The high binding rate only suggests a high activity of Ivermectin.
I don't believe that is the case. Most drugs and supplements, as well as endogenous substances, bind to proteins in the blood plasma to some degree. My understanding is that protein binding is a means of transport for some substances, especially if they have low solubility in the blood plasma.
The degree of plasma protein binding can be as low as 0%, or as high as 99% or more, depending on the drug or supplement. Most acidic drugs binds to the albumin protein in the blood; whereas basic drugs bind to alpha1-acid glycoprotein. Ref: here
Drugs and supplements can also bind to proteins in the tissues, I understand, but I am not clear on which proteins they bind to.
It can be very annoying for drug developers when substances have high plasma protein binding, as if a substance has say 99% binding, it means its effective free concentration in the blood is 100 times lower. So in these cases, the in vitro benefits of a substance may be lost in the body due to high protein binding, and the 100-fold reduction in effective concentration.
One antifungal drug called itraconazole is a potent antiviral for enterovirus in vitro (I have enterovirus-associated ME/CFS), and I was hoping to use it; but it turns out that itraconazole has 98.2% plasma protein binding, so its antiviral effects in vivo are greatly reduced.
Your calculation is based on a very simplified idea of drug delivery. Arshad et al. used a Rodgers and Rowland model and determined that, in lung tissue, Ivermectin's recommended oral dose attains over an order of magnitude greater concentration than the reported IC50 (10.1002/cpt.1909
It is certainly true that some drugs can have unusual tissue-accumulation effects which make simplified calculations invalid. I was looking at fluoxetine pharmacokinetics a few years while ago (it is antiviral for coxsackievirus B in vitro), and from what I could work out, the free levels of fluoxetine in the brain are about 400 times higher than free levels in the blood.
This means that fluoxetine may have useful antiviral effects in the brain, even though its antiviral effects in the blood and interstitial fluids are negligible. There are some case studies where fluoxetine has helped with coxsackievirus B encephalitis.
Unfortunately fluoxetine does not seem to help ME/CFS, even though there is evidence of enterovirus infection in ME/CFS brain autopsies. Though the chronic non-cytolytic
coxsackievirus B infections found in ME/CFS are not the same as acute lytic coxsackievirus B infections, so maybe this explains the failure. Dr John Chia experimented with fluoxetine for enterovirus-associated ME/CFS some years ago, but I did not hear of any positive results.
I had to learn a little bit about pharmacokinetics, as I spent many months looking at the pharmacokinetics of off-label drugs and supplements which were shown in vitro to be antiviral for the herpesviruses and enteroviruses found in ME/CFS (here
is my list of enterovirus antiviral compounds), in the hope of finding some compounds which might be useful as an antiviral treatment in ME/CFS.
Unfortunately I did not find many useful compounds, with the possible exception of very high dose genistein being effective for cytomegalovirus. Though I was only able to use simple pharmacokinetic models, like the one I outlined above for ivermectin.
I like the paper
you linked to; it explains the problem with all these in vitro coronavirus studies — that not enough effort has been made to examine the pharmacokinetics, to see if these antivirals might stand a chance of working in vivo against coronavirus:
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans.
Of the identified molecules with reported anti‐SARS‐CoV‐2 activity, the overwhelming majority are not expected to reach active concentrations within the key target compartments. However, a number of candidates were identified that are expected to exceed the concentrations necessary to provide viral suppression at doses approved for use in humans.
This paper says that using a model developed by Rodgers and Rowland, it predicts that ivermectin will reach concentrations in the lungs which are over 10-fold higher than its EC50. At this level, ivermectin may provide some modest antiviral effects (to get strong antiviral effects, you usually need to exceed the EC50 by about 50-fold, as most commercial antivirals drugs do).
However, I would like to know more about the Rodgers and Rowland model.
The ivermectin IC50 in this study
is 2 μM. Given that the blood concentration of free ivermectin are over 30000 times lower than this IC50, it is quite extraordinary that the Rodgers and Rowland model claims ivermectin can concentrate in the lungs to a level of over 10 times higher than the EC50 (see figure 4 of your paper
). That is a difference of nearly 6 orders of magnitude.
I'd like to understand how the lungs are able to concentrate free ivermectin at levels which are one million times higher than you find in the blood. Would you have any insight into this?
By the way, I am not clear on the difference between EC50 and IC50 in the context of in vitro viral testing. Do you know why some in vitro antiviral studies quote EC50 and others quote IC50 figures?
I understand what the EC50 is: the concentration which reduces viral replications by 50% in a cell line. Or sometimes it means the concentration which reduces cytopathic effects in the cell line by 50%.
Even if you inhibit viral replication, you still need a response from the host. SARS-CoV-2 has many subpathologies, including immune suppression, which, unless tackled, relativize the IC50.
Indeed. One theory I have for why ivermectin may be effective for COVID is because thus drug stimulates the production of antibodies (in mice), via a mechanism involving T-cells. Ref: here
Now one provisional study
suggests coronavirus may induce autoantibodies which actually attack the B-cells and T-cells of the immune system (B-cells are responsible for creating antibodies), and some speculate this attack could explain why the immune system struggles to control coronavirus.
So maybe ivermectin's stimulation of antibody production is helpful in COVID to overcome this autoimmune attack on the immune system.
You don't need to know which of the many mechanisms of action contribute to which degree in Ivermectin's efficacy when all the studies clearly show that Ivermectin works in the prophylaxis and treatment of COVID-19.
If there is good empirical evidence for efficacy, you should not need to understand the mechanisms in order to employ the treatment. But I think scientists are usually more convinced if they know how a drug is working.