Concentration-dependent mortality of chloroquine in overdose
- Mahidol University, Thailand
- Mahidol-Oxford Tropical Medicine Research Unit, Thailand
- Assistance Publique - Hôpitaux de Paris, France
- 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.
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Funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
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.
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Concentration-dependent mortality of chloroquine in overdose
eLife 9:e58631.
https://doi.org/10.7554/eLife.58631
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