Concentration-dependent mortality of chloroquine in overdose
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/58631 |
| _version_ | 1811253019807842304 |
|---|---|
| author | James A Watson Joel Tarning Richard M Hoglund Frederic J Baud Bruno Megarbane Jean-Luc Clemessy Nicholas J White |
| author_facet | James A Watson Joel Tarning Richard M Hoglund Frederic J Baud Bruno Megarbane Jean-Luc Clemessy Nicholas J White |
| author_sort | James A Watson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:44:20Z |
| format | Article |
| id | doaj.art-82cdd270d78049e7b2b50ad8040e2af9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:44:20Z |
| publishDate | 2020-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-82cdd270d78049e7b2b50ad8040e2af92022-12-22T03:24:39ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.58631Concentration-dependent mortality of chloroquine in overdoseJames A Watson0https://orcid.org/0000-0001-5524-0325Joel Tarning1https://orcid.org/0000-0003-4566-4030Richard M Hoglund2Frederic J Baud3Bruno Megarbane4Jean-Luc Clemessy5Nicholas J White6https://orcid.org/0000-0002-1897-1978Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United KingdomMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United KingdomMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United KingdomAssistance Publique - Hôpitaux de Paris, Paris, France; Université de Paris, Paris, FranceUniversité de Paris, INSERM UMRS-11 44, Paris, France; Reanimation Medicale et Toxicologique, Hopital Lariboisiere, Paris, FranceAssistance Publique - Hôpitaux de Paris, Paris, France; Reanimation Medicale et Toxicologique, Hopital Lariboisiere, Paris, France; Clinique du Sport, Paris, FranceMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United KingdomHydroxychloroquine 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.https://elifesciences.org/articles/58631chloroquineoverdosepharmacokineticspharmacodynamicsbayesian |
| spellingShingle | James A Watson Joel Tarning Richard M Hoglund Frederic J Baud Bruno Megarbane Jean-Luc Clemessy Nicholas J White Concentration-dependent mortality of chloroquine in overdose eLife chloroquine overdose pharmacokinetics pharmacodynamics bayesian |
| title | Concentration-dependent mortality of chloroquine in overdose |
| title_full | Concentration-dependent mortality of chloroquine in overdose |
| title_fullStr | Concentration-dependent mortality of chloroquine in overdose |
| title_full_unstemmed | Concentration-dependent mortality of chloroquine in overdose |
| title_short | Concentration-dependent mortality of chloroquine in overdose |
| title_sort | concentration dependent mortality of chloroquine in overdose |
| topic | chloroquine overdose pharmacokinetics pharmacodynamics bayesian |
| url | https://elifesciences.org/articles/58631 |
| work_keys_str_mv | AT jamesawatson concentrationdependentmortalityofchloroquineinoverdose AT joeltarning concentrationdependentmortalityofchloroquineinoverdose AT richardmhoglund concentrationdependentmortalityofchloroquineinoverdose AT fredericjbaud concentrationdependentmortalityofchloroquineinoverdose AT brunomegarbane concentrationdependentmortalityofchloroquineinoverdose AT jeanlucclemessy concentrationdependentmortalityofchloroquineinoverdose AT nicholasjwhite concentrationdependentmortalityofchloroquineinoverdose |