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

Anning Li; Wen Yao Mak; Tingyi Ruan; Fang Dong; Nan Zheng; Meng Gu; Wei Guo; Jingye Zhang; Haoxuan Cheng; Canjun Ruan; Yufei Shi; Yannan Zang; Xuequan Zhu; Qingfeng He; Xiaoqiang Xiang; Gang Wang; Xiao Zhu

doi:10.3389/fphar.2023.1215065

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

Front Pharmacol. 2023 Sep 4:14:1215065. doi: 10.3389/fphar.2023.1215065. eCollection 2023.

Authors

Anning Li^#^{1

2}, Wen Yao Mak^#³, Tingyi Ruan³, Fang Dong^{1

2}, Nan Zheng^{1

2}, Meng Gu³, Wei Guo^{1

2}, Jingye Zhang³, Haoxuan Cheng³, Canjun Ruan^{1

2}, Yufei Shi³, Yannan Zang^{1

2}, Xuequan Zhu^{1

2}, Qingfeng He³, Xiaoqiang Xiang³, Gang Wang^{1

2}, Xiao Zhu³

Affiliations

¹ The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China.
² Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.
³ Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China.

^# Contributed equally.

Abstract

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.

Keywords: Amisulpride; Monte Carlo simulation; NONMEM; external validation; population pharmacokinetics; renal impairment.

Grants and funding

XZ received research funding from Fudan University Scientific Research Foundation for Talented Scholars (No. JIF301052), National Natural Science Foundation–Youth Foundation (No. 82204544) and Shanghai Municipal Health Commission Clinical Research Youth Project (No. 20224Y0121). AL received research funding from Beijing Hospitals Authority Youth Program (No. QMS20201903); Beijing Municipal Administration of Hospitals Incubating Program (No. PX2019070); National Natural Science Foundation–Youth Foundation (No. 81801322).