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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 - SIDP · 2020. 10. 19. · ICON (Ivermectin in COvid Nineteen study) In multivariate analysis, ivermectin was associated with a significantly lower HR for mortality, 0.37

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  • 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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