Using translational in vitro-in vivo modeling to improve drug repurposing outcomes for inhaled COVID-19 therapeutics

The ongoing COVID-19 pandemic has created an urgent need for antiviral treatments that can be deployed rapidly. Drug repurposing represents a promising means of achieving this objective, 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. A clear example is the use of ivermectin in COVID-19, where the approved dose (administered orally) fails to achieve therapeutic concentrations in the lungs. Our proposed solution to the problem of ineffective drug repurposing for COVID-19 antivirals is two-fold: to broaden the therapeutic window by reformulating therapeutics for the pulmonary route, and to select drug repurposing candidates based on their model-predicted therapeutic index for inhalation. In this article, we propose a two-stage model-driven screening and validation process for selecting inhaled antiviral drug repurposing candidates. 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.