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HOW DOES PFIZER'S PAXLOVID COMPARE WITH IVERMECTIN?

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RELATED ARTICLES

Round 4: Pfizer's Paxlovid Is Approved. Will It Knock Out Covid?
Pfizer's COVID Drug Works Wonders. Here's How it Works.
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You're a Mouse
By Josh Bloom — December 2, 2021

A new rumor claims that Paxlovid, Pfizer's Covid drug, is merely a "dressed up"
ivermectin molecule with little difference other than price. The term
"Pfizermectin" is even being used to emphasize this. But biochemical and
pharmacokinetic data say otherwise. Here are the numbers.



Recent rumors speculate that ivermectin and Pfizer's promising experimental
Covid drug PF-07321332 (1) are both inhibitors of the viral main protease (Mpro)
(2) and can therefore be used interchangeably to treat Covid infections. It's
gotten so silly that a new term has been invented – "Pfizermectin," implying
that Pfizer's Paxlovid is little more than an expensive, big-pharma ripoff of
ivermectin. This rumor really has legs, so let's examine whether there is
anything to it. Are ivermectin and PF-07321332, more commonly known as
Paxlovid the same? Similar? (Note: The active component of Paxlovid
is PF-07321332; another drug called ritonavir is added to prolong its
half-life.) No, they are not.

To be able to compare ivermectin and PF-07321332 we need to look at
two pharmacological measurements. One is the IC50– the half-maximal inhibitory
concentration, which is the concentration at which either a biological process
(such as viral replication), or enzymatic reaction within a cell, is inhibited
by half. The other is Cmax – a measure of the highest attainable blood levels of
a drug after it is administered. They are intimately connected.

IC50 is sometimes called the EC50 (effective concentration 50%). They are
similar, but not identical. (3). When IC50 /EC50 values are high it means that
more drug will be required to inhibit the process in question (a low
potency drug). Conversely, when the IC50 is low it means that the drug is more
potent and less drug will be needed. Good drugs generally have low IC50 values.
It's one of the most important parameters in antiviral drug discovery –
something I did for 10 years.

Below is a table which can be used as a rough, descriptive guide of a range of
potencies and the probability of whether a compound of a given potency has a
reasonable chance of being "strong" enough to be a useful drug. Values are
approximate:



Table 1: The approximate IC50 values vs. Mpro of ivermectin (red arrow) and
PF-07321332  (green arrow) are shown.              

Ivermectin vs, PF-07321332 as inhibitors of the Mpro enzyme?

 * Ivermectin

Taval et. al. studied a group of chymotrypsin-like compounds as potential
inhibitors of Mpro. The group reported in the journal Communications Biology
that:

> "ivermectin was able to inhibit more than 85% (almost completely) of 3CLpro
> (another name for Mpro) activity in our in vitro enzymatic assay..."

While this may sound impressive to the uninitiated, it is not. This is because
in order to attain 85% inhibition of the Mpro enzyme a concentration of 50 µM
(micromolar) of ivermectin was required – an absurdly high number for a
potential drug. There are probably hundreds, if not thousands, of chemicals in
the world that will inhibit Mpro (and plenty of other enzymes) at this
concentration.

>  "...with an IC50 value of 21 µM"

A value this high is normally the kiss of death for a drug. Table 1 shows just
this. Inhibitors with IC50 values in this range are just not potent enough to be
useful drugs.

 * PF-07321332

Although Owen et.al. did not indicate the IC50 of PF-07321332 against Mpro in
their recent Science paper, the authors did report a binding constant (Ki) of
3.1 nM. There is a difference between the two and I'm BEGGING you not to ask me
to explain it. Suffice it to say that it has been estimated that for most
inhibitors, the IC50 is twice the Ki, making it something like 6 nM,
making PF-0732133 3,500-fold more potent than ivermectin in this assay. From
these values it can be concluded that PF-07321332 is a potent inhibitor
of Mpro while ivermectin barely inhibits the enzyme at all. Whatever antiviral
properties ivermectin may have cannot be a result of its inhibition of Mpro.

Ivermectin vs. PF-07321332 as inhibitors of viral replication in cultured cells

Cell-based (in vitro) assays are critical in developing antiviral (and other)
drugs because they demonstrate whether the drug in question can pass through a
cell membrane, perform its specified function, and inhibit the replication of
virus within the cell. The primary drawback of cell-based assays is they tell us
nothing about how the drug works (what the molecular target is). For example,
Merck's molnupiravir will inhibit the growth of SARS-CoV-2 in cells but will
show no activity in the Mpro assay because it operates by inhibiting a different
viral target.

 * Ivermectin (IVM)

Caly and colleagues reported that in a cell-based assay, ivermectin inhibited
viral replication (as measured by the production of viral RNA) with an IC50 of
~2 µM, quite a high concentration. Can this concentration be achieved in blood
following administration of a safe dose of the drug? A paper by Schmith and
colleagues titled "The Approved Dose of Ivermectin Alone is not the Ideal Dose
for the Treatment of COVID-19" (4) concluded no – it cannot. Some highlights
include:

At the approved ivermectin dose (200 micrograms per kilogram of body weight)
–12 mg for a 60 kilogram human – the maximum concentration (Cmax) of IVM in the
blood was 47 nanograms/mL. When compared to the IC50 of IVM (2 µM, 1,750 ng/mL)
the Cmax is far lower than the IC50 (by 35-fold). In other words, there is not
nearly enough drug in the blood to inhibit half of the viral replication.

Neither higher doses – 120 mg IVM (10X the recommended dose) nor multiple doses
of 60 mg provided a substantial increase in the Cmax. It is safe to conclude
that IVM is not potent enough to provide a concentration in blood that even
approaches the drug's antiviral IC50 value, so whatever effect IVM on may be
having on Covid it is not because of its antiviral properties.

 * PF-07321332

We see a very different profile for Pfizer's drug (Figure 1) 



Figure 1. A single dose of PF-07321332 (250 mg plus ritonavir, pink line)
provides blood levels at or above the drug's EC90 (black hatch line) – the
concentration of the drug that inhibits 90% of replication — a much more
stringent measurement of viral inhibition – for 24 hours (yellow arrow) while
remaining far below the no-observed-adverse-effect level (NOAEL, blue dotted
line) – the blood level at which no drug-related side effects are observed. This
is the type of profile expected of a antiviral drug. 

Source: Science

Bottom line

 * It is abundantly clear that the "Pfizermectin" myth is just that. PF-07321332
   is a potent enzymatic inhibitor of Mpro with proven efficacy in clinical
   trials. Ivermectin has very poor potency in this same assay. Ivermectin, if
   it works at all, is certainly not functioning as a protease inhibitor.
 * Based on in vitro studies, Ivermectin is a weak inhibitor of viral
   replication in cultured cells.
 * But the antiviral inhibition of ivermectin is weak enough that even at high
   or multiple doses of the drug blood concentrations do not reach its cellular
   assay IC50 of 2µM. 
 * PF-07321332 is a potent inhibitor in both the enzymatic and call-based
   assays.
 * The drug reaches and remains at blood concentrations sufficient to inhibit
   90% of viral replication in cells for one day and does so well below toxic
   levels.

These data tell us that ivermectin neither inhibits the viral protease in an
enzyme-based assay nor slows the production of virus in cells while Pfizer's
drug does both. If ivermectin is proven to be an effective Covid treatment
it must be acting by some yet-unknown mechanism. 

NOTES:

(1) PF-07321332 is sometimes used interchangeably with Paxlovid, the trade name
of the drug. This is mostly accurate but not entirely. Paxlovid contains the
active ingredient PF-07321332 in combination with a small amount of a second
drug called ritonavir, which improves the blood levels of PF-07321332 by
inhibiting the enzyme that metabolizes it. 

(2) For more information on Mpro see Pfizer's COVID Drug Works Wonders. Here's
How It Works.

(3) There is a very similar parameter used to measure inhibition called an EC50,
which stands for effective concentration rather than inhibitory concentration.
They are often used interchangeably. Let's play "don't ask, don't tell." You
don't ask and I won't tell.

(4) Clinical Pharmacology & Therapeutics,  Volume 108 #4, October
2020. doi:10.1002/cpt.1889

 

Tags: 
Ivermectin
Paxlovid
PF-07321332
enzyme inhibition
cell-based assays
drug potency

 * 

By Josh Bloom



Director of Chemical and Pharmaceutical Science

Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from
the world of drug discovery, where he did research for more than 20 years. He
holds a Ph.D. in chemistry.



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