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

Shanqing Huang,1,* Lu Li,1,2,* Zhanzhang Wang,1,2 Tao Xiao,1 Xiaolin Li,1 Shujing Liu,1 Ming Zhang,1,2 Haoyang Lu,1,2 Yuguan Wen,1,2 Dewei Shang1,2 1Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, 510370, People’s Republic of China; 2Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, 510370, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dewei Shang; Yuguan WenDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University, 36 Mingxin Road, Guangzhou, 510370, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]; [email protected]: 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

Keywords

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