Population Pharmacokinetics of Nebulized Polymyxin B in Epithelial Lining Fluid of Critically Ill Patients with Invasive Mechanical Ventilation.

Abstract

Background: 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.

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 non-linear 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 post-administration. 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 AUC_tau,ss ranged from 901 to 1620 mg·h/L (median, 1190 mg·h/L), the C_tau,ss from 0.39 to 9.84 mg/L (median, 2.23 mg/L), and T_1/2 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.