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The use of ivermectin has been applied to treat and prophylaxis of COVID-19. However, some areas are uncertain, for example, the effective dose range, the dosing interval, the safety profile in special populations, the in vitro study effective dose vs. the in vivo therapeutic dose. The risk factors of ivermectin neurological toxicities include co-infection of CNS, high inflammatory status, stressors, drug-drug interactions, and genetic variants of two metabolic/ transporter genes, CYP p450 3A4 enzyme and p-glycoprotein (MDR-1). To avoid adverse effects, the clinician should take the unique individual characteristics, such as body weight, fat composition, nutrition status, and liver functions. Finally, the author compared the ivermectin and COVID-19 vaccines' safety profile.
Myths of Ivermectin Treatment on Covid-19
By Susan Chen, RPh, PharmD, MS, BCGP
Medication Therapy Management Inc. PC.
1. "Ivermectin" is for animals or humans?
Ivermectin has been used to kill parasites of humans for over 30 years, and around 3.7
billion doses have been distributed to humans for parasites infections (1. Yagisawa M et al.).
2. "The effective concentration of Ivermectin against SARS-CoV-2 in an in vitro
experiment by Caly et al. is as high as 2 µM; in clinical practice, it is necessary to
administer tens of times the normal dose to obtain such a blood concentration. Therefore,
there are opinions from the IDSA and others that the therapeutic effect of COVID-19
cannot be expected by the administration of the normal dose of Ivermectin. However, in
actual medical practice, there are many study reports demonstrating that the
administration of a normal dose does indeed show a clinical response. As of 27 Feb
2021, the results of 42 clinical studies worldwide have undergone meta-analysis and
concluded101) that Ivermectin is effective in the treatment and prevention
of Mazzotti COVID-19. In the UK, a consensus-based recommendation by 75 healthcare
professionals from 17 countries around the world has been carried out and submitted to
the WHO to further encourage the issuance of guidelines for the use of Ivermectin in the
treatment and prevention of COVID-19. We must consider why such a discrepancy is
2021" (1.Yagisawa M et al.).
Ivermectin is a high lipid-soluble chemical. It is also highly protein-bound (>90%), e.g.,
albumin and globulin. Based on its high hydrophobic characters, high "volume
distribution" is expected. It can distribute wildly to different human organs, such as the
liver, skin, fat tissue, and more. In the study of Caly et al., need 2 µM ivermectin
concentration in vitro to inhibit Sars-Cov-2 viral gene replication (IC50); but in actual
clinical practice, if apply 2 µM concentration, the daily dose of ivermectin will be much
higher than the current FDA approved anthelmintic doses (150-200µg/kg).
1 mole of ivermectin= 872 gram. 1molar concentration =872g ivermectin in 1L solution.
1 µM of ivermectin is 1 µmole =872g x10-6=872 µg in one L solution.
2 µM =1,744 µg Ivermectin in one liter of solution.
The regular dose of Covid-19 used in trials is 150-400 µg/kg each day. If we
apply 200 µg/kg and the total dose to a 70 kg adult will be 14000 µg=14 mg daily,
Volume distribution (Vd) of ivermectin is 3.1-3.5 L/kg in healthy volunteers and 6.9-15.3
L/kg in patients with onchocerciasis (a parasite infection). Presumably, the Covid-19
patient does not have onchocerciasis), and Vd is 3.5 L/kg. So, presume the total Vd is 245
L in this 70 kg patient. Then, concentration of ivermectin is 14mg/245 L=0.000016
mole/245 L= 0.07 µM. Estimating the steady-state dose of ivermectin would be from 0.07
to 0.14 µM. As a result, in vitro 2 µM is 28.6-14.3 times of the commonly used in vivo
concentration claimed can inhibit Covid-19 viral replication.
Why can such low concentrations (0.07µM) in vivo suppress viral virulence? Does this
low concentration enough to stop Covid-19 in vivo?
First of all, let us take a look at the process of Sar-Cov-2 virulence:
1. Enter into a cell.
2. Accelerate the inflammatory reaction by elevating pro-inflammatory cytokines,
such as IL-6 and TNF-alfa.
3. Viral proteins enter the nucleus of the human cell.
4. Transcript/replicate viral RNA.
5. Translate viral protein.
The mechanism of ivermectin reviewed by Zaidi et al. has demonstrated that ivermectin
can suppress Sars-Cov-2 virulence by all the steps listed above (2.Zaidi, A.K).
Secondly, let us look at how in vitro viral suppression tests were done by Caly et al. (3).
They assessed the inhibition of replication of Sars-Cov-2genes: Gene E (the gene
encoding envelope protein) and RNA-dependent RNA polymerase (RdRp). The viral
replicated RNA was quantified from 28 cycles (cycle threshold, CT=28) PCR 48 hours
after the Sars-Cov-2 virus inoculation. Then the amplified viral genetic materials were
used in the IC50 tests as the control. And different concentrations of Ivermectin were
applied to detect the 50% inhibitory concentration of viral gene replication. Since the
100% control viral RNAs were obtained from PCR amplification instead of direct
detection of viral RNA (antigen tests), this IC50 experiment does not reflect the real viral
replication in vitro. Ivermectin blocks the early stages of the viral virulence and leaves
trace amount virion to their later stage for virulence progression, such as viral RdRp gene
replication; as a result, ivermectin will make viral gene replication less detectable (and
that is why apply PCR Ct=28 to detect). According to the study of Platten et al., 2021, the
Ct-value equal to 24-28 missed up antigen tests for 64.2-52.6% of Sars-Cov-2 infections
that tested positive by PCR. In other words, there is above 50% chance of false positives
if PCR Ct >24. And Ct <22 is the limitation to have 100% correlation between antigen
tests and PCR tests (4).
Thirdly, many clinical studies, including meta-analysis and real-life mass population
clinical outcomes, demonstrated that the dose range of 150-400µg/kg daily effectively
controls symptoms and reduces the virulence of Sars-Cov-2 (5,6). It seems this FDA-
approved anthelmintic dose of ivermectin (150-400 µg/kg daily 1-5 days) produces in
vivo concentration 0.07-0.14 µM is sufficient to control Covid-19 symptoms and
deterioration. De Melo et al. 2020 anti-Covid-19 study confirmed that ivermectin efficacy
is to reduce the inflammatory status and less to viral gene replication (7).
Because that in vitro study by Caly et al. could not compare the production of IL-6 or
TNF-α from macrophages or monocytes before and after the ivermectin treatment, it is
unfeasible to detect the anti-inflammatory effects of ivermectin in vitro.
In summary, despite the in vitro high concentration was needed to stop viral gene
replication at the IC50 tests, clinical practice should not require that high concentration
(e.g., 2µM), and the regular FDA-approved anthelmintic (150-400 µg/kg) daily dose
should be sufficient to control Covid-19 virulence.
3. Does ivermectin present in CSF? Yes, in the animal study
As we look back the case study cited by González et al. (8) that ivermectin was not found
in CSF by Marty et al. 2005 (9). This case study reported that a patient who treated with
ivermectin for disseminated stronglyoidasis. This patient had comorbidity of severe
hypoalbuminemia, severe mal-absorption, and paralytic ileus (9). "Ivermectin was not
detected in the cerebrospinal fluid……, after five subcutaneous ivermectin dose when
serum level was 12 ng/ml (=1.2 mcg/dl)" written in the review article of González et al.
2008. However, as the author read the Marty FM et al. original paper, it neither stated if
they detected ivermectin in the CSF nor if they did not detect ivermectin in the CSF. The
study detected ivermectin level only in the "plasma" level.
Ivermectin exists in CSF is proved in an animal study by Schinkel et al., 1994 (10). The
p-glycoprotein knockout mice study indicates that without p-glycoprotein efflux out
ivermectin, it can reach 90 fold of average ivermectin level of the brain. This p-
glycoprotein knockout mice study indirectly indicates that ivermectin can pass through
BBB by passive diffusion or another transporter (e.g., BCRP or ABCG-2 breast cancer
resistance protein?)(11) route and the BBB's p-glycoprotein are essential in removing
ivermectin from the brain.
4. The role of p-glycoprotein in ivermectin toxicity
The review article by Chandler et al., 2017 has reviewed severe neurological adverse
event cases due to ivermectin (12). Although most of them (25 out of 28) recovered from
headaches or unconsciousness, 3 out of 28 severe cases caused death.
The previous study of the p-glycoprotein binding drug can be efflux out by the p-
glycoprotein located on the capillary endothelium cells of the Blood-Brain-Barrier (13).
Ivermectin is the chemical will bind to p-glycoprotein. Same mechanism ivermectin can
be efflux out from the enterocytes and hepatocytes (11). As a result, because of p-
glycoprotein, ivermectin can be removed from CNS, liver, and GI tract.
Further study the inactivation of MRD-1 gene expressions, factors such as stressors,
inflammation (peripheral and CNS), co-infection of CNS (e.g., Loa Loa infection), and
drug interactions can facilitate the ivermectin neurotoxicity secondary to block p-
glycoprotein efflux ability (14).
5. What drug interactions will cause ivermectin toxicity?
Under the presumption that ivermectin can passively diffuse or active transport through
the cell membrane, p-glycoprotein plays an essential role in regulating the ivermectin
level in CNS. As a result, taking ivermectin with inhibitors of p-glycoproteins will
accumulate more ivermectin in the CNS (15), GI tract, and liver. Ivermectin is also a
weak substrate of the major drug metabolic enzyme in the liver, the CYP p450 3A4
enzyme, which metabolizes over half of medications. Similar to p-glycoprotein
inhibitors, drugs that are strong inhibitors of the CYP p450 3A4 enzyme can increase
ivermectin neurotoxicity as well. Symptoms of ivermectin neurotoxicity are tremor,
ataxia, sweating, lethargy, coma, and even death (16). In other words, patients who take
p-glycoprotein inhibitor (s) or CYP p450 3A4 enzyme inhibitors together with ivermectin
can increase toxicity. Examples of p-glycoprotein inhibitors or cytochrome enzyme 3A4
inhibitors are amiodarone, carvedilol, clarithromycin, cyclosporine, erythromycin,
itraconazole, ketoconazole, quinidine, ritonavir, tamoxifen, verapamil, and more.
Antiviral (e.g., protease inhibitors, atazanavir, darunavir, indinavir, ritonavir etc.) are
strong inhibitors of CYP p450 3A4 enzyme can increase ivermectin neurotoxicity as
well. Drugs with GABA potentiating activity (e.g., barbiturates, benzodiazepines, sodium
oxybate, or valproic acid) taken together with ivermectin is not recommended. Ivermectin
in persons who have chronic warfarin (vitamin K antagonist) might cause hypo-
coagulation status (16).
6. Is Ivermectin safe at a high dose?
Based on the study of Guzzo et al., 2002, high-single dose ivermectin reach up to 120 mg
single dose or 60 mg three times per week has minimum neurotoxicity. Limited toxic
events, even ten times of FDA-approved 200 µg/kg, were reported (17). However, the
author suggests that clinicians consider the accumulative dose of ivermectin due to its
potential accumulation in liver and fat tissues (18). Liver damage and extended
elimination duration of ivermectin (e.g., it takes an average of 12 days to eliminate
ivermectin, half-life from 12 hours to 54 hours) should correlate with its highly lipophilic
character and liver-produced active metabolites (e.g., active metabolites have four times
half-life of the parent drug) (18). Clinicians should consider the risk factors mentioned in
sections 5 and 6 when they consider using high-dose ivermectin with caution.
7. Is Ivermectin the wonder drug that does not have a safety issue? What is the safety
profile up to date?
Ivermectin is the same as other drugs that have side effects and adverse effects. The
safety reported from 1996 to 2021 worldwide has severe cases 2,349 and 379 death cases
in the FDA Adverse Event Reporting System (FAERS) (data collected at
10/03/2021)(Figure 1). Within the 2,349 total severe cases, the most frequently reported
severe neuro adverse events is asthenia (weakness) 719 cases, headache 675 cases,
pyrexia (high fever) 681 cases, pruritus (itch) 362 cases, conjunctival hemorrhage 324,
Coma 322, ocular hyperemia (redness of eyes) 266 cases, and vertigo (inbalance) 265
cases (Figure 2). The author would like the clinicians to take into consideration of the
patients' status drug interactions (e.g., concurrent medications that are inhibitors of
p-glycoprotein and CYPp450 3A4 enzyme), inflammation (peripheral and CNS),
stressors (diseases, chemical use, or emotional stress), genetic variant polymorphism
of p-glycoprotein and CYPp450 3A4 enzyme, and possible CNS co-infections.
Figure 1. The safety reported from 1996 to 2021 worldwide has severe cases 2,349 and 379 death cases in
the FDA Adverse Event Reporting System (FAERS).
Figure 2. Within the 2,349 total severe cases, the most frequently reported severe neuro adverse events is
asthenia (weakness) 719 cases, headache 675 cases, pyrexia (high fever) 681 cases, pruritus (itch) 362
cases, conjunctival hemorrhage 324, Coma 322, ocular hyperemia (redness of eyes) 266 cases, and vertigo
(inbalance) 265 cases.
And if you compare the Covid-19 vaccine caused deaths according to VAERS (Vaccines
Adverse Events Reporting System) were 8,986 since the beginning of vaccination up to
11/26/2021. Data can be reviewed at, click
the disclaimer-"I Agree" and click "VERSA data search." The search criteria are VAERS
ID, all Covid-19 vaccines, symptom: death, regions: all US territory/unknown regions. In
addition, many reports from newspapers and media, there are thousands of casualties
since started to have the vaccine up to November 28, 2021 (19). The total deaths of less
than one year caused by the Covid-19 vaccines (8,986) are far more than the total death
cases of 26-years (1996-2021) ivermectin (379). And we do not even compare the severe
adverse reactions caused by Covid-19 vaccines vs. ivermectin.
8. Is ivermectin safe for severe Covid-19 patients?
Pieces of evidence from other researches have found Sars-Cov-2 virus infects CNS as
Covid-19 progressed (20, 21). Almost all effective Covid-19 medications reported show
extraordinarily high lipophilic characters; examples are hydroxychloroquine,
lopinavir/ritonavir, and ivermectin; and lipophilic character is the most significant
character to predicate BBB permeable. Most meta-analysis data indicating the early-stage
or prophylaxis ivermectin usages demonstrate better outcomes than in the later stage of
Covid-19 (22). The author interprets that the treatment of the later stage Covid-19 will
need to consider the potential Sars-Cov-2 infection progressing into CNS and overall
high inflammatory status; both will reduce expression of p-glycoprotein and lead to
ivermectin CNS accumulation/toxicity. Therefore, higher ivermectin failure cases were
reported in the severe (or later stages) cases (22).
9. Genetic mutations of CYP p450 3A4 and p-glycoprotein (MDR-1)
If patients already have genetic tests, the clinician should consider these two genetic
variants into consideration.
Baudou et al., 2020 reported a case on the MDR-1 mutation that can cause impaired
consciousness after 0.23mg (230mcg)/kg dose in a 13-year old boy (23).
10. Unique pharmacokinetics/pharmacodynamics (PK/PD) of ivermectin (8,18)
a). Large ranges of half-life (12-54 hours). Therapeutic half-life is correlated to liver
metabolism. More parent drugs are metabolized by the liver, the longer the efficacy
Active metabolites have four times the half-life of the parent drug. Therefore, liver
metabolism can extend its effectiveness. Since ivermectin has additional metabolites
accumulation, good liver function is essential for ivermectin effectiveness.
b). Volume distribution of ivermectin is correlated to the lipid composition of the body.
c). High lipid food and alcohol increase absorption due to reducing GI mobility.
d). Parasites co-infection will increase volume distribution and may need a higher dose if
treated with Covid-19.
e). Malnutrition, such as hypoalbuminemia, will cause a higher free fraction of
ivermectin in the plasma and generate a higher chance of toxicity.
f) Only 1% of the parent drug was eliminated via urine; clinicians can omit renal-
function-based dose adjustment.
Based on the unique PK/PD characters, the author suggests adjusting ivermectin doses or
dose intervals based on patients' "unique characters." Examples of the individual
characters are
Fat composition (higher composition might need a higher dose, e.g., younger
children with lower body fat),
Dosing by body weight or by body height has been used in anti-parasite regimens.
Usually, the range by weight is 150-200 µg/kg, similar dosing regimens have been
applied to Covid-19 treatment and prophylaxis,
Liver functions (lower dose if liver dysfunction, such as aging and cirrhosis),
Oral absorption (factors that affect GI tract mobility, e.g., slower mobility leads to
higher absorption, alcohol and high-fat food can increase absorption), and
Nutrition status (e.g., lower serum albumin), such as low serum albumin, will
increase the fraction of free ivermectin and increase toxicity. Therefore,
malnourished patients should avoid high-single doses.
From the experience of ivermectin use in humans, the author concludes that ivermectin is
safe to use within the following limitations.
-The proper doses range (150-400 µg/kg daily, max 120 mg single dose).
-The proper dosing intervals (daily up to 5 days, every 48-72 hour, or weekly up to 10
-Within limited period of time, monitor total accumulative doses.
-Avoid using ivermectin in young children with a body weight of less than 15 kg who
have less CYP p450 enzyme effectiveness, less developed BBB, and less body fat
-Caution use in liver dysfunction patients, pregnancy, and nursing mothers.
-Avoid drug-drug interactions with CYP3A4 inhibitors and p-glycoprotein inhibitors,
-Caution used in the genetic variant polymorphism of CYP3A4 enzyme weak
metabolizers and p-glycoprotein weak variants.
-Caution on pre-existing high inflammatory status, hypo-coagulation status, co-CNS
-The higher doses are not necessarily appropriate. Clinicians should consider the potential
risk factors of ivermectin toxicities.
-!In the late stage of Covid-19 / severe cases, clinicians should consider the potential
higher chances of neurological adverse reactions, e.g., gene expression of p-glycoprotein
suppressed by high-inflammatory status. Therefore, lower doses might have better
outcomes in severe cases.
In terms of the effectiveness, many meta-analyses and mass population real-life trials
(e.g., India
do-it-not-with-covid-injections-but-a-drug-that-costs-less-than-2-per-person-ivermectin/) already
illustrated its efficacy; the author will strongly recommend using ivermectin as an off-
label indication in early-stage Covid-19 treatment/prophylaxis.
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review. AAPS J. 2008;10(1):42-46. doi:10.1208/s12248-007-9000-9!
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In their recent article published in Viruses, Michel Drancourt and colleagues [...]
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Considering the urgency of the ongoing COVID-19 pandemic, detection of various new mutant strains and future potential re-emergence of novel coronaviruses, repurposing of approved drugs such as Ivermectin could be worthy of attention. This evidence-based review article aims to discuss the mechanism of action of ivermectin against SARS-CoV-2 and summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between Ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications have been proposed.
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Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways. Electronic supplementary material The online version of this article (doi:10.1186/s12936-017-1801-4) contains supplementary material, which is available to authorized users.
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Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread.
Encephalopathy and coma developed in a 13-year-old boy shortly after he received a single dose of ivermectin to prevent scabies infection. ABCB1 sequencing identified the child as a compound heterozygote for two nonsense mutations.