Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy

Figures & data

Table 1 Pharmacokinetic (PK) parameters of brexpiprazole and practical implications³

	PK study results	Implications
Absorption	• Oral bioavailability 95% • Absorption not significantly impacted by food or omeprazole	• Dosing can be with or without food • Unlikely that changes in pH will significantly impact absorption
Distribution	• Volume of distribution: 1.56±0.42 L/kg • >99% protein bound in plasma ○ not displaced by warfarin digoxin or diazepam ○ not impacted by renal or hepatic dysfunction	• High volume of distribution: medication enters extravascular tissue • Despite high protein binding, drug–drug interactions with other highly protein-bound medications (warfarin, digoxin, diazepam), and renal or hepatic dysfunction are not likely to cause clinically significant changes in protein binding
Metabolism	• Primarily metabolized by CYP3A4 and CYP2D6 • Not predicted to significantly impact common metabolizing enzymes or transporters (CYP2D6, CYP3A4, CYP2B6, BCRP, and P-gp) • Major metabolite is not considered active	Half dose in presence of: • known CYP2D6 poor metabolizers • strong CYP2D6 inhibitors OR CYP3A4 inhibitors Quarter dose in presence of: • strong/moderate CYP2D6 inhibitors (or in persons who are CYP2D6 poor metabolizers) in combination with strong/moderate CYP3A4 inhibitors Double dose in presence of: • strong CYP3A4 inducers ○ increase brexpiprazole dose over 1–2 weeks • Brexpiprazole is unlikely to impact the serum concentration of other medications
Excretion	• ~25% recovered in urine, 1% unchanged • ~46% recovered in feces, 14% unchanged • t½: 91 hours	• Moderate or worse renal impairment (CrCl <60 mL/minute) and moderate–severe hepatic impairment (Child–Pugh score ≥7): maximum recommended dose is 3 mg daily for schizophrenia • Long t½ allows for once-daily dosing

Abbreviations: CrCl, creatinine clearance; t_½, elimination half-life.

Table 2 Overview of three 52-week clinical trials investigating the efficacy and safety of brexpiprazole for the maintenance treatment of schizophrenia

ClinicalTrials.gov ID Study	Study design	Number of participants	Average dose (mg)	Comments
NCT01668797 Fleischhacker et al^Citation8	Phase III multiple-phase study: • 1- to 4-week open-label conversion phase (if necessary) • 12- to 36-week single-blind stabilization phase • 52-week double-blind placebo-controlled maintenance phase	524 enrolled 202 entered randomized placebo- controlled phase	3.6	Trial was terminated at an interim analysis after 45 impending relapse events had occurred
NCT01397786 (also enrolled patients from NCT01668797, NCT01396421, and NCT01393613) Forbes et al^Citation10	Phase III open-label safety and tolerability study: • 1- to 4-week open-label conversion phase (if necessary) • 52-week open-label phase Following an amendment, the 52-week open-label phase was shortened to 26 weeks based on cumulative safety data from ongoing and current brexpiprazole studies	1,044 entered the 52- week open-label phase	3.0	952 were enrolled when the duration of open-label phase was 52 weeks; another 120 were enrolled when the duration was shortened to 26 weeks 409 participants (43% of those enrolled for 52 weeks) completed the trial 99 participants (82.5% of those enrolled for 26 weeks) completed the trial
NCT01456897 (also enrolled patients from NCT01451164) Ishigooka et al^Citation9	Phase III open-label safety and tolerability study: • 1- to 4-week open-label conversion phase (if necessary) • 52-week open-label phase	282 entered the 52- week open-label phase	3.1	Trial was not terminated early There was no maximum age cap 150 participants completed the 52-week open-label phase (53.4% of safety population)

Table 3 TEAEs and key safety data from 52-week brexpiprazole studies for the treatment of schizophrenia

Relapse-prevention study^Citation8				Safety study 1^Citation10		Safety study 2^Citation9
	Stabilization phase (n=464), n (%)	Maintenance phase			Total (n=1,031), n (%)		Total (n=281), n (%)
At least one TEAE	267 (57.5)	42 (43.3)	58 (55.8)	At least one TEAE	623 (60.4)	At least one TEAE	235 (83.6)
Serious TEAE	34 (7.3)	3 (3.1)	11 (10.6)	Serious TEAE	82 (8.0)	Serious TEAE	37 (13.2)
TEAE leading to discontinuation	41 (8.8)	5 (5.2)	12 (11.5)	TEAE leading to discontinuation	151 (14.6)	TEAE leading to discontinuation	43 (15.3)
Headache	23 (5.0)	6 (6.2)	10 (9.6)	Worsening of schizophrenia	120 (11.6)	Nasopharyngitis	65 (23.1)
Insomnia	56 (12.1)	5 (5.2)	8 (7.7)	Insomnia	89 (8.6)	Worsening of schizophrenia	63 (22.4)
Nasopharyngitis	16 (4.3)	3 (3.1)	7 (6.7)	Weight gain	80 (7.8)	Akathisia	24 (8.5)
Worsening of schizophrenia	28 (6.0)	3 (3.1)	7 (6.7)	Headache	66 (6.4)	Headache	22 (7.8)
Psychotic disorder	5 (1.1)	1 (1.0)	6 (5.8)	Agitation	56 (5.4)	Weight gain	19 (6.8)
Agitation	30 (6.5)	1 (1.0)	3 (2.9)	Akathisia	49 (4.8)	Insomnia	17 (6.0)
Akathisia	42 (9.1)	1 (1.0)	1 (1.0)			Back pain	17 (6.0)
Weight gain	24 (5.2)	1 (1.0)	0			Somnolence	16 (5.7)
Additional key events (%)
Weight gain ≥7%	11.3	5.2	1.0	Weight gain ≥7%	18.6	Weight gain ≥7%	24.2
Suicidal ideation	NR	NR	NR	Suicidal ideation	3.6	Suicidal ideation	7.8
Suicidal behavior	0.2	NR	NR	Suicidal behavior	0.2	Suicidal behavior	0.4

Notes: TEAEs occurring in ≥5% of participants in any group after the conversion phase for the three phase III brexpiprazole studies focusing on the efficacy or safety of brexpiprazole in the treatment of adults with schizophrenia were included in this table. Akathisia occurred at a rate <5% in safety study 1, but was included in this table because akathisia had occurred at rates of >5% in previous placebo-controlled brexpiprazole studies. Also included are safety data pertaining to weight gain ≥7% total body weight from enrollment to last observation and suicidal ideation/behavior.

Abbreviations: TEAEs, treatment-emergent adverse events; NR, not reported.

Table 4 Efficacy measures from the two open-label 52-week safety studies of brexpiprazole for the treatment of schizophrenia

	Safety study 1^Citation10		Safety study 2^Citation9
	Open-label phase, baseline (n=1,024), mean (SD)	Change for completers (n=410), mean (SD)	Open-label phase, baseline (n=279), mean (SD)	Change for completers (n=150), mean (SD)
PANSS total score	68.5 (17.1)	−12.2 (15.0)	72.6 (22.4)	−7.7 (12.0)
PANSS positive	16.3 (5.4)	−3.6 (4.8)	15.7 (6.0)	−1.3 (3.3)
PANSS negative	19.0 (5.3)	−2.8 (4.6)	20.0 (6.9)	−2.2 (4.0)
PANSS excited	8.6 (3.3)	−1.5 (3.2)	9.5 (3.8)	−0.8 (1.9)
CGI-S	3.5 (0.9)	−0.6 (0.9)	3.5 (1.1)	−0.3 (0.7)
PANSS Marder factor scores
Positive	20.2 (6.1)	−4.2 (5.4)	19.8 (7.2)	−1.8 (3.8)
Negative	17.6 (5.4)	−2.8 (4.4)	19.4 (6.8)	−2.4 (4.4)
Disorganized thought	16.7 (4.9)	−2.9 (4.0)	17.5 (6.2)	−2.0 (3.2)
Uncontrolled hostility/excitement	6.6 (2.8)	−1.1 (2.7)	7.4 (3.2)	−0.6 (1.5)
Anxiety/depression	7.3 (3.0)	−1.2 (2.9)	8.5 (3.0)	−1.0 (2.3)

Note: Efficacy data in this table include only those who completed the 52-week phase of brexpiprazole treatment in either safety study.

Abbreviations: CGI-S, Clinical Global Impression – Severity; PANSS, Positive and Negative Syndrome Scale.

OtsukaREXULTI (brexpiprazole) tablets, for oral use2018 Available from: https://www.otsuka-us.com/media/static/Rexulti-PI.pdfAccessed December 26, 2018

 Google Scholar

FleischhackerWWHobartMOuyangJEfficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomized, double-blind, placebo-controlled studyInt J Neuropsychopharmacol2017201112127566723

 PubMed Web of Science ®Google Scholar

ForbesAHobartMOuyangJShiLPfisterSHakalaMA Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Maintenance Treatment in Adults with SchizophreniaInt J Neuropsychopharmacol201821543344129415258

 PubMed Web of Science ®Google Scholar

IshigookaJIwashitaSTadoriYLong-term safety and effectiveness of brexpiprazole in Japanese patients with schizophrenia: a 52-week, open-label studyPsychiatry Clin Neurosci201872644545329582518

 PubMed Web of Science ®Google Scholar