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

Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Li, Anning;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Mak, Wen Yao;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Ruan, Tingyi;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Dong, Fang;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Zheng, Nan;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Gu, Meng;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Guo, Wei;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Zhang, Jingye;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Cheng, Haoxuan;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Ruan, Canjun;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Shi, Yufei;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Zang, Yannan;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Zhu, Xuequan;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
He, Qingfeng;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Xiang, Xiaoqiang;
Affiliation
The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders ,Beijing Anding Hospital ,Capital Medical University ,Beijing ,China
Wang, Gang;
Affiliation
Department of Clinical Pharmacy and Pharmacy Administration ,School of Pharmacy ,Fudan University ,Shanghai ,China
Zhu, Xiao

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 m 2 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.

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

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