Dear editor,
Given time, drug discovery programmes will undoubtedly yield highly
potent drugs to form the basis of optimised COVID-19 regimens. However,
if efficacious therapies can be identified from current medicines,
repurposing represents the fastest route to establish deployable
interventions and buy time for vaccine and novel drug development. It is
important to note that effective medicines were rigorously optimised for
the treatment of specific indications. Route of administration, dosage
and schedules for existing therapies were optimised to provide adequate
plasma/tissue pharmacokinetics and safety for their target disease or
condition. These cannot be assumed to be optimal for COVID-19 but are
often highly predictable from pre-existing data and clinical experience.
For example, hydroxychloroquine and lopinavir/ritonavir recently failed
to deliver benefits in RCTs for mild/moderate and severe
disease,1, 2 but the clear disconnect between reportedin vitro antiviral activity and known human pharmacokinetics
after administration of approved doses was
predictable.3
Interpretation of laboratory-based antiviral activity assessments is
complicated by current uncertainty regarding the appropriateness of the
existing model systems. The majority of in vitro antiviral
screening assays have utilised Vero cells, which were derived from the
kidney of African Green Monkey in the 1970s, and the lack of clinical
evidence for which to validate the exposure-response relationship in
humans is problematic. Evidence is emerging that the anti-SARS-CoV-2
activity of drugs may be higher in cells derived from humans. However,
the question of which cell types are most representative of in
vivo performance is yet to be addressed, and all that can really be
concluded from current knowledge is that the susceptibility of
SARS-CoV-2 to antivirals is cell-type-dependent. The consequences of
this in terms of the variety of cell types known to be infected and/or
sustain productive infection in vivo is equally uncertain, and
further exacerbated by the lack of robustly validated animal models.
However, repurposed drugs cannot be assumed to be active against
SARS-CoV-2 at a dose that was optimised on the basis of potency for and
accumulation at their initial therapeutic target.
Nucleoside/nucleotide polymerase inhibitors have proven highly
successful for other viruses, but usually require combination with
another drug class. Remdesivir and favipiravir have in vitro anti-SARS-CoV-2 activity across multiple studies, and the unprecedented
speed at which they have transitioned through COVID-19 RCTs can only be
commended.4, 5, 6 Daily IV infusion may make inherent
sense for severely ill patients, but a transformational impact for
COVID-19 can only be realised if wide compatibility with global
healthcare systems and equitable access across all country contexts is
achieved. While reduction in symptom duration may mitigate healthcare
saturation in high-income countries, the absence of a clear benefit for
mortality diminishes game-changing potential. However, the clinical
validation of the antiviral activity of such drugs will make them clear
candidates for implementation as part of community-based interventions
if other challenges are addressed. Importantly, the combination of
nucleoside analogues with a secondary target such as the protease has
stood the test of time in antiviral pharmacology. The recent reports of
low-dose dexamethasone leading to an impact on
mortality7 is a significant step forward but long-term
mitigation of viral transmission, with subsequent economic and social
restrictions, requires antiviral treatment or prevention to minimise
hospitalisation through a community-targeted approach.
Focussing on existing single drugs, and not appropriately formulated
medicines, will require the rethinking of a number of medicine
development parameters such as posology, reformulation and therapeutic
index (Figure 1); current HIV medicines, for example, are formulated for
chronic (life-long) dosing to moderate and control disease but a
successful COVID-19 therapy will likely require only a short term acute
administration to rapidly cure the patient. Conversely, different
considerations are required for longer-term applications in COVID-19
chemoprophylaxis, which could have a dramatic effect on control of the
pandemic.
Many advanced drug delivery technologies have emerged in recent years.
Long-acting drug delivery involving injectable, implantable or
microarray patch mediated delivery have attracted enormous recent
interest for prevention of other infectious diseases,8,
9 and the ability to deliver potent antiviral combinations for a period
of months could play a transformational role in the absence of a safe
and efficacious vaccine. The physicochemistry and activity of the
polymerase inhibitors, and other drugs with known anti SARS-Cov-2
activity, also warrants investigation of pulmonary delivery via
nebuliser or metered dose inhaler for direct dosing to the upper airways
to supplement systemic drug delivery as pre- or post-exposure
prophylaxis. Several advanced drug delivery strategies can be applied
rapidly and do not need to be prohibitively expensive for global
community programmes. It seems unlikely that a global pandemic can be
ended if effective medicines are only available to the few and equitable
access is therefore of benefit to all. Importantly, relying solely upon
pre-existing formulations and posologies optimised for other diseases
carries inherent risk of rejecting drug candidates with an otherwise
high potential for global impact.