The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID‐19

  1. Virginia D. Schmith
  2. Jie (Jessie) Zhou
  3. Lauren R.L. Lohmer

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Abstract

Caly et al . 1 reported that ivermectin inhibited severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) in vitr o for up to 48 hours using ivermectin at 5 μM. The concentration resulting in 50% inhibition (IC 50 ; 2 µM) was > 35× higher than the maximum plasma concentration (C max ) after oral administration of the approved dose of ivermectin when given fasted. Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration‐time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total C max was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung C max after administration of each single dose. Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC 50 , even for a dose level 10× higher than the approved dose. Even with the high lung:plasma ratio, ivermectin is unlikely to reach the IC 50 in the lungs after single oral administration of the approved dose (predicted lung: 0.0873 µM) or at doses 10× higher that the approved dose administered orally (predicted lung: 0.820 µM). In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro . Repurposing drugs for use in coronavirus disease 2019 (COVID‐19) treatment is an ideal strategy but is only feasible when product safety has been established and experiments of repurposed drugs are conducted at clinically relevant concentrations.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.21.20073262: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Simulations (n=100) were performed using NONMEM version 7.4 (ICON).
    NONMEM
    suggested: (NONMEM, RRID:SCR_016986)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1002/cpt.1889
  3. ScreenIT

    SciScore for 10.1101/2020.04.21.20073262: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variableBody weights were sampled from Center for Disease Control weight chart assuming 20 year old adults, with male:female ratio being 1:1 (9).

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Simulations (n=100) were performed using NONMEM version 7.4 (ICON).
    NONMEM
    suggested: (NONMEM, SCR_016986)

    Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, please follow this link.

  4. Version published to 10.1101/2020.04.21.20073262v1 on medRxiv