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. 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.
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 VC, VP1, VP2, Q1, Q2, Vm and Km 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.
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 VC, VP1, VP2, Q1, Q2, Vm and Km 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.
Authors: Katherine M C Totten; Scott A Cunningham; Naomi M Gades; Athema Etzioni; Robin Patel Journal: Front Pharmacol Date: 2022-05-20 Impact factor: 5.988
Authors: Marion C Bichet; Wai Hoe Chin; William Richards; Yu-Wei Lin; Laura Avellaneda-Franco; Catherine A Hernandez; Arianna Oddo; Oleksandr Chernyavskiy; Volker Hilsenstein; Adrian Neild; Jian Li; Nicolas Hans Voelcker; Ruzeen Patwa; Jeremy J Barr Journal: iScience Date: 2021-03-09