Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions
8 affiliations
- 1Titus Family Department of Clinical Practice, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA USA
- 2Center for Quantitative Drug and Disease Modeling, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA USA
- 3Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
- 4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC USA
- 5Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA USA
- 6Biomedicine Discovery Institute, Infection Program, Department of Microbiology, Monash University, Melbourne, VIC 3800 Australia
- 7Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, IN USA
- 8Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA USA
Abstract
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s11095-026-04194-1.
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BibTeX
@article{mahadevan2026physiologically,
title = {{Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions}},
author = {Ramya Mahadevan and Shekhar Yeshwante and Rajnikant Sharma and Quentin Valle and ChunFu Cheng and Rani S. Sellers and Maria Soledad Ramirez and Jian Li and Qi Tony Zhou and David Z. D’Argenio and Gauri G. Rao},
journal = {Pharmaceutical Research},
year = {2026},
month = sep,
doi = {10.1007/s11095-026-04194-1},
url = {https://doi.org/10.1007/s11095-026-04194-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions
AU - Ramya Mahadevan
AU - Shekhar Yeshwante
AU - Rajnikant Sharma
AU - Quentin Valle
AU - ChunFu Cheng
AU - Rani S. Sellers
AU - Maria Soledad Ramirez
AU - Jian Li
AU - Qi Tony Zhou
AU - David Z. D’Argenio
AU - Gauri G. Rao
PY - 2026
DA - 2026/09/17
JO - Pharmaceutical Research
DO - 10.1007/s11095-026-04194-1
UR - https://doi.org/10.1007/s11095-026-04194-1
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s11095-026-04194-1.
SN - 0724-8741
SN - 1573-904X
ER -