PBPK modeling identifies optimal Polymyxin B IV dosing for pulmonary infections, targeting MIC-guided ELF concentrations.

Multidrug-resistant (MDR) Gram-negative pneumonia poses a significant threat, with intravenous Polymyxin B (PMB) often serving as a last-line defense. Despite its utility, PMB's efficacy in pulmonary infections is often limited due to poor lung penetration and dose-dependent nephrotoxicity (affecting 25-50% of patients). Current dosing strategies struggle to balance therapeutic concentrations at the infection site with systemic toxicity, creating a critical gap in individualized treatment for severe pulmonary infections.

Researchers developed physiologically based pharmacokinetic (PBPK) models using existing data from mice, healthy subjects, and critically ill patients. These models predicted Polymyxin B concentrations in both epithelial lining fluid (ELF) and plasma. All models underwent validation against published pharmacokinetic data. Monte Carlo simulations were then performed to evaluate various dosing regimens, with the primary therapeutic target defined as an ELF steady-state 24 h area under the concentration-time curve to minimum inhibitory concentration (AUCss,24h/MIC) of ≥ 50.

Simulations revealed that intravenous Polymyxin B maintenance regimens of 100 mg q12h, 1.25 mg/kg q12h, or 1.50 mg/kg q12h enabled 94.4%, 82.2%, and 93.5% of critically ill patients, respectively, to achieve the ELF PK/PD target for pathogens with an MIC of 1 mg/L. A plasma AUCss,24h/MIC threshold of 80.6 was identified as a potential alternative PK/PD target.

Retrospective analysis confirmed significantly better outcomes for patients exceeding this plasma AUCss,24h/MIC threshold (p = 0.038), warranting prospective validation. For pathogens with MICs ≤ 0.5 mg/L, a 50 mg q12h regimen was deemed sufficient. Conversely, for MICs ≥ 2 mg/L, adjunctive nebulization or combination therapy was advised.