A framework for treating the host with repurposed
drugs.
Treating the host in COVID-19 brings together two key pharmacological
principals. The first involves the understanding of how a proposed
therapeutic agent integrates within the pathogenic response. This
approach thus involves understanding initially the integration of the
host into the consequences of viral pathogenesis. This relationship has
been well described for microbial pathogenesis in the Damage–Response
Framework (DRF) in infectious diseases (9). The damaging host factors
described in this microbial model, namely cytokine release (storm),
chemical mediators signalling, oxygen radical production and immune
complexes leading to aberrant inflammation are not specific and in fact
apply equally to viruses such as influenza and the current COVID-19
disease.
The second principal involves the appropriate use of therapeutics
approved for one indication but used effectively in a different setting
within the DRF. Approaches used for drug repurposing, the challenges and
ways in which these challenges may be tackled have been described
recently in detail (10). The application to COVID-19 involves
identification of drugs that in a new indication, in the correct dosage
for the new disease have a substantial impact on the consequences of
infection in the host.
A logical framework based on the above considerations for identifying
repurposed drugs for treatment of the host would potentially include:
- Pathogenesis . Homology with the novel action of the
repurposed drug and the molecular events that drive the consequences
of viral pathogenesis in
COVID-19 disease.
- Target homology of COVID-19 and therapeutic agents.Ideally the repurposed drug
should target the pathophysiology of COVID-19 that is tightly linked
to the conserved mutational properties of the virus and its class.
- Prevention to
treatment . An understanding of how the repurposed drug provides
benefit in treating the host across the cascade from prevention to the
life-threatening consequences of other viral pathogenesis in COVID-19
disease.
- Dose and safety . Ideally an application of the repurposed
drug either within the approved dose ranges for its initial
indications for which the pharmacokinetics and toxicology are
documented as part of the registration for the drug’s initial
indication, or
- A new application of an already registered drug in another
indication, using doses based on pharmacological and physiological
attributes of the new disease and the specific chosen effect of the
drug at different dosages and/or plasma concentrations.
Using similar deduction, in 2020 Fedson et al. proposed clinical trials
should be undertaken with combinations of the RAS agents angiotensin
receptor blockers (ARB) and statins in patients with severe COVID-19
infection (5). His proposal provides an excellent opportunity to use our
framework in evaluating repurposed RAS drugs for use in COVID-19. In the
following example we focused upon drugs targeted to the RAS, but the
procedure would equally apply to statins either alone or in combination
with ARBs.