Researcher Fractal Therapeutics, California, United States
Disclosure(s):
Lin Yuan, MS: No financial relationships to disclose
Objectives: Despite their pandemic potential, respiratory viruses have limited options for treatment. Drug repurposing represents a promising means of broadening the armamentarium of treatments, but repurposing efforts are often unsuccessful. A common hurdle to effective drug repurposing is a failure to achieve a sufficient therapeutic window in the new indication. For COVID-19, systemically administered repurposed antivirals have proven largely unsuccessful.
Methods: We propose that repurposed antivirals administered via inhalation may provide a broader therapeutic window by targeting a site of entry into systemic circulation, thus curtailing viral spread throughout the body while keeping systemic concentrations low. In this article, we develop a two-stage model-driven screening and validation process for selecting inhaled antiviral drug re-purposing candidates based on estimated therapeutic index (TI). We then use our proposed screen to evaluate eight repurposing candidates with clinical tolerability data in the inhaled setting. We advance the best candidate to the validation stage and assess potential administration schedules for COVID-19 treatment.
Results: Through our rapid TI estimation screen, we demonstrate that TI likely constrains success for systemically administration of repurposed antiviral candidates. However, several of the repurposing candidates show promise in the inhaled setting. We further evaluated ribavirin [1], demonstrating with a lightweight lung pharmacokinetic model that delivering the drug by nebulizer two or three times daily could have efficacy in COVID-19.
Conclusions: While we have applied this approach in the specific context of COVID-19, this in vitro-in vivo translational methodology is also broadly applicable to repurposing drugs for diseases of the lower respiratory tract. The method described here can also be used to rapidly develop treatments for deployment in a front-line setting during the emergence of a novel respiratory virus.
Citations: [1] Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) in Vitro. Cell Res 2020, 30, 269–271, doi:10.1038/s41422-020-0282-0.
