Zhang Xiaolin, Hu Huiliang, Li Ziran, Zhang Peng, Pan Lei, Wang Lei, Mao Jingqin, Li Feng, Zhang Lijun
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Fundam Clin Pharmacol. 2025 Apr;39(2):e70001. doi: 10.1111/fcp.70001.
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.
To understand the PK characteristics of sivelestat for optimizing the dose in Chinese patients with severe pneumonia.
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 8-12 mg/L).
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.
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.
西维来司他钠是一种中性粒细胞弹性蛋白酶抑制剂，广泛用于治疗重症肺炎。然而，西维来司他在重症肺炎患者中的药代动力学（PK）特征仍不清楚。
了解西维来司他的PK特征，以便优化中国重症肺炎患者的用药剂量。
在本研究中，我们招募了15名参与者，他们每24小时接受300-500mg西维来司他，输注持续时间为5至14天。采集48份血样并分离，通过超高效液相色谱/串联质谱法检测血浆药物浓度。使用monolix2024R1软件对西维来司他进行群体药代动力学（PPK）分析。进行蒙特卡洛模拟，以评估在所需治疗药物监测浓度范围（C 8-12mg/L）内的各种给药方案和不同协变量水平。
患者的平均年龄为65岁（范围35-87岁），其中女性2名，男性13名。这些数据用具有比例残差误差的单室模型能得到最佳描述。西维来司他的表观分布容积和表观清除率（CL）分别为20.88L和1.79L/h。西维来司他的清除率受协变量总胆红素（TBIL）影响，提示TBIL水平升高的患者建议减少剂量。
总之，我们的研究结果表明，重症肺炎患者的CL/F与健康个体相似。TBIL可影响西维来司他的CL/F；因此，基于TBIL的给药方案为实现西维来司他治疗提供了一种实用策略。
