Population pharmacokinetics of brexpiprazole in Japanese healthy subjects and patients with schizophrenia

• Published in: Drug metabolism and pharmacokinetics Vol. 62; p. 101057
• Main Authors: Higashi, Koushi, Sasaki, Tomohiro, Aoki, Kazuo, Sekine, Daisuke, Maeda, Kenji, Shiomi, Yuki, Kawai, Yosuke
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2025
• Subjects: Administration, Oral; Adult; Aged; Antipsychotic; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Dopamine D2 receptor partial agonist; Dopamine D2/D3 receptor occupancy; East Asian People; Female; Healthy Volunteers; Humans; Japan; Japanese patients; Male; Middle Aged; Models, Biological; Nonlinear mixed effects; Quinolones - administration & dosage; Quinolones - blood; Quinolones - pharmacokinetics; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - metabolism; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - metabolism; Thiophenes - administration & dosage; Thiophenes - blood; Thiophenes - pharmacokinetics; Young Adult; Japan; Schizophrenia; Nonlinear mixed effects; Antipsychotic; Japanese patients; Dopamine D2/D3 receptor occupancy; Dopamine D2 receptor partial agonist; Dopamine D/D receptor occupancy; Dopamine D receptor partial agonist
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2025.101057

Brexpiprazole, widely approved for the treatment of schizophrenia, is an atypical antipsychotic that modulates serotonin–dopamine activity. To better understand the pharmacokinetics (PK) of brexpiprazole in Japanese patients, a population PK model was constructed and used to estimate steady state PK profiles and parameters as well as dopamine D2/D3 receptor occupancy profiles after repeated oral administrations of brexpiprazole at 1 and 2 mg/day. Nonlinear mixed effects modelling was used to analyse data from a total of 398 healthy subjects and patients with schizophrenia who received brexpiprazole in three Japanese clinical trials. The PK of brexpiprazole were well described by a two-compartment disposition model with transit absorption compartments. Estimated glomerular filtration rate, age and cytochrome P450 2D6 phenotype were identified as significant covariates on CL/F only. The model predicted that, at a dose of 2 mg/day, trough plasma concentration (90 % prediction interval) of brexpiprazole is 77.1 (22.4–173) ng/mL and that dopamine D2/D3 receptor occupancy is >80 % over one day for most patients at steady state. This suggests the recommended maintenance dose of 2 mg/day of brexpiprazole leads to clinically useful dopamine D2/D3 receptor occupancy at steady state in Japanese patients.