Concentration-dependent mortality of chloroquine in overdose

Abstract

Background: Hydroxychloroquine and chloroquine have been used extensively in malaria and rheumatological conditions. Although generally safe and well tolerated they are potentially lethal in overdose. These two drugs are now candidates for the prevention and treatment of COVID19. In vitro data suggest that high concentrations and thus high doses will be needed if they are to be of benefit, but as yet there is no convincing evidence they are clinically effective. Nevertheless they are already being used very widely and fatal accidental overdoses have been reported.Methods: Individual data from prospectively studied French patients who had taken intentional chloroquine overdoses and were managed in the national toxicology intensive care unit in Paris were pooled. Bayesian logistic regression was used to estimate a concentration-fatality curve. The probabilities of fatal iatrogenic toxicity with the chloroquine regimens currently being trialled for the treatment of COVID19 were estimated from a combined pharmacokineticpharmacodynamic model.Findings: In total, 258 patients were studied of whom 26 died (10%). There was a steep sigmoid relationship between admission whole blood chloroquine concentrations and death. Concentrations above 13µmol/L (95% credible interval (C.I.), 10 to 16) were associated with greater than 1% mortality. Based on peak concentrations, absolute fatality ratios in the high dose arm (chloroquine base equivalent adult dose of 600mg given twice daily for ten days) of a recently terminated trial were estimated between 0.06% (90kg adult, 95%C.I. 0 to 0.3%) and 4.8% (40kg adult, 95% C.I. 1.9 to 9.7%). This regimen results in peak concentrations above 10µmol/L in more than 60% of adults weighing 70kg. The other high dose regimens trialled currently for COVID19 result in peak concentrations above 10µmol/L in only 0.2% of adults weighting 70kg.Interpretation: High-dose chloroquine treatment regimens which result in whole blood chloroquine concentrations below 10µmol/L for the majority of patients should not result in life-threatening cardiovascular toxicity. Evidence before this studyWe searched Pubmed using the terms (chloroquine OR hydroxychloroquine) AND (suicide OR intoxication OR poisoning) AND concentration NOT mice, which returned 90 results. After excluding reviews, case reports with concentrations measured post mortem, healthy volunteer studies, animal studies and laboratory studies, 16 publications were retained. Of these, 12 were case reports and 4 were hospital cohorts. Case reports exhibited significant bias towards individuals with high concentrations who survived. Of the 4 hospital cohorts, we extracted data manually from one, and obtained the original data for two.Added value of this study We provide an objective methodology to evaluate the risk of overdose for chloroquine treatment or prevention regimens currently being trialled in COVID19. This can be used to assess formally the risk-benefit trade-off when administering large doses for treatment .Implications of all the available evide...

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial

“…However in that study, chloroquine 600 mg base was given twice daily for ten days, a substantially higher total dose than used in other trials, including RECOVERY. 34,35 Pharmacokinetic modelling in combination with blood concentration and mortality data from a case series of 302 chloroquine overdose patients predicts that the base equivalent chloroquine regimen to the RECOVERY hydroxychloroquine regimen is safe. 35 Hydroxychloroquine is considered to be safer than chloroquine.…”

“…34,35 Pharmacokinetic modelling in combination with blood concentration and mortality data from a case series of 302 chloroquine overdose patients predicts that the base equivalent chloroquine regimen to the RECOVERY hydroxychloroquine regimen is safe. 35 Hydroxychloroquine is considered to be safer than chloroquine. 15 We did not observe excess mortality in the first 2 days of treatment with hydroxychloroquine, the time when early effects of dose-dependent toxicity might be expected.…”

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform

“…Lastly, our population included regular users of hydroxychloroquine, who were No hydroxychloroquine Hydroxychloroquine prescribed doses routinely used in clinical practice, with clarity that hydroxychloroquine administration occurred before exposure to SARSCoV2. The optimal timing 25 and dose 26 of hydroxychloroquine for therapeutic and prophylactic use for COVID19 has been debated. The standard dose of hydroxychloroquine in clinical use in England is 200 mg per day or 400 mg per day, commenced without loading dose.…”

Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: authors' response

“…The statement that the RECOVERY Trial used a toxic dose comes from a misunderstanding of pharmacokinetic models on (hydroxyl)chloroquine. In the RECOVERY Trial, 2400mg were only used for the first day to provide free plasma concentrations as high as safely possible and faster than when using only the maintenance dose from the start [ [15] , [16] , [17] ].…”