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.

Age, Sex, and Comedication Effects on the Steady-State Plasma Concentrations of Amisulpride in Chinese Patients with Schizophrenia

“…In particular, in participants aged .18 years, renal function was reported to be fully developed. 18 Moreover, the organic cationic drug of amisulpride belongs to the organic cation transporter substrates in the kidney, which can be taken up from the blood and secreted into urine, demonstrating again that highly active renal secretion may be the main elimination pathway. [18][19][20] Pharmacokinetics and pharmacodynamics of amisulpride are influenced by multiple factors, including function of renal organic cation transporter substrates, genetic polymorphisms, and interindividual variability.…”

“…18 Moreover, the organic cationic drug of amisulpride belongs to the organic cation transporter substrates in the kidney, which can be taken up from the blood and secreted into urine, demonstrating again that highly active renal secretion may be the main elimination pathway. [18][19][20] Pharmacokinetics and pharmacodynamics of amisulpride are influenced by multiple factors, including function of renal organic cation transporter substrates, genetic polymorphisms, and interindividual variability. 20 To our knowledge, this is the first clinical naturalistic study of Chinese patients with schizophrenia treated at the Zigong Affiliated Hospital of Southwest Medical University (Zigong Psychiatric Research Center).…”

Amisulpride steady-state plasma concentration and adverse reactions in patients with schizophrenia: a study based on therapeutic drug monitoring data

“…However, the amisulpride plasma levels of 36% of patients in the UK were higher than 320 ng/ml (Bowskill et al , 2012), whereas in China was 54.4% of patients higher than that (Wang et al , 2018). A PK model study in 121 Chinese patients was built to explore the factors that induced higher interindividual variability and exceed the laboratory alert level (640 ng/ml) (Huang et al , 2021). Although the recommended range (100–320 ng/ml) and laboratory alert level in guidelines were recognized not suitable for Chinese, the model was not yet established the reference range of amisulpride.…”

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients

“…Pirana software (version 2.9.0, Uppsala University, Sweden) was used to model design and validation. Using an R script (version 4.1.2), the diagnostic charts of NONMEM ® results were tabulated and summarized graphically ( Huang et al, 2021 ).…”