In rabbit, vertebral malformations were seen in 3 foetuses from 2 litters at maternally toxic brexpiprazole oral doses corresponding to exposure approximately 16.5-fold the clinical exposure at MRHD.

Delayed growth, physical development and impaired viability of the offspring were observed at maternally toxic brexpiprazole doses in a pre-/post-natal developmental toxicity study in orally administered rats.

Following oral administration in pregnant rats, foetus and milk transfer of brexpiprazole was demonstrated at concentrations that were generally comparable to levels seen in maternal blood.

Environmental risk assessment (ERA)

Brexpiprazole is very persistent and very bioaccumulative but not toxic, to the environment: possible enrichment of brexpiprazole in terrestrial food chains might pose a concern.