Population Pharmacokinetics of Amisulpride in Chinese Schizophrenia Patients: Quantifying Drug-Drug Interactions and Renal Function-Guided Dosing Individualization

Objective Patients with schizophrenia often require antipsychotic combinations, among which amisulpride is widely used due to its predominant renal excretion and low dependence on CYP450 enzymes. However, the impact of concomitant medications on the pharmacokinetics of amisulpride remains poorly characterized. The objective of this study was to establish a population pharmacokinetic model to quantitatively evaluate the effects of concomitant medications on amisulpride clearance. Additionally, we aimed to use simulation to recommend effective dosing regimens based on the newly revised therapeutic reference range (100–600 ng/mL). Methods A total of 386 therapeutic drug monitoring samples of amisulpride from 194 hospitalized patients were utilized to develop a PPK model, for which a one-compartment model with first-order absorption was developed using nonlinear mixed-effects modeling. The model systematically evaluated demographics, creatinine clearance, and co-medications as covariates. After model evaluation using bootstrap, goodness-of-fit plots, and normalized prediction distribution error (NPDE), simulations were conducted to assess drug-drug interactions, and to optimize dosing across renal function strata. Results CLcr and metformin coadministration were ultimately identified as significant covariates influencing amisulpride apparent clearance (CL/F). CL/F decreased by 16 L/h per 10 mL/min reduction in CLcr, while metformin inhibited CL/F by 23%. Metformin coadministration increases amisulpride exposure by ≥ 45% across a wide range of renal function. The revised therapeutic range (100–600 ng/mL) was suitable for most clinical scenarios, with 58.3% of simulated concentrations within this window in patients with normal renal function (CLcr 90–120 mL/min). Renal function-based effective dosing recommendations were as follows: renal impairment (CLcr 30–60 mL/min): 200–600 mg/day; mild impairment (60–90 mL/min): 200–800 mg/day; normal function (90–120 mL/min): 300–800 mg/day; mild hyperfiltration (120–150 mL/min): 300–1000 mg/day; hyperfiltration (150–180 mL/min): 400–1000 mg/day. Conclusion This study provides the first clinical evidence of significant amisulpride-metformin interactions, warranting caution during concomitant use. The Cockcroft-Gault formula is optimal for renal function assessment to optimize amisulpride dosing. Individualized regimens stratified by CLcr and adherence to the 100–600 ng/mL therapeutic range can optimize treatment efficacy and safety in Chinese patients with schizophrenia.