Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Mycobacteriophages: Insights into Pulmonary Distribution and Clearance

Abstract

Bacteriophage therapy is being explored as an alternate therapeutic approach for treating drug- resistant bacteria, including mycobacteria. However, rational phage dosing remains limited by scarce pharmacokinetic (PK) data and an incomplete understanding of tissue distribution. We performed dose-ranging studies in mice of three therapeutic mycobacteriophages (BPs{Delta}, ZoeJ{Delta}, Muddy) after intravenous (IV) and intratracheal (IT) administration. All phages behaved similarly. IV dosing produced biphasic kinetics with non-proportional exposure and declining tissue-to-plasma ratios, indicating saturable uptake and elimination. IT delivery yielded monophasic profiles with [~]390-fold higher lung exposure and [~]490-fold lower plasma exposure, supporting inhaled therapy for pulmonary mycobacterial infections. Using BPs{Delta} data, we developed a mechanistic PBPK model incorporating transcytosis, saturable host clearance, plasma elimination, and lymphatic transport. The model accurately predicted ZoeJ{Delta} and Muddy PK, enabled cross-species extrapolation, and showed that phage morphology influences disposition. This framework advances phage therapy toward model-informed, exposure-guided dose and route selection for multidrug-resistant bacterial infections.