The approved dose of ivermectin alone not useful in treating COVID-19

A new paper published on the preprint server medRxiv in April 2020 shows that the use of the already approved drug ivermectin in clinical trials to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not feasible. This contradicts earlier reports of its ability to suppress the virus in vitro.

An earlier research article published in the journal Antiviral Research claimed that ivermectin in vitro had an inhibitory action on the novel coronavirus, reducing the load of viral RNA by 5,000 times at 48 hours. The ivermectin dose used in this study was 5 μM.

Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Plasma concentration of ivermectin

The in vitro study used ivermectin at a concentration that inhibits 50% of proliferating viruses (IC50). This concentration of 2 μM is 35 times higher than the maximum plasma concentration achieved in blood on oral administration of ivermectin at the approved dose of approximately 200 μg/kg. And this refers to the total plasma concentration.

Ivermectin is bound extensively by plasma protein, to the tune of 93%, which means that the maximum concentration of unbound ivermectin in the plasma is several orders of magnitude less.

When oral ivermectin is administered in humans, it reaches the lungs in unbound form, and the final concentration also depends on the presence of specific transport proteins that can keep the drug in the lung tissue, as well as how rapidly it binds to and crosses the fatty cell membrane of the cell.

Unrealistic dosing

The actual concentration in the human lung cannot be measured. In cattle experiments, a single dose was shown to produce lung levels almost three times higher than the total plasma level. Despite this, lung ivermectin concentrations are “unlikely to reach the IC50 after oral administration of the approved dose in humans,” say the researchers.

Ivermectin has a wider therapeutic margin, allowing some increase in the dose if warranted, without unduly pushing up the risk of toxicity. This has led to the evaluation of higher than usual doses of ivermectin in a phase 3 trial to assess the safety. Another phase I trial looked at doses, 10-fold the approved dose.

The results showed the drug was tolerated with the ten-fold dosing regime as well as at 60 mg three times a week.

How was the study done?

The current study was aimed at analyzing the human dose necessary to achieve the experimental IC50 in the lungs. This is crucial to planning a clinical trial.

The researchers used a population model to study the pharmacokinetics of the drug. This included the transit absorption, drug elimination, and weight of the patient. The model was based on healthy participants who took 12 mg ivermectin orally after food.

A hundred simulations of total and bound ivermectin were performed to track the total plasma concentration-time profile. Different doses were used, such as the approved dose of 200 μg/kg, 120 mg in a single weekly dose, and 60 mg three times a week (at 72-hour intervals, in healthy subjects).

These additional simulations were carried out because of the observation that after a subcutaneous dose, ivermectin levels remained stable in cattle lungs for eight days. They then declined slowly over 30 days.

The concentration-time graph for unbound plasma ivermectin was also predicted from the data. Maximum total plasma concentrations were derived.

What did the results show?

The researchers found that the plasma concentrations, whether of total, bound, or unbound ivermectin did not reach the IC50 even with a tenfold rise in the dosage or after repeated dosing. The lung concentration in cattle is 2.7 times higher than in plasma, but even so, lung concentrations fall short of the IC50 of 2 μM.

To reach this level, ivermectin would need to accumulate in the lungs more than 25 times the calculated rate at the approved weekly dose. For the weekly 120 mg dose, it would need to build up over 2.5 times. With the 72-hourly dosing of 60 mg, it would have to rise to 5 times the observed level.

The estimated accumulation ratio in the lung tissue is 2.20, which results in lung concentrations reaching only a tenth of the IC50 at the approved dose given three times a week. Even with daily dosing at approved doses, it rises to only a fourth of the IC50

What are the implications of the study?

The current approach to finding a viable therapy for the SARS-CoV-2 is to repurpose existing drugs. All over the world, ivermectin came into widespread use of off-label in response to the news of the in vitro success against the virus.

At a dose of 150 μg/kg, observation of 52 patients on mechanical ventilation appeared to show clinical benefit with the drug in contrast to over 1,900 patients on conventional treatment. Though these results need to be analyzed to rule out confounding factors and biases, on the surface, they would seem to suggest that very low lung concentrations of ivermectin are able to inhibit the virus.

In other words, even when the ivermectin concentration is not anywhere near the IC50, it appears to have antiviral activity. This could suggest that the lung distribution or accumulation of this drug is far greater in humans than in cattle.

In contrast, the concentrations of ivermectin reported inhibiting the coronavirus in vitro were markedly higher than those achieved in human lung or plasma with the approved doses of ivermectin. As a result, say the researchers, “the likelihood of a successful clinical trial using the approved dose of ivermectin is low.”

This should be a warning to conduct in vitro studies of repurposed drugs at concentrations that are safe and tolerable in humans.

Future recommendations

The researchers advise a dose-response study using a control group, as well as testing the possibility of inhaled ivermectin and combination therapy.

The dose-response study should begin with the addition of potentiating compounds to reduce the threshold of viral inhibition to the tune of 0.1 μM rather than the 5 μM of the original experiment. Close monitoring is required since these dosage levels and protocols have not been widely studied.

Inhaled ivermectin would allow for higher dosage and increased local lung concentrations without additional systemic exposure. However, preclinical studies of its safety and tolerability are required.

The study sums up: “Ivermectin is unlikely to reach the IC50 in lungs after oral administration of the approved dose or doses 10x higher than the approved doses as a single dose. The approved dose of ivermectin alone has a low probability of success in the treatment of COVID-19.”

Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


It has come to our attention that the original title of this article, "Ivermectin alone not useful in treating COVID-19" was inadvertently misleading. The title has been corrected to better reflect the research paper's title, "The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19".

Journal references:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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  1. Alex Buckwheat Alex Buckwheat United States says:

    Usefulness of Ivermectin in COVID-19 Illness -

  2. Justin McCarthy Justin McCarthy United States says:

    Well, here's the obvious statement: Just because you can't reach IC50 safely in humans doesn't mean it isn't effective to any degree. There's lots of anecdotal evidence that it IS effective at a lesser concentration. Your article title is misleading.

  3. Brad Richards Brad Richards Thailand says:

    Here we have another article trying to pre-emptively dismiss a cheap and possibly effective treatment.  Sorry, a clinical trial showing significant success has already been done.  Refer to the link provided by the earlier commenter.

    The paragraph beginning "in contrast" simply dismisses successful in vivo results and refers back to the pointless in vitro experiment meant to challenge an earlier in vitro experiment.  The researchers obviously were blindsided by an actual successful in vivo trial, yet try to re-assert some relevance to their meaningless in vitro work and simulated concentrations.

    The article is useless and outdated, biased and dismissive against ivermectin.

  4. Boingy Rasputin Boingy Rasputin Thailand says:

    Yes, it could be that ivermectin works in the blood vessels, which are also affected.  The article states much of the ivermectin is "plasma bound", it could possibly be helping there, who knows?  Their assumptions about concentrations in the lung seem baseless.

  5. Justin McCarthy Justin McCarthy United States says:

    Well,the article is ridiculous.Author says that just because safe ivermectin levels cannot be stretched to levels of IC50 in humans, as the AU in vitro study did,then it follows that "Ivermectin alone not useful in treating COVID-19". The subject and title should be about the practical uselessness to humans of the AU study findings rather than stating that ivermectin itself is useless against covid. Idk, am i not understanding her assertions peoperly, because it sounds like faulty logic to me.

  6. Luke DP Luke DP United Kingdom says:

    I wouldn't say it's ridiculous- it's certainly outlandish to make conclusions, but the inability to reach the in vitro IC50 is not an insignificant finding and emphasizes the need for researched alternative methods of delivery.
    Because the mechanism is most likely inhibition of the Importin alpha beta 1 dimer which is involved in the entry of Sars-Cov-2, it is hard to see how bound ivermectin could be significantly beneficial
    The data on pulmonary accumulation is from the study she cited
    It seemed like she also acknowledged that a lower dose than the IC50 could still have a beneficial antiviral effect, but rightfully called for caution before pinning hopes on it as a panacea.
    I agree that the title is sensationalistic at best.

  7. S J S J United States says:

    The title of this article is completely misleading. This person should have their MD taken away for incompetence. The lab data indicates that the concentrations used in the initial in vitro studies will probably not be achievable in humans. However, this does not rule out the potential for clinical benefit and in fact initial clinical data at several centers indicate that drug may be useful. This person is incompetent.

    • Boingy Rasputin Boingy Rasputin Thailand says:

      They added "The approved dose of" to the title, but still the article refers to, then ignores an actual clinical study of ivermectin used in real live human patients, trying to salvage some relevance for the in vitro study the article is about.  A dose of 150mcg/kg of body weight showed significant benefit even in intubated patients.

  8. James Smeltzer James Smeltzer United States says:

    The 120 mg oral dose, already shown to be benign in healthy persons (slightly more than I use to worm a horse and well-tolerated in horses and humans, as are the analogs used to kill fleas on cats - usually more sensitive creatures), with the molecular weight of 875 is almost 2 micromoles per kilogram in a standard 70 kg man. If it is well-absorbed as the analogs are from the skin of my cat, it should have a plasma concentration of over 2 micromolar (the IC50 dose). If it is further concentrated in the lungs, as it is in cattle to about 2.5 times, the lung dose will, in fact, be 5 micromolar. If this persists, as it does in cattle, then a single 120 mg dose will maintain IC 90 in the human lung.
    So at least a Phase 2 trial of the 120 mg dose is warranted. If GI perfusion or absorbtion is a problem, a topical dose can be tried.  The misleading title is STILL misleading. Ivermectin has a very safe therapeutic index. Based on the linearity seen in other Phase 1 research, the concentration in the lungs may be about 2uM (the IC50) with a 120 mg oral dose.

    • Larry Simmons Larry Simmons United States says:

      Agree James....I'm not a Dr. or Vet, but have some chemistry/biology background, and have used this product on my animals for years....saw the "bias" in the title before reading their "correction" or the other comments below the article.  This report was very biased and misleading.  What I got out of it was a positive and promising discovery that needs to be expanded on.  I know some doctors in LA and TX who are already treating patients with Ivermectin with good results....some are the same ones who used the HCQ/Azithromycin/Zinc/Budesonide by nebulizer/aspirin/and vitamins C,D-3, etc....with great success....they didn't lose a single patient, had none hospitalized (that sought medical treatment early enough).  Just need to keep politics separated from saving human lives.  I agree with most everything that has been posted here, so enough said on that....but I didn't see anyone comment on the suggestion under "future recommendations" concerning the "inhalable ivermectin" far as I know that doesn't exist at this time, but sounds like it might be a good idea.  Getting almost any steroid (but especially Budesonide) deep into the lungs as early as possible has been one of the most beneficial parts of any treatment well as any med that would prevent pneumonia, and inhibit inflammation, mucus production, infection, etc....your thoughts?

  9. Lee Read Lee Read United States says:

    It's more than obvious that as far as the US is concerned no one in the democratic party wants any drug to work until after the election. Period..

  10. DrSunil Jadhav DrSunil Jadhav India says:

    Tiered of searching doses of Ivermectin.
    can any body tell Prophylaxis dose schedule and actual tratment dose  schedule?

  11. Janine Coetzer Janine Coetzer South Africa says:

    can diabetic person use ivermactin

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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