Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study. (September 2020)

• Record Type: Journal Article
• Authors: Lin, Y.W.; Chang, R. Yoon; Rao, G.G.; Jermain, B.; Han, M.-L.; Zhao, J.X.; Chen, K.; Wang, J.P.; Barr, J.J.; Schooley, R. Turner; Kutter, E.; Chan, H.-K.; Li, J.
• Is Part Of: Clinical microbiology and infection. Volume 26:Number 9(2020)
• Page Start: 1229
• Page End: 1235
• Publication Date: 2020-09
• Subjects: Antibiotic resistance -- Gram-negative bacteria -- Phage therapy -- Pharmacokinetics/Pharmacodynamics -- Pseudomonas aeruginosa; Medical microbiology -- Periodicals; Diagnostic microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.01
• DOI: 10.1016/j.cmi.2020.04.039
• Languages: English
• ISSNs: 1198-743X

Abstract

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-log10 PFU/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 × 10 10 PFU/h/rat (10.2%) and 1.64 × 10 7 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.