Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Mycobacteriophages: Insights into Pulmonary Distribution and Clearance.
6 affiliations
- 1USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California90033, United States.
- 2Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina27599, United States.
- 3Department of Microbiology & Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina27599, United States.
- 4Engineering and Advanced Technology Department, RTI International, Durham, North Carolina27713, United States.
- 5Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania15260, United States.
- 6Mycobacteria Research Laboratories, Department of Microbiology, Immunology & Pathology, Colorado State University, Fort Collins, Colorado80202, United States.
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 (BPsΔ, ZoeJΔ, 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 ∼390-fold higher lung exposure and ∼490-fold lower plasma exposure, supporting inhaled therapy for pulmonary mycobacterial infections. Using BPsΔ data, we developed a mechanistic PBPK model incorporating transcytosis, saturable host clearance, plasma elimination, and lymphatic transport. The model accurately predicted ZoeJΔ 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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BibTeX
@article{sharma2026pharmacokinetics,
title = {{Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Mycobacteriophages: Insights into Pulmonary Distribution and Clearance.}},
author = {Rajnikant Sharma and Ramya Mahadevan and Sai Divyash and Shekhar Yeshwante and Saikumar Matcha and ChunFu Cheng and Hunter S Talley and Alan A Schmalstig and Pradeep Neupane and Sara E Maloney Norcross and Anthony J Hickey and Graham F Hatfull and Miriam Braunstein and Gauri G Rao},
journal = {Molecular pharmaceutics},
year = {2026},
month = oct,
doi = {10.1021/acs.molpharmaceut.6c00604},
url = {https://europepmc.org/article/MED/42906173},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Pharmacokinetics and Physiologically Based Pharmacokinetic Modeling of Mycobacteriophages: Insights into Pulmonary Distribution and Clearance.
AU - Rajnikant Sharma
AU - Ramya Mahadevan
AU - Sai Divyash
AU - Shekhar Yeshwante
AU - Saikumar Matcha
AU - ChunFu Cheng
AU - Hunter S Talley
AU - Alan A Schmalstig
AU - Pradeep Neupane
AU - Sara E Maloney Norcross
AU - Anthony J Hickey
AU - Graham F Hatfull
AU - Miriam Braunstein
AU - Gauri G Rao
PY - 2026
DA - 2026/10/01
JO - Molecular pharmaceutics
DO - 10.1021/acs.molpharmaceut.6c00604
UR - https://europepmc.org/article/MED/42906173
AB - 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 (BPsΔ, ZoeJΔ, 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 ∼390-fold higher lung exposure and ∼490-fold lower plasma exposure, supporting inhaled therapy for pulmonary mycobacterial infections. Using BPsΔ data, we developed a mechanistic PBPK model incorporating transcytosis, saturable host clearance, plasma elimination, and lymphatic transport. The model accurately predicted ZoeJΔ 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.
SN - 1543-8384
SN - 1543-8392
ER -