Future directions
Our model-informed analysis underscores the need to include the key features of the viral cell cycle from the perspective of dynamic models to leverage the significance of cell-cycle checkpoints (vis-à-vis specific rate constants) for emerging therapeutics. Our model builds upon previously described models by extending their utility into assessment of the value of combinations. Such an approach will be invaluable for clinicians and trialists to develop informed hypotheses based on cell cycle selectivity and specificity. The fundamental premise for this approach assumes that cell kinetics and durability of response are intricately regulated and can only be disrupted by a drug that has the specificity for that particular phase.
The model leveraged here is parsimonious and offers a quick, reliable method to triage therapeutics entering clinical assessment for the ongoing pandemic. Efforts are ongoing to further build in wet-lab inputs on the virus characterization model including replication dynamics, tropism and cell culture susceptibility, but also integrating with drug characterization (including ADME profiles), and emerging clinical data from ongoing studies. We hope that further refinements as well as extension to broader incorporation of the down-stream host inflammatory response and associated interventions such as immunomodulators including IL-6 inhibitors, will provide a comprehensive disease model backbone that could be fungible for inputing emerging virus pathogens. We believe that a comprehensive quantitative and systems pharmacology approach linking to wet-lab for emerging viruses, can provide a structured scientific back-bone that could revolutionize and rationalize our approach to selecting therapeutic interventions for future pandemics.