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Billions of doses of chloroquine have been administered worldwide over the past 70\u2009years 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 (<jats:italic>n<\/jats:italic>\u00a0=\u00a0119) were randomized into 5 arms: placebo, chloroquine alone (600\u2009mg base), or chloroquine with either 500 mg, 1,000\u2009mg, or 1,500\u2009mg of azithromycin all given daily for 3\u2009days. Chloroquine and azithromycin levels, measured using liquid\u2010chromatography tandem mass spectrometry, and electrocardiograph intervals were recorded at frequent intervals. Time\u2010matched changes in the PR, QRS, and heart rate\u2010corrected JT, and QT intervals were calculated and the relationship with plasma concentrations was evaluated using linear and nonlinear mixed\u2010effects modeling. Chloroquine and azithromycin pharmacokinetics were described satisfactorily by two\u2010 and three\u2010compartment distribution models, respectively. No drug\u2013drug interaction between chloroquine and azithromycin was observed. Chloroquine resulted in concentration\u2010dependent prolongation of the PR, QRS, JTc and QTc\u00a0intervals with a minimal additional effect of azithromycin. QRS widening contributed ~\u200928% of the observed QT prolongation. Chloroquine causes significant concentration\u2010dependent delays in both ventricular depolarization and repolarization. Co\u2010administration 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.<\/jats:p>","DOI":"10.1002\/cpt.2665","type":"journal-article","created":{"date-parts":[[2022,5,22]],"date-time":"2022-05-22T11:21:22Z","timestamp":1653218482000},"page":"824-835","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacometric and Electrocardiographic Evaluation of Chloroquine and Azithromycin in Healthy Volunteers"],"prefix":"10.1111","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3839-9777","authenticated-orcid":false,"given":"Palang","family":"Chotsiri","sequence":"first","affiliation":[{"name":"Mahidol\u2010Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University  Bangkok 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