Whole-body Bacteriophage Distribution Characterized by a Physiologically based Pharmacokinetic Model

Area of Science:

• Pharmacology
• Microbiology
• Biotechnology

Background:

• Antibiotic-resistant bacterial infections pose a significant global health threat, with Gram-negative organisms showing high mortality rates.
• Bacteriophage therapy is a promising alternative to antibiotics, but understanding phage pharmacokinetics (PK) is crucial for effective treatment.
• Standardized protocols for phage purification, tissue assay, and labeling have been lacking, hindering PK characterization.

Purpose of the Study:

• To develop robust methods for ultrapure bacteriophage preparation and non-destructive radiolabeling.
• To assess the biodistribution and pharmacokinetics of radiolabeled bacteriophages in a preclinical mouse model.
• To construct a physiologically based pharmacokinetic (PBPK) model for bacteriophages to predict their behavior in vivo.

Main Methods:

• Purification and radiolabeling of bacteriophage strains (PAML-31-1, OMKO1, Luz24) lytic to Pseudomonas aeruginosa using a Sulfo-SHPP linker and radio-iodide (I-125).
• Biodistribution studies in CD-1 mice, with tissue/organ collection and scintillation counting at various time points post-injection.
• Development of a PBPK model incorporating compartments for major organs and estimating key PK parameters like permeability and partition coefficients.

Main Results:

• The study established reliable methods for phage purification and stable radiolabeling.
• Biodistribution data revealed rapid phage elimination, with blood concentrations falling below the limit of quantification by 12 hours post-injection.
• The PBPK model provided estimates for permeability, partition coefficients, and elimination rates, crucial for understanding phage disposition.

Conclusions:

• The developed PBPK model is the first rigorous preclinical assessment of phage PK using contemporary pharmacometric approaches.
• The model predicts rapid phage elimination in humans, suggesting that multi-dose or continuous infusion regimens may be necessary for sustained therapeutic concentrations.
• Phage concentrations are predicted to reach approximately 10^7 PFU/g at a maximum dose of 10^12 PFU, informing potential dosing strategies.