LB-002 - A MINIMAL PHYSIOLOGICALLY BASED PHARMACOKINETIC (MPBPK) MODEL TO CHARACTERIZE PSA07 BACTERIOPHAGE (PHAGE) PHARMACOKINETICS (PK) FOLLOWING INTRAVENOUS (IV) ADMINISTRATION IN MICE FOR TREATMENT OF P. AERUGINOSA (PSA) INFECTIONS

R. Mahadevan¹, R. Sharma², S. Yeshwante³, Q. Valle², M. Bui², J. Barr⁴, D. Van Tyne⁵, G. Rao²; ¹USC Alfred E Mann school of pharmacy, , , ²USC Alfred E Mann school of pharmacy, , United States, ³UNC Eshelman school of pharmacy, , , ⁴Monash University, , , ⁵University of Pittsburgh, , .

Background: PsA is a Gram-negative opportunistic pathogen that colonizes the airway of immunocompromised patients, thereby increasing their chances of developing infections. Treating these infections is challenging as certain PsA strains are resistant to most currently approved antibiotics. Phage therapy is attractive as its mechanism of action is independent of traditional antimicrobial resistance. However, limited knowledge about phage PK poses a challenge when designing effective treatments. Our objective is to develop a mPBPK model using preclinical in vivo data describing phage distribution to potential biophases.

Methods: Phage PSA07 was obtained from the University of Pittsburgh produced using the Phage-on-Tap protocol. Immunocompromised mice were administered a single IV PSA07 dose (4x1010 PFU/kg). Mice (n=3) were sacrificed at 0.25, 0.5, 2, 4, 8, 24, 48 & 72 h. Phage titers quantified in plasma & lung were modeled in ADAPT5 (Naïve pooled approach).

Results: The model consists of plasma, lung, lymph & remainder compartments. Blood flow, lymph flow & tissue volume were fixed to physiological values based on a 25g mouse with lymph reflection coefficient=0.2. Additive residual error was considered for log-transformed data. Phages may enter the target tissues via macropinocytosis followed by trafficking via the Golgi apparatus before undergoing exocytosis to the apical or basolateral regions. Based on this knowledge about phage distribution the lung & remainder compartments were divided into vascular, endosomal & interstitial compartments. The higher macropinocytosis uptake rate (0.0367 h-1) compared to exocytosis rate (0.0123 h-1) explains the accumulation of phage in the lung tissue. The observed phage concentrations do not support lysosomal degradation of phage in tissue; hence it was not included in the model. Instead, the inclusion of linear clearance from plasma (48.3 ml/h) describes the rapid clearance of phages from circulation due to phagocytosis by liver & spleen macrophages. The model predictions captured the phage distribution well (CV% < 21).

Conclusion: The mPBPK model has furthered our understanding about phage distribution & clearance following IV administration. Phage exposure in the lung phage can be linked with change in bacterial density over time to understand the resulting pharmacodynamic activity.