Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study

Y W Lin; R Yoon Chang; G G Rao; B Jermain; M-L Han; J X Zhao; K Chen; J P Wang; J J Barr; R Turner Schooley; E Kutter; H-K Chan; J Li

doi:10.1016/j.cmi.2020.04.039

Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study

Clin Microbiol Infect. 2020 Sep;26(9):1229-1235. doi: 10.1016/j.cmi.2020.04.039. Epub 2020 May 5.

Authors

Y W Lin¹, R Yoon Chang², G G Rao³, B Jermain³, M-L Han⁴, J X Zhao⁴, K Chen⁴, J P Wang⁴, J J Barr⁵, R Turner Schooley⁶, E Kutter⁷, H-K Chan², J Li⁸

Affiliations

¹ Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia. Electronic address: yu-wei.lin@monash.edu.
² Advanced Drug Delivery Group, School of Pharmacy, The University of Sydney Faculty of Medicine and Health, Sydney, NSW, Australia.
³ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
⁴ Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia.
⁵ School of Biological Sciences, Monash University, Clayton, VIC, Australia.
⁶ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁷ The Evergreen State College, Olympia, WA, USA.
⁸ Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia. Electronic address: jian.li@monash.edu.

PMID: 32387436
DOI: 10.1016/j.cmi.2020.04.039

Abstract

Objectives: Pan-drug-resistant (PDR) Pseudomonas aeruginosa is one of the three top-priority pathogens identified by the WHO, and bacteriophages have been investigated as an alternative therapy. However, knowledge on the pharmacokinetics/pharmacodynamics (PK/PD) of phage therapy is sparse, limiting its clinical applications. This study aimed to evaluate the PK/PD of the antipseudomonal phage øPEV20 in vivo following intravenous administration.

Methods: Healthy Sprague-Dawley rats were given øPEV20 as a single intravenous bolus of ~6, 9 and 11-log₁₀PFU/rat. Arterial blood was sampled over 72 h. At 72 h, the animals were killed and multiple tissues were harvested for biodistribution studies. A PK model was developed using the importance sampling algorithm and deterministic simulations with a PD model were performed.

Results: A three-compartment model with non-linear clearance described the exposure of øPEV20 in blood. Model evaluation indicated that the model was robust and parameter estimates were accurate. The median (standard error) values of model-predicted PK parameters for V_C, V_P1, V_P2, Q₁, Q₂, V_m and K_m were 111 mL/rat (8.5%), 128 mL/rat (4.97%), 180 mL/rat (4.59%), 30.4 mL/h/rat (19.2%), 538 mL/h/rat (4.97%), 4.39 × 10¹⁰ PFU/h/rat (10.2%) and 1.64 × 10⁷ PFU/mL/rat (3.6%), respectively. The distribution of øPEV20 was not homogeneous; there was preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of the host immune system in facilitating phage-mediated bacterial elimination.

Conclusions: We developed a robust PK model to describe the disposition of phages in healthy rats. This model may have significant potential in facilitating future preclinical and clinical PK/PD investigations.

Keywords: Antibiotic resistance; Gram-negative bacteria; Phage therapy; Pharmacokinetics/Pharmacodynamics; Pseudomonas aeruginosa.

MeSH terms

Animals
Bacteriophages / physiology*
Drug Resistance, Multiple, Bacterial
Phage Therapy*
Pseudomonas aeruginosa / drug effects
Pseudomonas aeruginosa / virology*
Rats
Rats, Sprague-Dawley

Grants and funding

R33 AI121627/AI/NIAID NIH HHS/United States