Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 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 or agitation associated with dementia due to Alzheimer’s disease, REXULTI does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetic Properties

12.3 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 to 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 brexpiprazole 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 pharmacokinetic (PK) analysis indicated exposure of brexpiprazole in patients with moderate renal impairment was higher compared to patients with normal renal function.
Figure 1: Effects of Intrinsic Factors on Brexpiprazole Pharmacokinetics 


Pediatric Patients
A multiple dose PK study (0.5, 1, 2, 3 or 4 mg/day) has been conducted in 43 pediatric patients aged 13 years to 17 years old. Population PK analysis indicated systemic exposure (Cmax and AUC) of brexpiprazole in pediatric patients (13 to 17 years of age) was comparable to that in adult patients across the dose range from 0.5 to 4 mg.



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 Drug Interactions (7.1)].

Figure 2: The Effects of Other Drugs on Brexpiprazole Pharmacokinetics The effects of REXULTI on the exposures of other drugs are summarized in Figure 3.

Figure 3: The Effects of REXULTI on Pharmacokinetics of Other Drugs