Towards Fixed Dosing of Tocilizumab in ICU-Admitted COVID-19 Patients: Results of an Observational Population Pharmacokinetic and Descriptive Pharmacodynamic Study

  1. Dirk Jan A. R. Moes
  2. David J. van Westerloo
  3. Sandra M. Arend
  4. Jesse J. Swen
  5. Annick de Vries
  6. Henk-Jan Guchelaar
  7. Simone A. Joosten
  8. Mark G. J. de Boer
  9. Teun van Gelder
  10. Judith van Paassen

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Abstract

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  1. Version published to 10.1007/s40262-021-01074-2
  2. ScreenIT

    SciScore for 10.1101/2021.05.10.21256933: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study was conducted in compliance with the Declaration of Helsinki and approved by the COVID-19 scientific and ethics committee of the Leiden University Medical Center with number coco 2020-033.
    Consent: Furthermore a waiver for the requirement for informed consent was granted.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisStatistical analysis and model development: The sample size calculation was based the sample size of the registration study of the cytokine release syndrome indication for tocilizumab approved by the FDA for.

    Table 2: Resources

    Antibodies
    SentencesResources
    Tocilizumab concentrations were determined with a validated ELISA-method using rabbit anti-tocilizumab antibodies to capture tocilizumab, and rabbit anti-tocilizumab F(ab’)2 fragments for detection as described earlier.10, 11 The lower limit of quantification (LLOQ) in plasma was 0·2 ug/mL; the overall precision and accuracy were 8% and 93%, respectively.
    anti-tocilizumab
    suggested: None
    anti-tocilizumab F(ab’)2
    suggested: None
    Software and Algorithms
    SentencesResources
    For the development of alternative dosing schedules Monte Carlo simulations in NONMEM using the final model were performed to assess whether the bodyweight dosing or fixed dosing was more appropriate to reduce variability in tocilizumab exposure.
    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: We detected the following sentences addressing limitations in the study:
    Our study has some limitations. Due to the observational study design and unpredictable course of COVID-19 patients during ICU admission sampling could be not performed in an equal manner for all patients. Nevertheless the population approach used in the analysis allows to draw solid conclusions from unevenly distributed datasets. Furthermore a total of no less than 139 samples resulted in reliable pharmacokinetic parameter estimates. The sample size is relatively low, but similar to the dataset that was required (30 patients 140 samples) to obtain a FDA registration for CRS of tocilizumab, and model performance was good.9 In conclusion, our findings strongly support fixed dosing of tocilizumab in ICU admitted COVID-19 patients with a dose of 600 mg, as it leads to less variability in exposure compared to the currently applied bodyweight dosing. In patients with low bodyweight the fixed dose will avoid relative under-exposure, while in patients with high bodyweight the fixed dosing strategy will avoid unnecessary overexposure and excessive costs. Our findings also suggest that alternative cost saving regimens with even lower doses than 600 mg are likely to be as effective.

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  3. Version published to 10.1101/2021.05.10.21256933v1 on medRxiv