AIM: To optimize the clinical dosage and administration regimen of a novel long-acting injectable aripiprazole microsphere (LZMT05) using plasma concentration data from two clinical trials. METHODS: Plasma concentrations were collected from 196 schizophrenia patients administered LZMT05, and a population pharmacokinetic (PopPK) model was developed. The therapeutic window was defined as the steady-state trough-to-peak concentration range (94.0-534 ng/mL) of oral aripiprazole. Multiple clinical scenarios were simulated to identify the optimal regimen. RESULTS: A one-compartment model with dual first-order absorption and first-order elimination characterized LZMT05 pharmacokinetics. Covariates like sex and CYP2D6 genotype were integrated into the final model. Simulations demonstrated that switching from 10 mg oral aripiprazole to 350 mg LZMT05 every 4 weeks sustained concentrations within the therapeutic window with minimal peak-to-trough fluctuations. CONCLUSION: The PopPK-guided optimized LZMT05 regimen maintained drug exposure within the therapeutic window, suggesting favorable efficacy and safety.