Second-order kinetics describe systemic clearance of therapeutic bacteriophages

Bacteriophage therapy is a promising alternative to antibiotics, yet its clinical translation is limited by the lack of a quantitative pharmacological framework to guide dosing and to predict efficacy. Here, we define the pharmacokinetics of therapeutic phages using a rat tissue cage model, which allows parallel sampling from blood and an artificial interstitial compartment. Across five virulent phages of three morphotypes targeting two pathogens, systemic clearance consistently followed second-order, concentration-dependent kinetics, representing a paradigmatic shift from frequently assumed first-order models. Phages rapidly distributed to peripheral compartments, where exposure was strongly influenced by administration route. Intravenous delivery maximized systemic titers but limited peripheral exposure, whereas local administration achieved high concentrations at target sites with undetectable systemic redistribution. Repeated dosing enhanced exposure but not peak titers. These findings define fundamental parameters to establish a quantitative framework for phage pharmacokinetics and support rational dose design.