Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions.

OBJECTIVES: Despite the potential of aerosolized polymyxin B (PMB) to enhance local lung exposure while minimizing nephrotoxicity in multidrug-resistant pneumonia, clinical adoption remains limited by insufficient inhaled pharmacokinetic (PK) data. This study developed a physiologically based pharmacokinetic (PBPK) modeling framework to translate preclinical PK data from rabbits to humans and coupled it with a mechanism-based pharmacodynamic model to define optimal inhaled PMB regimens. METHODS: A whole-body PBPK model was developed using plasma and tissue concentration data following subcutaneous and intratracheal PMB administration (2 mg/kg) in rabbits, extrapolated to humans using allometric scaling, and validated against clinical plasma and epithelial lining fluid (ELF) data. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) and probability of toxicity attainment (PToXA). RESULTS: Intratracheal administration achieved ~ 10.4-fold higher lung exposure relative to subcutaneous dosing while reducing kidney exposure by 27.7%. A plasma exposure threshold of 92.9 mg·h/L and a kidney tissue exposure threshold of 157 mg·h/L were identified as indicators of higher risk of AKI. Inhaled PMB monotherapy achieved favorable ELF PTA with 0% PToXA and predicted substantial bacterial load reduction (≥ 4 log10 CFU/mL at 24 h), whereas IV monotherapy failed to achieve ELF PTA, with several regimens exceeding 40% PToXA and minimal bactericidal activity. CONCLUSION: Inhaled PMB provides superior site-specific exposure with minimal predicted nephrotoxicity. Our PBPK-mechanism-based modeling framework suggests that nebulized PMB rapidly clears bacteria while avoiding dose-limiting nephrotoxicity associated with intravenous therapy. These findings support advancing aerosolized PMB toward clinical implementation as a precision-dosing strategy for MDR pulmonary infections.