PHARMACOKINETICS LIMITS CLINICAL USE OF IVERMECTIN FOR COVID-19
Hundreds of researchers are working on developing a vaccine or testing
drugs to mitigate COVID-19 worldwide. If novel compounds are found,
geopolitical and economic variables will determine their introduction to
communities. Therefore, finding low-cost and accessible substances for
prevention or treatment of COVID-19 would be ideal.
Earlier in April, a new hope emerged when the antiviral effect of
ivermectin, a known anti-parasite drug, upon SARS-CoV-2 was published.
Caly et al unveiled that 5uM ivermectin induces a profound reduction
(~5000 fold) in SARS-CoV-2 replication (RNA levels) in
cultured human cells 1. The authors suggested that
this drug could reduce viral load in infected patients, with a potential
effect on disease progression and spread. Amidst fear of the pandemic,
the public and some physicians may be tempted to use ivermectin as
prophylaxis, or as a coadjuvant, for COVID-19. These actions 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 2.
It is vital to be careful with the translation of molecular findings
into clinical outcomes, and it is especially important to understand the
pharmacokinetic profile of drugs that could be repurposed for COVID-19,
in order to design optimal dosing regimens3. There is
no evidence that the concentration of ivermectin used in this study can
be achieved in humans. Multiple teams have evaluated the
pharmacokinetics of ivermectin in humans 4-6 (fig 1),
and protocols using the highest doses (approx. 1800 µg/kg and about 10
times the usual dose), have achieved maximum plasma concentrations of
about 0.28 µM 6. Therefore, the highest concentration
reached is 17.5 times lower than what is required to reduce the
replication of SARS-CoV-2. Consequently, although ivermectin may have anin vitro antiviral effect, it probably will not effectivein vivo . Pharmacokinetics may explain lack of effectiveness of
ivermectin (400 µg/kg for 3 days) for treatment of viral infections such
as dengue fever 7.
These results should not discourage us. We do not know what the ceiling
concentration of ivermectin in humans is, and administering higher doses
of ivermectin may be useful, but could also increase the risk of adverse
effects. Besides, some more potent ivermectin analogs may also have an
antiviral effect on SARS-CoV-2, although this idea requires further
study. In summary, it is crucial to be cautious and consider the
clinical pharmacokinetics of potential treatments for COVID-19 before
initiating off-label therapies in communities and health care workers.