Pharmacometric and Electrocardiographic Evaluation of Chloroquine and Azithromycin in Healthy Volunteers.

Chloroquine and azithromycin were developed in combination for the preventive treatment of malaria in pregnancy, and more recently were proposed as coronavirus disease 2019 (COVID-19) treatment options. Billions of doses of chloroquine have been administered worldwide over the past 70 years but concerns regarding cardiotoxicity, notably the risk of torsades de pointes (TdP), remain. This investigation aimed to characterize the pharmacokinetics and electrocardiographic effects of chloroquine and azithromycin observed in a large previously conducted healthy volunteer study. Healthy adult volunteers (n = 119) were randomized into 5 arms: placebo, chloroquine alone (600 mg base), or chloroquine with either 500 mg, 1,000 mg, or 1,500 mg of azithromycin all given daily for 3 days. Chloroquine and azithromycin levels, measured using liquid-chromatography tandem mass spectrometry, and electrocardiograph intervals were recorded at frequent intervals. Time-matched changes in the PR, QRS, and heart rate-corrected JT, and QT intervals were calculated and the relationship with plasma concentrations was evaluated using linear and nonlinear mixed-effects modeling. Chloroquine and azithromycin pharmacokinetics were described satisfactorily by two- and three-compartment distribution models, respectively. No drug-drug interaction between chloroquine and azithromycin was observed. Chloroquine resulted in concentration-dependent prolongation of the PR, QRS, JTc and QTc intervals with a minimal additional effect of azithromycin. QRS widening contributed ~ 28% of the observed QT prolongation. Chloroquine causes significant concentration-dependent delays in both ventricular depolarization and repolarization. Co-administration of azithromycin did not significantly increase these effects. The arrhythmogenic risk of TdP associated with chloroquine may have been substantially overestimated in studies which did not separate electrocardiograph QRS and JT prolongation.

COVID-19 and cardiac arrhythmias: a global perspective on arrhythmia characteristics and management strategies.

BACKGROUND: Cardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients. However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described. We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide cross-sectional survey. METHODS: The Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe. The survey was active from March 27 to April 13, 2020. RESULTS: A total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents. Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital. Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias. Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively. There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication. One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA. Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management. CONCLUSIONS: In this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening. Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes. Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted.