Population pharmacokinetic analysis and exposure-response analysis of brexpiprazole in Japanese patients with agitation in Alzheimer's dementia.

The efficacy and safety of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD) were demonstrated in Japanese study with 1 and 2 mg/day doses. The purpose of this study was to investigate need for dose adjustment in Japanese patients with AAD using population pharmacokinetics (PopPK) and exposure-response (ER) analysis, given that this population was older and renally impaired. First, using PopPK analysis, applicability of the previous PopPK model for Japanese healthy volunteers and patients with schizophrenia, established in a previous study, was confirmed to predict brexpiprazole concentrations in Japanese patients with AAD. Then, using exposure data from the PopPK model, ER analysis demonstrated that ER relationship was adequately described by sigmoid Emax model, although some parameters (EC50 and Hill) had RSEs >60%. Covariate analysis using PopPK model indicated that older age and/or reduced renal function were associated with increased exposure. However, these changes were considered to remain within the plateau region of ER relationship, suggesting limited clinical impact on efficacy. Therefore, brexpiprazole dose adjustment according to patient characteristics was not considered necessary in Japanese patients with AAD. Given the limited data and residual model instability in ER analysis, further investigation may be warranted to confirm the findings.