Population pharmacokinetics of sivelestat in Chinese patients with severe pneumonia

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,C-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.