Population pharmacokinetics of sivelestat in Chinese patients with severe pneumonia

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2025-02-09 DOI:10.1111/fcp.70001

Xiaolin Zhang, Huiliang Hu, Ziran Li, Peng Zhang, Lei Pan, Lei Wang, Jingqin Mao, Feng Li, Lijun Zhang

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Abstract

Background

Sivelestat sodium, an inhibitor of neutrophil elastase, was broadly used in the treatment of severe pneumonia. However, the pharmacokinetic (PK) characteristics of sivelestat in patients with severe pneumonia were still unknown.

Objectives

To understand the PK characteristics of sivelestat for optimizing the dose in Chinese patients with severe pneumonia.

Methods

In this study, we enrolled 15 participants who received sivelestat 300–500 mg every 24 h with an infusion duration of 5 to 14 days. Blood samples of 48 were collected and separated for plasma drug concentration detection by an ultra-high-performance liquid chromatography/tandem mass spectrometry. A population pharmacokinetic (PPK) analysis of sivelestat was performed using a monolix2024R1 software. A Monte Carlo simulation was conducted to assess various dosing schedules and varying covariate levels within the desired therapeutic drug-monitoring concentration range (C_min,ss 8–12 mg/L).

Results

The patients had a mean age of 65 years (range, 35–87), with 2 females and 13 males. These data were best described by a one-compartment model with proportional residual error. The apparent distribution volume and apparent clearance (CL) of sivelestat were 20.88 L and 1.79 L/h, respectively. The clearance of sivelestat is influenced by the covariate total bilirubin (TBIL), prompting a recommendation for a reduced dose in patients with elevated TBIL levels.

Conclusion

In conclusion, our findings suggest that the CL/F in patients with severe pneumonia is similar to that in healthy individuals. TBIL can affect CL/F of sivelestat; therefore, TBIL-based dosing regimens provide a practical strategy for achieving sivelestat therapy.

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中国重症肺炎患者西司他的人群药代动力学

西维司他钠是一种中性粒细胞弹性酶抑制剂，被广泛用于治疗重症肺炎。然而，西维司他在重症肺炎患者中的药代动力学（PK）特征尚不清楚。目的了解西司他的药代动力学特征，为我国重症肺炎患者优化用药剂量提供依据。在这项研究中，我们招募了15名参与者，他们每24小时接受西司他300 - 500mg的输注，输注时间为5 - 14天。采用超高效液相色谱/串联质谱法对48例患者进行血药浓度检测。采用monolix2024R1软件对西司他进行群体药代动力学（PPK）分析。通过蒙特卡罗模拟来评估各种给药方案和所需治疗药物监测浓度范围（Cmin,ss 8 - 12mg /L）内不同的协变量水平。结果患者平均年龄65岁（35 ~ 87岁），其中女性2例，男性13例。这些数据最好的描述是一个具有比例残差的单室模型。西司他的表观分布体积和表观清除率分别为20.88 L和1.79 L/h。西司他的清除率受协变量总胆红素（TBIL）的影响，提示建议在TBIL水平升高的患者减少剂量。结论重症肺炎患者的CL/F与健康人群相似。TBIL可影响西维司他的CL/F；因此，基于tbil的给药方案为实现西司他治疗提供了一种实用的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.