Whole-body distribution of three Pseudomonas phages characterized by a translational physiologically based pharmacokinetic model

作者：Arne Echterhof, Tejas Dharmaraj, Patrick Blankenberg, Bobby Targ, Thomas D. Nguyen, Paul L. Bollyky, Nicholas M. Smith, Francis G. Blankenberg · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2025 · DOI：10.1128/aac.01506-25 · 被引用次数：4 · 研究领域：Bacteriophages and microbial interactions、Monoclonal and Polyclonal Antibodies Research、Cancer Research and Treatments

ABSTRACT Bacteriophage (phage) therapy holds great promise for treating antimicrobial-resistant infections. However, the pharmacokinetics (PK) of phage have been difficult to characterize due to a lack of standardized protocols for phage purification, labeling, and in vivo quantification. Here, we present robust methods for ultrapure phage preparation, as well as non-destructive, highly stable attachment of radio-iodide to phage using a well-described Sulfo-SHPP linker. We purified and radiolabeled the phage strains, PAML-31-1, OMKO1, and Luz24, lytic to drug-resistant Pseudomonas aeruginosa, for biodistribution assay in normal young adult CD-1 mice injected via intravenous injection. Groups of five mice were euthanized, and tissues/organs were removed for weighing and scintillation well counting of 125 I activity. A physiologically based PK model was then constructed, focusing on compartments describing blood, lung, muscle, bone, liver, stomach, spleen, small intestines, large intestines, and kidney. Tissue partition coefficients (K P ) were estimated for high-perfusion organs (lung and kidney) as 0.000138, GI organs (liver, spleen, and stomach) as 0.627, and all other organs as 0.220. Monte Carlo simulations predicted rapid elimination of phage in humans, with blood concentrations being <10 2 PFU/mL by 12 h, whereas simulated multi-dose regimens and continuous infusion regimens were predicted to have sustained concentrations. Our physiologically based PK model of phage r...