{
  "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.\n\nMethods: 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).\n\nResults: 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.\n\nConclusion: 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.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s11095-026-04194-1.",
  "abstract_shown": true,
  "affiliations": [
    "Titus Family Department of Clinical Practice, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA USA",
    "Center for Quantitative Drug and Disease Modeling, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA USA",
    "Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC USA",
    "Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC USA",
    "Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA USA",
    "Biomedicine Discovery Institute, Infection Program, Department of Microbiology, Monash University, Melbourne, VIC 3800 Australia",
    "Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, IN USA",
    "Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Ramya Mahadevan"
    },
    {
      "affs": [
        2
      ],
      "name": "Shekhar Yeshwante"
    },
    {
      "affs": [
        0
      ],
      "name": "Rajnikant Sharma"
    },
    {
      "affs": [
        0
      ],
      "name": "Quentin Valle"
    },
    {
      "affs": [
        0
      ],
      "name": "ChunFu Cheng"
    },
    {
      "affs": [
        3
      ],
      "name": "Rani S. Sellers"
    },
    {
      "affs": [
        4
      ],
      "name": "Maria Soledad Ramirez"
    },
    {
      "affs": [
        5
      ],
      "name": "Jian Li"
    },
    {
      "affs": [
        6
      ],
      "name": "Qi Tony Zhou"
    },
    {
      "affs": [
        7
      ],
      "name": "David Z. D’Argenio"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Gauri G. Rao",
      "orcid": "0000-0002-8704-7770"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aqsgn7esjdvsz.bib",
  "cited_by": 0,
  "doi": "10.1007/s11095-026-04194-1",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736267/",
  "id": "aqsgn7esjdvsz",
  "issns": [
    "0724-8741",
    "1573-904X"
  ],
  "landing_url": "https://doi.org/10.1007/s11095-026-04194-1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research Article"
    ],
    [
      "openalex",
      "2736|Antibiotics Pharmacokinetics and Efficacy"
    ]
  ],
  "openalex": "W7213507081",
  "pdf_url": "https://link.springer.com/content/pdf/10.1007/s11095-026-04194-1.pdf",
  "pmcid": "PMC13736267",
  "pmid": "42754780",
  "published": "2026-09-17",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/aqsgn7esjdvsz.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:21:45Z",
      "native_id": "PMC13736267",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s11095-026-04194-1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2736|Antibiotics Pharmacokinetics and Efficacy",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions",
  "title_text": "Physiologically Based Pharmacokinetic Modeling of Inhaled Polymyxin B: From Rabbit Optimization to Human Predictions",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:21:45Z",
  "url": "https://research.draconitic.com/paper/aqsgn7esjdvsz",
  "venue": "Pharmaceutical Research",
  "versions": []
}