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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A whole-body PBPK model was developed using plasma and tissue concentration data following subcutaneous and intratracheal PMB administration (2\u00a0mg\/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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Intratracheal administration achieved\u2009~\u200910.4-fold higher lung exposure relative to subcutaneous dosing while reducing kidney exposure by 27.7%. A plasma exposure threshold of 92.9\u00a0mg\u00b7h\/L and a kidney tissue exposure threshold of 157\u00a0mg\u00b7h\/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 (\u2265\u20094 log\n                      <jats:sub>10<\/jats:sub>\n                      CFU\/mL at 24\u00a0h), whereas IV monotherapy failed to achieve ELF PTA, with several regimens exceeding 40% PToXA and minimal bactericidal activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-026-04194-1","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:06:51Z","timestamp":1789675611000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions"],"prefix":"10.1007","author":[{"given":"Ramya","family":"Mahadevan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shekhar","family":"Yeshwante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajnikant","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ChunFu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rani S.","family":"Sellers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Soledad","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi Tony","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Z.","family":"D\u2019Argenio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-7770","authenticated-orcid":false,"given":"Gauri G.","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"4194_CR1","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1186\/s12879-025-11515-z","volume":"25","author":"L Zhou","year":"2025","unstructured":"Zhou L, Wang D, Li X, Cheng Y, Lin Y, Weng Q, et al. 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