Population Pharmacokinetic Modeling and Simulation to Support the Regulatory Submission of the Two-Injection Start Regimen with Aripiprazole Once-Monthly Long-Acting Injectable Intramuscular Administration in Japanese Patients with Schizophrenia or Bipolar I Disorder.

To improve medication adherence in Japanese patients with schizophrenia or bipolar I disorder, this population pharmacokinetic (popPK) modeling and simulation was conducted to support the regulatory submission of the two-injection start (TIS; two aripiprazole once-monthly long-acting injectable [LAI; 400 mg each] administered at different sites, along with a single oral dose of aripiprazole [6-15 mg]) regimen by comparing it with the original regimen (single LAI with 2-week concomitant oral dose of aripiprazole [6-15 mg]). Pharmacokinetic data from four Japanese clinical trials in patients with schizophrenia were used to externally validate and update a previously validated popPK model developed from seven non-Japanese trials in healthy subjects or in patients with schizophrenia/schizoaffective disorders. Simulations were conducted assuming two types of patients: with and without prior stabilization on oral aripiprazole. The dataset of 1123 participants (13,985 observations) from clinical trials, including 306 Japanese patients (5699 observations) from Japanese clinical trials, was used as the input in the popPK model. Simulations showed that the plasma concentration-time profiles of the original regimen and the TIS regimen were similar in the Japanese population. In addition, the currently available postmarketing safety data did not show any new safety concerns and/or an incremental safety risk with the TIS regimen compared with the original regimen. The aripiprazole TIS regimen provides a new option by reducing the oral aripiprazole administration period to a single day. This is expected to reduce the medication burden on patients and, consequently, reduce the burden on healthcare professionals and caregivers.