Hundreds of researchers are working to develop a vaccine and are
evaluating drugs to mitigate the adverse health and economic
consequences of COVID-19 (Coronavirus disease 19) worldwide. If novel
compounds are found, geopolitical and economic variables will determine
their introduction to communities. Therefore, finding low-cost and
widely accessible drugs for prevention or treatment of COVID-19 would be
ideal.
A recent study found that ivermectin, an FDA-approved anti-parasitic
drug, has inhibitory effects on replication of the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)1.
Ivermectin has broad anti-viral activity through inhibition of viral
proteins including importin α/β1 heterodimer and integrase
protein2. Caly and colleagues reported that the
addition of ivermectin at a concentration of 5 micromolar (μM) (twice
the reported IC50) to Vero-hSLAM cells, 2 hours post infection with
SARS-CoV-2, resulted in a reduction in the viral RNA load by 99.98% at
48 hours1. The authors suggested that this drug could
reduce the viral load in infected patients, with potential effect on
disease progression and spread.
While the findings by Caly and colleagues provide some promise, there is
no evidence that the 5 μM concentration of ivermectin used by Caly and
colleagues in their in vitro SARS-CoV-2 experiment, can be
achieved in vivo . The pharmacokinetics of ivermectin in humans is
well described (Figure 1)3-5, and even with the
highest reported dose of approximately 1700 µg/kg (i.e. 8.5 times the
FDA-approved dose of 200 μg/kg), the maximum plasma concentration was
only 0.28 µM5. This is 18 times lower than the
concentration required to reduce viral replication of SARS-CoV-2in vitro . Ivermectin accumulation in tissues is mild and would
not be sufficient to achieve the antiviral effect with conventional
doses6. Although high doses of ivermectin in adults or
children are well tolerated5,7, the clinical effects
of ivermectin at a concentration of 5 μM range are unknown and may be
associated with toxicity. Consequently, ivermectin has in vitroactivity against SARS-CoV-2 but this effect is unlikely to be observedin vivo using current dosing.
Amidst fear of the pandemic, the public and some physicians are now
using ivermectin off-label for prophylaxis or as adjuvant therapy for
COVID-19. Because ivermectin is only commercially available as a 3 or 6
mg tablets or a 6 mg/ml oral suspension, in order to administer a high
dose, some people may experiment with more concentrated veterinary
formulations. These actions are not based on clinical trials and have
motivated cautionary statements from institutions such as the FDA
against the use of pharmaceutical formulations of ivermectin intended
for animals as therapeutics in humans 8.
Potential avenues for further investigation into repurposing ivermectin
for SARS-CoV-2 may be to: (i) develop an inhaled formulation to
efficiently deliver a high local concentration in the lung, whilst
minimizing systemic exposure; and (ii) evaluate more potent ivermectin
analogs (e.g. doramectin) which may also inhibit SARS-CoV-2. These are
areas for research – clearly, further studies are needed before
ivermectin can be used for the prevention and treatment of COVID-19. As
recently discussed in BJCP, this highlights the critical need to
consider pharmacological principles to guide in vitro testing
when repurposing old drugs for therapeutic use against
COVID-199.