Modeling and Simulation for Individualized Therapy of Amisulpride in Chinese Patients with Schizophrenia: Focus on Interindividual Variability, Therapeutic Reference Range and the Laboratory Alert Level

Abstract

Purpose

To explain the high inter-individual variability (IIV) and the frequency of exceeding the therapeutic reference range and the laboratory alert level of amisulpride, a population pharmacokinetic (PPK) model in Chinese patients with schizophrenia was built based on therapeutic drug monitoring (TDM) data to guide individualized therapy.

Patients and Methods

Plasma concentration data (330 measurements from 121 patients) were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach with first-order conditional estimation with interaction (FOCE I). The concentrations of amisulpride were detected by HPLC-MS/MS. Age, weight, sex, combination medication history and renal function status were evaluated as main covariates. The model was internally validated using goodness-of-fit, bootstrap and normalized prediction distribution error (NPDE). Recommended dosage regimens for patients with key covariates were estimated on the basis of Monte Carlo simulations and the established model.

Results

A one-compartment model with first-order absorption and elimination was found to adequately characterize amisulpride concentration in Chinese patients with schizophrenia. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. Age significantly affected the clearance of amisulpride and the final model was as follows: CL/F=1.04×(AGE/32)^−0.624 (L/h). To avoid exceeding the laboratory alert level (640 ng/mL), the model-based simulation results showed that the recommended dose of amisulpride was no more than 600 mg/d for patients aged 60 years, 800 mg/d for those aged 40 years and 1200 mg/d for those aged 20 years, respectively.

Conclusion

Dosage optimization of amisulpride can be carried out according to age to reduce the risk of adverse reactions. The model can be used as a suitable tool for designing individualized therapy for Chinese patients with schizophrenia.

Keywords:

• amisulpride
• population pharmacokinetics
• therapeutic drug monitoring
• modeling and simulation
• individualized therapy

Acknowledgments

This work was supported by Bureau of Guangdong Province Traditional Chinese Medicine Bureau Research Project (No.20201272), Bureau of Health and Family Planning Science and Technology Project of Guangzhou City (No.20211A011043), Guangzhou Science and technology project (202002030399), Science and Technology Plan Project of Guangdong Province (2019B030316001), and Guangzhou Municipal Key Discipline in Medicine (2021–2023). Shanqing Huang and Lu Li are co-first authors of this study.

Ethics Approval and Informed Consent

This study was approved by the Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University (approval number: 2021-027). All patients in the study gave written informed consent after admission. We confirm that this study was conducted in accordance with the Declaration of Helsinki.

Disclosure

The authors report no conflicts of interest in this work.