Pharmacokinetics and physiologically based pharmacokinetic modeling of mycobacteriophages

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 nonproportional exposure and declining tissue-to-plasma ratios, indicating saturable uptake and elimination. IT delivery yielded monophasic profiles with similar to 390-fold higher lung exposure and similar to 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.