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TO THE EDITOR:
A recent commentary published in BJCP used lopinavir/ritonavir as an
example to highlight the importance of the clinical pharmacology
principles in the repurposing of old drugs for therapeutic use against
Coronavirus disease 19 (COVID-19).1 Here, we provide
another example to support this point.
A recent study found that ivermectin, an FDA-approved anti-parasitic
drug, has inhibitory effects on the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2).2 Ivermectin has broad
anti-viral activity through inhibition of viral proteins including
importin α/β1 heterodimer and integrase protein.3 In
the in vitro study reported by Caly and colleagues, the addition
of ivermectin at a concentration of 5 micromolar (μM) (twice the
reported IC50) to Vero-hSLAM cells 2 hours post infection of with
SARS-CoV-2 resulted in a reduction in the viral RNA load by 99.98% at
48 hours.2
Large trials of mass drug administration of ivermectin in adults and
children have shown that ivermectin is well
tolerated.4 Even at doses that are 10 times greater
than the highest FDA-approved dose of 200 μg/kg, central nervous system
toxicity has not been reported.5 However, following
the oral administration of supra-therapeutic doses of ivermectin (i.e.
120 mg) the maximum plasma concentration achieved was 0.28 ± 0.18
(standard deviation) μM, a value 18 times lower than the reported 5 μM
ivermectin concentration used by Caly et al in their SARS-CoV-2
experiment.5 To date, the clinical effects of
ivermectin at a concentration of 5
μM range are unknown, but likely
to be toxic. Furthermore, ivermectin is only commercially available as a
3 mg oral tablet.6 These factors hinder our ability to
immediately repurpose ivermectin in its current form for the treatment
of COVID-19.
While the findings by Caly and colleagues provide some promise, viral
suppression was not seen at concentrations observed with standard doses
in humans. Further preclinical in vivo studies should evaluate
the pharmacokinetics and pharmacodynamics to determine the kill pattern
of ivermectin. A potential alternate solution may be to develop an
inhaled formulation of ivermectin to efficiently deliver a high local
concentration in the lung, whilst minimising systemic toxicity. As
therapeutic agents to tackle the COVID-19 pandemic are urgently sought,
careful consideration of the pharmacokinetics of these drugs should be
considered to guide in vitro testing.