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.