Concentration-dependent mortality of chloroquine in overdose

  1. James A Watson
  2. Joel Tarning
  3. Richard M Hoglund
  4. Frederic J Baud
  5. Bruno Megarbane
  6. Jean-Luc Clemessy
  7. Nicholas J White

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Abstract

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1–17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.

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  1. Version published to 10.7554/elife.58631 on eLife
  2. Version published to 10.1101/2020.04.24.20078303v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2020.04.24.20078303: (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
    Data were extracted using the web version of WebPlotDigitizer (https://automeris.io/WebPlotDigitizer/).
    WebPlotDigitizer
    suggested: (WebPlotDigitizer, RRID:SCR_013996)
    To review reports of Torsade de Pointes associated with chloroquine or hydroxychloroquine PubMed and EmBase were searched using the terms ‘HYDROXYCHLOROQUINE’or’CHLOROQUINE’AND either’TORSADE’,’ARRHYTHMIA’,’SUDDEN DEATH’ or’CARDIAC ARREST’.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Code and data availability: All code (including the NONMEM simulation scripts) and data can be found on github at: https://github.com/jwatowatson/Chloroquine-concentration-fatality.
    NONMEM
    suggested: (NONMEM, RRID:SCR_016986)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: There are several limitations to this study. It is a retrospective individual patient data analysis. In the suicide attempts, other drugs or alcohol were often taken as well, although none with the acute lethal toxicity of chloroquine. Patients were managed by experienced intensivists on intensive care units where there was close clinical and laboratory monitoring. Mortality might be higher in less well supported settings, or in overloaded hospitals in high-income settings. The age range in self-poisoning is also younger than in the majority of more seriously ill COVID-19 patients. The spectrophotometric assay method does not separate chloroquine from its desethylated metabolite, and is relatively insensitive. Desethychloroquine has generally similar biological properties, and the assay performs well at the high concentrations of relevance to this study. We corrected for the presence of the metabolite under the Bayesian model, but this correction increases uncertainty around the threshold concentration associated with 1% mortality. The predictions of absolute mortality under the regimens simulated in this work are sensitive to the parameterization of the pharmacokinetic model. Cmax is not observed directly but is an output model-based quantity estimated from data. There are no large population pharmacokinetic studies to verify the precision of the Cmax predictions, especially for the critical upper tails of the distribution. The pharmacokinetic-pharmacodynamic mo...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04323527CompletedChloroquine Diphosphate for the Treatment of Severe Acute Re…
    NCT04330690RecruitingTreatments for COVID-19: Canadian Arm of the SOLIDARITY Tria…
    NCT04381936RecruitingRandomised Evaluation of COVID-19 Therapy
    NCT04329923TerminatedThe PATCH Trial (Prevention And Treatment of COVID-19 With H…

    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

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  4. eLife

    ###This manuscript is in revision at eLife

    The decision letter after peer review, sent to the authors on May 28, 2020, follows.

    Summary

    This paper describes a modelling and simulation project which utilises a mixture of data-sets to predict the likely concentrations (total blood) from the currently recommended hydroxychloroquine (HCQ) (chloroquine (CQ)) dose regimens for COVID-19.

    Essential Revisions

    Line 93: The NONMEM simulation code could not be found in the list of contents of the GitHub site. When searching for NONMEM in the Rmd file it does not appear. Please provide full details on how to access the PK modelling used.

    Line 171: Please describe the model used to simulate the PK profile in order to obtain peak concentrations.

    As not all regimens could be tested in the model, it would be highly informative to have the loading, maintenance and duration of dose used in the ~90 registered clinical trials summarised in a supplementary table. This would clarify how the wide range of chloroquine dosages currently being used relate to dosages modelled in terms of predicted exposure and mortality risk. This is needed to support the Impact statement that "Most chloroquine regimens trialled for the treatment of COVID19 will not result in life-threatening cardiovascular toxicity".

  5. Version published to 10.1101/2020.04.24.20078303v1 on medRxiv