Concentration-dependent mortality of chloroquine in overdose

  1. James A Watson  Is a corresponding author
  2. Joel Tarning
  3. Richard M Hoglund
  4. Frederic J Baud
  5. Bruno Megarbane
  6. Jean-Luc Clemessy
  7. Nicholas J White  Is a corresponding author
  1. Mahidol University, Thailand
  2. Mahidol-Oxford Tropical Medicine Research Unit, Thailand
  3. Assistance Publique - Hôpitaux de Paris, France
  4. Hopital Lariboisiere, France

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 umol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarisation is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modelling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.

Data availability

All data analysed during this study are included in the github repository linked in the manuscript. All Figures can be generated from the scripts in this repository.

Article and author information

Author details

  1. James A Watson

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    For correspondence
    jwatowatson@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5524-0325
  2. Joel Tarning

    Clinical Pharmacology, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4566-4030
  3. Richard M Hoglund

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  4. Frederic J Baud

    Toxicologie, Assistance Publique - Hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Bruno Megarbane

    Reanimation Medicale et Toxicologique, Hopital Lariboisiere, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Jean-Luc Clemessy

    Clinique du Sport, Assistance Publique - Hôpitaux de Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Nicholas J White

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    For correspondence
    nickw@tropmedres.ac
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1897-1978

Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Arduino A Mangoni, Flinders Medical Centre, Australia

Ethics

Human subjects: This is a retrospective analysis of previously published data. All the patients enrolled in the studies gave full consent and studies had ethical approval.

Version history

  1. Received: May 6, 2020
  2. Accepted: July 7, 2020
  3. Accepted Manuscript published: July 8, 2020 (version 1)
  4. Version of Record published: August 10, 2020 (version 2)

Copyright

© 2020, Watson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,304
    views
  • 267
    downloads
  • 23
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2020)
Concentration-dependent mortality of chloroquine in overdose
eLife 9:e58631.
https://doi.org/10.7554/eLife.58631

Share this article

https://doi.org/10.7554/eLife.58631