International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases · 2025
Population pharmacokinetics of nebulized polymyxin B in epithelial lining fluid of critically ill patients with invasive mechanical ventilation.
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Zhang Qun, Wang Mingyue, Hu Linlin, Lin Yu-Wei, Bergen Phillip J, Zhou Ji, Qian Qian, Sun Wenkui
Аннотация
OBJECTIVES: Nebulized polymyxin B (PMB) is increasingly used to treat multidrug-resistant (MDR) respiratory infections. However, pharmacokinetics (PK) data for nebulized PMB in the epithelial lining fluid (ELF) of critically ill patients are limited due to clinical challenges. This study characterized the PK of nebulized PMB in ELF.
DESIGN AND METHODS: Bronchoalveolar lavage fluid (BALF) and blood samples were obtained from 13 intubated patients receiving nebulized PMB (25 mg) for severe pneumonia caused by MDR gram-negative pathogens, without intravenous PMB administration. PMB1 concentrations were quantified using HPLC-MS/MS, and ELF concentrations were calculated using urea dilution. Data were analyzed using nonlinear mixed effect modelling, and steady-state exposure metrics were determined through simulation.
RESULTS: Plasma PMB1 concentrations were undetectable in all patients. Maximum ELF concentrations ranged from 208.5 to 596.7 mg/L one-hour postadministration. A one-compartment PK model best described the data, indicating rapid elimination from ELF. Using the final population PK model, at steady-state, the total AUCtau,ss ranged from 901 to 1620 mg·h/L (median, 1190 mg·h/L), the Ctau,ss from 0.39 to 9.84 mg/L (median, 2.23 mg/L), and T1/2 from 1.15 to 2.06 h (median, 1.51 h).
CONCLUSION: This robust PK model provides critical insights into the pulmonary PK of nebulized PMB, informing optimal clinical use.
DESIGN AND METHODS: Bronchoalveolar lavage fluid (BALF) and blood samples were obtained from 13 intubated patients receiving nebulized PMB (25 mg) for severe pneumonia caused by MDR gram-negative pathogens, without intravenous PMB administration. PMB1 concentrations were quantified using HPLC-MS/MS, and ELF concentrations were calculated using urea dilution. Data were analyzed using nonlinear mixed effect modelling, and steady-state exposure metrics were determined through simulation.
RESULTS: Plasma PMB1 concentrations were undetectable in all patients. Maximum ELF concentrations ranged from 208.5 to 596.7 mg/L one-hour postadministration. A one-compartment PK model best described the data, indicating rapid elimination from ELF. Using the final population PK model, at steady-state, the total AUCtau,ss ranged from 901 to 1620 mg·h/L (median, 1190 mg·h/L), the Ctau,ss from 0.39 to 9.84 mg/L (median, 2.23 mg/L), and T1/2 from 1.15 to 2.06 h (median, 1.51 h).
CONCLUSION: This robust PK model provides critical insights into the pulmonary PK of nebulized PMB, informing optimal clinical use.