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

Sharma, R.; Mahadevan, R.; Divyash, S.; Yeshwante, S.; Matcha, S.; Cheng, C.; Talley, H. S.; Schmalstig, A. A.; Neupane, P.; Maloney Norcross, S. E.; Hickey, A. J.; Hatfull, G. F.; Braunstein, M.; Rao, G. G.

doi:10.64898/2026.01.27.702067

bioRxiv · 10.64898/2026.01.27.702067

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

Sharma, R.·Mahadevan, R.·Divyash, S.·Yeshwante, S.·Matcha, S.·Cheng, C.·Talley, H. S.·Schmalstig, A. A.·Neupane, P.·Maloney Norcross, S. E.·Hickey, A. J.·Hatfull, G. F.·Braunstein, M.·Rao, G. G.

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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.

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Sharma, R., Mahadevan, R., Divyash, S., Yeshwante, S., Matcha, S., Cheng, C., Talley, H. S., Schmalstig, A. A., Neupane, P., Maloney Norcross, S. E., Hickey, A. J., Hatfull, G. F., Braunstein, M., Rao, G. G.. 2026-01-28. Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Mycobacteriophages: Insights into Pulmonary Distribution and Clearance. https://doi.org/10.64898/2026.01.27.702067

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