Ivermectin Kati Shihadeh, PharmD, BCIDP Clinical Pharmacy Specialist, Infectious Diseases Denver Health Medical Center [email protected] @kcshihadeh A Review of Pertinent Drug Information for SARS-CoV-2 Data as of October 7, 2020
Ivermectin
Kati Shihadeh, PharmD, BCIDPClinical Pharmacy Specialist, Infectious Diseases
Denver Health Medical [email protected]
@kcshihadeh
A Review of Pertinent Drug Information for SARS-CoV-2
Data as of October 7, 2020
Sharun, et al. Ann Clin Microbiol Antimiccrob 2020;19:23 https://doi.org/10.1186/s12941-020-00368-wwww.sklice.com/hcp/about-ivermectin
Mechanism of Action - ParasitesBroad spectrum, semisynthetic anti-parasitic
Binds to glutamate-gated chloride channels
Increased permeability of cell membranes to chloride ions
Hyperpolarization of the nerve or muscle cell
Death of parasite
https://doi.org/10.1186/s12941-020-00368-w
Dosing
Ivermectin [package insert]. Parsippany, NJ 07054: Edenbridge Pharmaceuticals;2012.Vora A, et al. Indian J Tuberc 2020;67:448-51.
• Most helminth infections: 200 mcg/kg as a single dose• Lice, scabies: 200-400 mcg/kg every 7 days x 2-3 doses• Crusted scabies: 200 mcg/kg days 1, 2, 8, 9, 15• Doses for children ≥ 15 kg are similar to adult doses
• Available as a 3 mg tablet
Pharmacokinetics
Ivermectin [package insert]. Parsippany, NJ 07054: Edenbridge Pharmaceuticals;2012.
• Drug-drug interactions: may increase anticoagulant effect of warfarin
• Food: bioavailability is increased 2.5-fold when administered following a high fat meal
• Hepatic metabolism via CYP3A4• No renal or hepatic dose adjustments required
Pharmacokinetics
Guzzo CA, et al. J Clin Pharmacol 2002;42:1122-33.
• Peak after standard dose of 200 mcg/mL ~50 ng/mL• Escalating dose study up to 2000 mcg/kg achieve levels of 250
ng/mL• Increases in Cmax and AUC
are proportional and predictable
Sharun et al. Ann Clin Microbiol Antimicrob 2020;19:23. https://doi.org/10.1186/s12941-020-00368-w
Broad spectrum, antiviral activity against animal and human viruses,
including RNA and DNA viruses
Mechanism of Action - Viruses
Sharun et al. Ann Clin Microbiol Antimicrob 2020;19:23. https://doi.org/10.1186/s12941-020-00368-w
Broad spectrum, antiviral activity against animal and human viruses,
including RNA and DNA viruses
Mechanism of Action - Viruses
In vitro Data – SARS-CoV-2
Caly L, et al. Antiviral Res 2020;178:104787. doi.org/10.1016/j.antiviral.2020.104787.
• Caly and colleagues found that the addition of 5 μM of ivermectin to Vero-hSLAM cells infected with SARS-CoV-2 resulted in a reduction in viral RNA by 99.98% at 48 hrs.
5000-fold reduction in viral load!
Concentration needed to reduce viral load by 50%
In vitro Data – SARS-CoV-2
Caly L, et al. Antiviral Res 2020;178:104787. doi.org/10.1016/j.antiviral.2020.104787.
• Caly and colleagues found that the addition of 5 μM of ivermectin to Vero-hSLAM cells infected with SARS-CoV-2 resulted in a reduction in viral RNA by 99.98% at 48 hrs.
5000-fold reduction in viral load!
Concentration needed to reduce viral load by 50%
Authors’ conclusion: Ivermectin warrants further investigation
Ivermectin Frenzy
4/3/2020Caly et al published
4/6/2020Pre-print showing survival benefit
4/10/2020FDA warning
issued
4/19/2020Pre-print retracted
and replaced
Late MayPre-print retracted
again
Caly L, et al. Antiviral Res 2020;178:104787. doi.org/10.1016/j.antiviral.2020.104787.FDA Letter to Stakeholders. https://www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-ivermectin-intended-animals-treatment-covid-19-humans
Ivermectin Frenzy
4/3/2020Caly et al published
4/6/2020Pre-print showing survival benefit
4/10/2020FDA warning
issued
4/19/2020Pre-print retracted
and replaced
Late MayPre-print retracted
again
Ivermectin Frenzy
4/3/2020Caly et al published
4/6/2020Pre-print showing survival benefit
4/10/2020FDA warning
issued
4/19/2020Pre-print retracted
and replaced
Late MayPre-print retracted
again
Ivermectin Frenzy
4/3/2020Caly et al published
4/6/2020Pre-print showing survival benefit
4/10/2020FDA warning
issued
4/19/2020Pre-print retracted
and replaced
Late MayPre-print retracted
again
Ivermectin Exposure
Jermain B, et al. J Pharm Sci 2020:https://doi.org/10.1016/j.xphs.2020.08.024.
• Ivermectin plasma and lung concentrations in calves were used to determine plasma:lung tissue partition coefficient
• Data from published PK studies in humans were used to develop a mPBPK model
• Model was used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses
Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19
Lung exposure following 120 mg dose
Plasma concentration following 120 mg
dose
Ivermectin Exposure
Schmith V, et al. Clin Pharmacol Ther 2020;108(4):762-65. doi: 10.1002/cpt.1889.
• Analysis conducted to evaluate what doses in humans would potentially result in lung concentrations reaching IC50
• A population PK model was used to simulate the following doses:
• 200 mcg/kg q7d x 3 doses• 120 mg x 1 dose• 60 mg q72h x 3 doses
The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19
IC50 reported by Caly et al ~2μM/L (1750 ng/mL)
Ivermectin Exposure
Momekov G, et al. Biotechnol. Biotechnol. Equip 2020;34(1):469-474, DOI: 10.1080/13102818.2020.1775118
PK study DoseCmax -plasma(ng/mL)
Inhibitoryconcentrations
(ng/mL) IC50
Krishna et al., 1993 12 mg (150-200 μg/kg) 30.4 -
Munoz, et al., 2018 36 mg (550-700 μg/kg) 96.2 -
Guzzo et al., 2002 120 mg (1400-2000 μ/kg) 247.8 -
Caly et al., 2020 5 μM -2190 (converted from 2.5 μM/L as reported in the
study)
The inhibitory concentration is 72x Cmax of a standard
dose and 9x that of the highest dose ever
studied
ICON (Ivermectin in COvid Nineteen study)
Rajter JC, et al. 2020. medRxivpreprint: https://doi.org/10.1101/2020.06.06.20124461
Retrospective, cohort study in 4 Florida hospitals
307 patients admitted for COVID-19
173 patients received ivermectin 200 mcg/kg + usual care
107 patients received usual care
27 excluded:multiple admissions, lack of positive test during hospitalization, age
ICON (Ivermectin in COvid Nineteen study)Retrospective, cohort study in 4 Florida hospitals
307 patients admitted for COVID-19
173 patients received ivermectin 200 mcg/kg + usual care
107 patients received usual care
27 excluded:multiple admissions, lack of positive test during hospitalization, age
ICON (Ivermectin in COvid Nineteen study)Retrospective, cohort study in 4 Florida hospitals
Outcomes Usual Care n=107 (%) Ivermectin n=173 (%) OR (CI) P value
Total mortality 27 (25.2) 26 (15.0) 0.52 (0.29-0.96) 0.03
Mortality in those with severe disease
21/26 (80.7) 19/49 (38.8) 0.15 (0.05-0.47) 0.001
Successful extubation 4/26 (15.4) 13/36 (36.1) 3.11 (0.88-11.00) 0.07
Length of stay, median (IQR) 7.0 (4.0, 10.0) 7.0 (4.0, 13.3) - 0.34
307 patients admitted for COVID-19
173 patients received ivermectin 200 mcg/kg + usual care
107 patients received usual care
27 excluded:multiple admissions, lack of positive test during hospitalization, age
ICON (Ivermectin in COvid Nineteen study)
In multivariate analysis, ivermectin was associated with a significantly lower HR for mortality, 0.37 (CI 0.19-0.70, p=0.003)
Retrospective, cohort study in 4 Florida hospitals
307 patients admitted for COVID-19
173 patients received ivermectin 200 mcg/kg + usual care
107 patients received usual care
27 excluded:multiple admissions, lack of positive test during hospitalization, age less
than 18, pregnant, incarcerated
280 included patients
Rajter JC, et al. 2020. medRxivpreprint: https://doi.org/10.1101/2020.06.06.20124461
Outcomes Usual Care n=107 (%) Ivermectin n=173 (%) OR (CI) P value
Total mortality 27 (25.2) 26 (15.0) 0.52 (0.29-0.96) 0.03
Mortality in those with severe disease
21/26 (80.7) 19/49 (38.8) 0.15 (0.05-0.47) 0.001
Successful extubation 4/26 (15.4) 13/36 (36.1) 3.11 (0.88-11.00) 0.07
Length of stay, median (IQR) 7.0 (4.0, 10.0) 7.0 (4.0, 13.3) - 0.34
Ef fe c t i v e n e s s o f I v e r m e c t i n a s A d d - O n T h e ra p y
Gorial FI, et al. 2020. medRxiv preprint doi: https://doi.org/10.1101/2020.07.07.20145979
• Pilot, interventional, single center study with synthetic control arm
• Adults ≥ 18 years old• Hospital admission• Mild-moderate COVID-19 with
+SARS-CoV-2 PCR
Inclusion: Exclusion:• Severe COVID-19 (O2 saturation
≤93% on room air, ≥30 breaths/min)
HCQ 400 mg BID x 1 day, then 200 mg BID x 4 days
Azithromycin 500 mg x 1 dose, then
250 mg daily x 4 days
Ivermectin 200 mcg/kg x
1 dose
Ef fe c t i v e n e s s o f I v e r m e c t i n a s A d d - O n T h e ra p y
Variables Ivermectin=16 Controls=71 P value
Age, mean ± SD (range) 44.87 ± 10.64 (28- 60) 45.23 ± 18.47 (8-80) 0.78
Male 11 (69) 52 (73) 0.72
SeverityMildModerate
9 (56)7 (44)
40 (56)31 (44)
1.00
Diabetes 3 (19) 15 (21) 0.83
Hypertension 3 (19) 14 (20) 0.79
Outcome Ivermectin=16 Controls=71
Cure 16 (100) 69 (97.2)
Mortality 0 2 (2.8)
*Length of stay, days, mean ± SD 7.62 (2.75) 13.22 (5.90)
*P value = 0.00005, no p value reported for other outcomes
Gorial FI, et al. 2020. medRxiv preprint doi: https://doi.org/10.1101/2020.07.07.20145979
Conclusion: When added to hydroxychloroquine/azithromycin, ivermectin contributed to a shorter length of stay. Larger prospective studies are needed to validate these data.
Ivermectin RCT in Outpatients
Podder CS, et al. IMC J Med Sci 2020;14(2):002. Epub.
• Open-label, randomized controlled trial in Bangladesh
• Included adult outpatients with mild-moderate disease with +SARS-CoV-2
• Excluded patients taking hydroxychloroquineor symptoms >7 days
• Ivermectin 200 mcg/kg x 1 dose + standard of care (SOC) vs SOC alone
• SOC = antipyretics, cough suppressant, and doxycycline 100 mg bid x 7d
Ivermectin RCT in Outpatients
Podder CS, et al. IMC J Med Sci 2020;14(2):002. Epub.
• Open-label, randomized controlled trial in Bangladesh
• Included adult outpatients with mild-moderate disease with +SARS-CoV-2
• Excluded patients taking hydroxychloroquineor symptoms >7 days
• Ivermectin 200 mcg/kg x 1 dose + standard of care (SOC) vs SOC alone
• SOC = antipyretics, cough suppressant, and doxycycline 100 mg bid x 7d
1657
• # suspected patients tested with PCR
416• SARS-CoV-2 PCR+ patients
82
• After exclusion of 334 patients based on exclusion criteria
• Recruited and randomized
62
• Selected for analysis after exclusion of 18 patients due to symptoms >7 days and 2 patients due to insufficient data
Ivermectin RCT in Outpatients
Characteristics Control n=30 (%)Ivermectin n=32 (%) P value
Age, yrs, mean ± SD 40 ± 13 38 ± 11 >0.05
Male 21 (70.0) 23 (71.9) >0.05
Severity of illnessMildModerate
24 (80.0)6 (20.0)
26 (81.3)6 (18.8)
>0.05
Presenting symptoms (select)
FeverCoughShortness of breathFatigueMyalgia
23 (76.7)21 (70.0)6 (20.0)
7 (23.3)8 (26.7)
27 (84.4)21 (65.6)6 (18.8)
5 (15.6)14 (43.8)
>0.05
Podder CS, et al. IMC J Med Sci 2020;14(2):002. Epub.
Ivermectin RCT in Outpatients
Characteristics Control n=30 (%)Ivermectin n=32 (%) P value
Age, yrs, mean ± SD 40 ± 13 38 ± 11 >0.05
Male 21 (70.0) 23 (71.9) >0.05
Severity of illnessMildModerate
24 (80.0)6 (20.0)
26 (81.3)6 (18.8)
>0.05
Presenting symptoms (select)
FeverCoughShortness of breathFatigueMyalgia
23 (76.7)21 (70.0)6 (20.0)
7 (23.3)8 (26.7)
27 (84.4)21 (65.6)6 (18.8)
5 (15.6)14 (43.8)
>0.05
P >0.05CI -0.77 - 2.81
P >0.05CI -0.86 – 3.67
Podder CS, et al. IMC J Med Sci 2020;14(2):002. Epub.
Conclusion:Ivermectin had no
benefit on disease course in mild-moderate disease
Chart1
From enrollment dateFrom enrollment date
From onset of illnessFrom onset of illness
Control
Ivermectin
Average Time (days) to Resolution of All Symptoms
6.11
5.31
11.5
10
Sheet1
ControlIvermectin
From enrollment date6.115.31
From onset of illness11.510
To resize chart data range, drag lower right corner of range.
A Comparative Study on Ivermectin and Hydroxychloroquine on the COVID-19 Patients in Bangladesh
Chowdhury AT, et al. pre-print. https://doi.org/10.21203/rs.3.rs-38896/v1
Ivermectin RCT in Outpatients
Purpose Methods ResultsTo compare ivermectin + doxycycline (IVMD) with hydroxychloroquine + azithromycin (HCQA)
Ivermectin 200 mcg/kg x1Doxycycline 100 mg BID
x10dHCQ 400 mg BID x1d, 200
mg BID x9dAzithromycin 500 mg daily
x5d
Included outpatients +SARS-CoV-2
Excluded asthma, COPD, ischemic heart disease, uncontrolled diabetes,
advanced renal or hepatic disease, carcinoma,
immunocompromised
Excluded O2 saturation
Safety• Hypersensitivity reactions• Large doses cross blood-brain barrier which can lead to
depression, ataxia, psychosis, confusion, and seizure
Guzzo CA, et al. J Clin Pharmacol 2002;42:1122-33.Ivermectin [package insert]. Parsippany, NJ 07054: Edenbridge Pharmaceuticals;2012.
Standard dose:• Pruritus• Lymphadenitis • Arthralgia• Fever• Tachycardia• Diarrhea• Nausea• ALT, and/or AST elevation
10x standard dose:• Headache• Nausea• Dizziness• Rash
Adverse Drug Reactions
Guzzo CA, et al. J Clin Pharmacol 2002;42:1122-33.Ivermectin [package insert]. Parsippany, NJ 07054: Edenbridge Pharmaceuticals;2012.
Relevant Cl inical Tr ials39 trials registered on ClinicalTrials.gov (ivermectin & SARS-CoV-2)
• 33 for treatment; 6 for prevention • Majority are actively recruiting
Trial number(Location)
Study Title or type Intervention Comparator Primary outcome Estimated date of completion
NCT04422561 (Egypt)
Randomized, open label prevention trial (Phase 2/3)
Ivermectin 2 doses 72 hrs apart: 40-60 kg (15mg), 60-80kg (18mg), >80kg (24mg)
Noprophylaxis
Development of symptoms
Completed (7/14/2020)
NCT04446104 (Singapore)
Randomized, open label prevention trial (Phase 3)
Ivermectin 12 mg x1 OR hydroxychloroquine OR Zinc/vit C OR povidone-iodine throat spray
Vitamin C 500 mg daily
Incidence of lab-confirmed SARS-CoV-2
Completed (8/31/2020)
NCT04523831 (Bangladesh)
Randomized, double-blind, placebo-controlled trial(Phase 3)
Ivermectin 6 mg x 1 dose + doxycycline 100 mg BID x 5 days + standard of care
Standard of care
Time to clinical improvement
Completed (9/10/2020)
Clinical Pearls
Safety •Well tolerated
Dosing•Standard: 200 mcg/kg x 1
•COVID-19: unknown
In vitro•Active against SARS-CoV-2
•IC50: 2.5 μM
In vivo•Substantially higher doses needed to achieve viral inhibition
•Very limited data
• IDSA Guidelines do not mention ivermectin.
• NIH Guidelines recommend against use of ivermectin, except in the context of a clinical trial.
Bhimraj A, et al. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
Ivermectin
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
Summary
Ivermectin has proven safe and effective for helminth infections, but there is little evidence to date to suggest ivermectin is a safe and effective therapy for prevention or treatment of COVID-19.
Ivermectin
Kati Shihadeh, PharmD, BCIDPClinical Pharmacy Specialist, Infectious Diseases
Denver Health Medical [email protected]
@kcshihadeh
A Review of Pertinent Drug Information for SARS-CoV-2
Data as of October 1, 2020
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