Chloroquine for treatment of COVID-19 - a pig in a poke?

  1. R.J. Brüggemann
  2. D.J.A.R. Moes
  3. K.P. van Rhee
  4. N.E. van ’t Veer
  5. B.C.P. Koch
  6. M. van Rossum
  7. A. Vermeulen Windsant - van den Tweel
  8. M.H.E. Reijers
  9. R.R.J. van Kimmenade
  10. J.C. Rahamat- Langedoen
  11. T.C.D. Rettig
  12. R. van Raalte
  13. J. van Paassen
  14. F.N. Polderman
  15. P.D. van der Linden
  16. T. Frenzel
  17. Q. de Mast
  18. D.M. Burger
  19. J. Schouten
  20. F.L. van de Veerdonk
  21. P. Pickkers
  22. R. ter Heine

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Abstract

Objective

Chloroquine has been frequently administered for treatment of coronavirus disease 2019 but there are serious concerns about its efficacy and cardiac safety. Our objective was to investigate the pharmacokinetics and safety of chloroquine in hospitalized COVID-19 patients.

Design

A prospective observational study.

Setting

Dutch hospitals

Patients

Patients admitted to the hospital for treatment of COVID-19.

Interventions

Pharmacokinetic sampling

Measurements

The plasma concentrations of chloroquine and desethylchloroquine and QTc time.

Main Results

A total of 83 patients were included. The median (IQR) plasma concentration chloroquine during treatment was 1.05 μmol/L (0.63 - 1.55 μmol/L). None of the patients reached exposure exceeding the concentration to inhibit SARS-CoV-2 replication by 90% ( IC90 ) of 6.9 μM. Furthermore, ΔQTc >60 milliseconds occurred after initiation of chloroquine treatment in 34% patients and during treatment QTc ≥500 milliseconds was observed in 46% of patients.

Conclusions

Recommended dose chloroquine treatment results in plasma concentrations that are unlikely to inhibit viral replication. Furthermore, the incidence of QTc prolongation was high. The preclinical promise of chloroquine as antiviral treatment in patients with COVID-19 is overshadowed by its cardiac toxicity and lack of effective exposure. It is unlikely that a positive clinical effect will be found with chloroquine for treatment of COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.06.20147470: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The institutional review boards of the Radboud University Medical Center and Leiden University Medical Center waived the need for formal ethics approval as all data were collected anonymously using minimally invasive measures.
    RandomizationPlasma concentrations of chloroquine and its metabolite desethylchloroquine were measured in samples collected as a 4-point pharmacokinetic curve over an 8 hour interval or in randomly collected surplus samples from routine laboratory monitoring by means of a validated bioanalytical assay.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    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 10.1101/2020.07.06.20147470v1 on medRxiv