Population pharmacokinetics of Amisulpride in Chinese patients with schizophrenia with external validation: the impact of renal function

Frontiers in Pharmacology

Pharmacology

Tingyi Ruan¹  Qingfeng He¹  Jingye Zhang¹  Haoxuan Cheng¹  Xiaoqiang Xiang¹  Wen Yao Mak¹  Meng Gu¹  Yufei Shi¹  Xiao Zhu¹  Gang Wang²  Anning Li²  Yannan Zang²  Fang Dong²  Nan Zheng²  Xuequan Zhu²  Wei Guo²  Canjun Ruan² 

[1] Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China;The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China;Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China;

关键词: Amisulpride;    external validation;    Monte Carlo simulation;    renal impairment;    population pharmacokinetics;    NONMEM;   

DOI  :  10.3389/fphar.2023.1215065

 received in 2023-05-01, accepted in 2023-08-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Amisulpride is primarily eliminated via the kidneys. Given the clear influence of renal clearance on plasma concentration, we aimed to explicitly examine the impact of renal function on amisulpride pharmacokinetics (PK) via population PK modelling and Monte Carlo simulations.Method: Plasma concentrations from 921 patients (776 in development and 145 in validation) were utilized.Results: Amisulpride PK could be described by a one-compartment model with linear elimination where estimated glomerular filtration rate, eGFR, had a significant influence on clearance. All PK parameters (estimate, RSE%) were precisely estimated: apparent volume of distribution (645 L, 18%), apparent clearance (60.5 L/h, 2%), absorption rate constant (0.106 h−1, 12%) and coefficient of renal function on clearance (0.817, 10%). No other significant covariate was found. The predictive performance of the model was externally validated. Covariate analysis showed an inverse relationship between eGFR and exposure, where subjects with eGFR= 30 mL/min/1.73 m2 had more than 2-fold increase in AUC, trough and peak concentration. Simulation results further illustrated that, given a dose of 800 mg, plasma concentrations of all patients with renal impairment would exceed 640 ng/mL.Discussion: Our work demonstrated the importance of renal function in amisulpride dose adjustment and provided a quantitative framework to guide individualized dosing for Chinese patients with schizophrenia.

【 授权许可】

Unknown   
Copyright © 2023 Li, Mak, Ruan, Dong, Zheng, Gu, Guo, Zhang, Cheng, Ruan, Shi, Zang, Zhu, He, Xiang, Wang and Zhu.