Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: A Proof-of-Concept study.

Abstract Objectives Pandrug-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 an antipseudomonal phage oPEV20 in vivo following intravenous administration. Methods Healthy Sprague-Dawley rats were given oPEV20 as a single intravenous bolus of ∼6, 9, and 11-log10PFU/Rat. Blood was sampled from artery across 72 h. At 72 h, the animals were sacrificed and multiple tissues were harvested for biodistribution study. A PK model was developed using Importance Sampling Algorithm and deterministic simulations with PD models were performed. Results A three-compartment model with nonlinear clearance described the exposure of oPEV20 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 oPEV20 was not homogeneous with preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of 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.