4 April 2020 Is Ivermectin a useful anti-COVID drug?

Sun, 04/05/2020 - 14:50

Our colleague Bob Colebunders informed me about an interesting paper that appeared yesterday on the ant-SARS-CoV-2 effect of the worm killer Ivermectin. 

As you can see in the Fig on p.14, there is indeed a very clear antiviral effect in the low micromolar range.  

On p. 15 (and in the Discussion) you can see and read what the proposed mechanism of action is: interference with the nuclear import of an as yet unknown viral protein that “somehow” via the cell nucleus exerts an anti-viral effect.  The authors refer to a review in Current Opinion 2012  (by one of them), suggesting that HIV-integrase and Flavivirus (e.g. Dengue) NS5 can also be targeted in this way.  In the Trends review of 2017 on p. 470, the antiviral effect is ascribed to inhibition of RNA helicase in the first place, but also (for HIV and Dengue) by effecting the Importin at concentrations in the 25 to 50 µM range (hence slightly higher concentration required than what is shown in this paper for the antiSARS-CVoV-2 effect).  Obviously, it remains to be seen whether or not this mechanism of inhibition is really involved for SARS-CoV-2, but at least the in vitro antiviral effect is clear.

What would be the required in vivo dosage for a significant anti-SARS-CoV-2 inhibition?  

Table 2 on p. 469 of the Trends review gives an idea on how to translate in vitro activity to in vivo dosage.  As you can see a low µM in vitro concentration corresponds to tens of milligrams per kg, while the effect on human nematodes requires hundred-fold lower dosage.  According to https://www.drugs.com/dosage/ivermectin.html#Usual_Adult_Dose_for_Onchocerciasis  the advised dosage for parasitic infections is indeed 0.2 mg/kg.

This higher required dosage for the antiviral as compared to the antiparasitic effects is presumably due to different mechanisms involved with a much higher sensitivity of the parasitic chloride channels as opposed to the interaction between the viral protein and the mammal importin.

Can you give a hundred-fold dose of what is presently used without side effects?

The authors refer to a recent metanalysis in JAC, where “high doses” did not show more side effects than standard dose. However, if you watch Table 1 p. 5 of the JAC paper, you can see that these high doses range between 600-800 µg/kg, which is still at least 10-50 times lower than what you presumably would need for a sufficient ant-SARS-CoV-2 effect in vivo.

With regard to toxicity, it is known that Ivermectin has an effect on GABA receptors in the CNS and that there are drug interactions with benzodiazepines and valproic acid. I could only find 2 case reports about acute intoxication  (see Word document with the 2 abstracts, sorry no access to the papers). Clearly very serious neurological intoxication with coma has been seen in one patient at a dose of 15.4 mg/kg and in another patient at a dose of 414 mg/kg. 

Finally, the authors refer to a phase 3 trial in Dengue infection in Thailand, which “resulted in a significant reduction in serum levels of viral NS1 protein, but no change in viremia or clinical benefit was observed”. Unfortunately, I could not have access to this paper that was published in a local journal.  Since there is apparently no way to get access to this journal, we cannot know what dose they used.

In summary: According to my preliminary literature search, Ivermectin has a clear-cut in vitro effect against SARS-CoV-2 and several other viruses in vitro at µM concentrations. To obtain that concentration in vivo, a dosage of about 20 mg/kg would need to be given to patients (100-fold more than the antiparasitic dose). It is unclear whether that can be safely done. 

Best wishes,