Pharmacokinetic modeling reveals inhaled polymyxin B maximizes lung exposure and prevents renal toxicity, indicating its potential for multidrug-resistant pulmonary infections.
Key Points
To develop a translational physiologically based pharmacokinetic (PBPK) and pharmacodynamic modeling framework for aerosolized polymyxin B to optimize inhaled dosing regimens for multidrug-resistant pneumonia.
Constructed a whole-body PBPK model using rabbit plasma and tissue concentrations following subcutaneous and intratracheal polymyxin B administration at 2 mg/kg.
Extrapolated the model to humans via allometric scaling and validated it using clinical plasma and epithelial lining fluid (ELF) concentration data.
Conducted Monte Carlo simulations to assess pharmacokinetic/pharmacodynamic target attainment and toxicity attainment risks.
Intratracheal polymyxin B dosing achieved ~10.4-fold higher lung exposure compared to subcutaneous delivery while reducing renal exposure by 27.7%.
Model-defined acute kidney injury thresholds were established at a plasma exposure of 92.9 mg·h/L and a kidney tissue exposure of 157 mg·h/L.
Inhaled monotherapy achieved favorable ELF target attainment with 0% probability of toxicity attainment and substantial bacterial reduction (≥ 4 log10 CFU/mL at 24 h), whereas intravenous therapy failed lung target attainment and exceeded 40% toxicity risk.