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Each drug or drug combination was tested in patch clamp assays on seven cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay) using control (healthy) or high\u2010risk cell populations, and in human\u2010induced pluripotent stem cell (hiPSC)\u2010derived cardiomyocytes. In each assay, concentration\u2010response curves encompassing and exceeding therapeutic free plasma levels were generated. Both CLQ and OH\u2010CLQ showed blocking activity against some potassium, sodium, and calcium currents. CLQ and OH\u2010CLQ inhibited <jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub> (half\u2010maximal inhibitory concentration [IC<jats:sub>50<\/jats:sub>]: 1\u00a0\u00b5M and 3\u20137\u00a0\u00b5M, respectively) and <jats:italic>I<\/jats:italic><jats:sub>K1<\/jats:sub> currents (IC<jats:sub>50<\/jats:sub>: 5 and 44\u00a0\u00b5M, respectively). When combining OH\u2010CLQ with AZI, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC<jats:sub>50<\/jats:sub>\u00a0&gt;\u00a0300\u20131000\u00a0\u00b5M). Using Virtual Assay, both antimalarials affected several TdP indicators, CLQ being more potent than OH\u2010CLQ. Effects were more pronounced in the high\u2010risk cell population. In hiPSC\u2010derived cardiomyocytes, all drugs showed early after\u2010depolarizations, except AZI. Combining CLQ or OH\u2010CLQ with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off\u2010label use in COVID\u201019, CLQ and OH\u2010CLQ use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.<\/jats:p>","DOI":"10.1111\/cts.13011","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T10:41:05Z","timestamp":1614076865000},"page":"1133-1146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off\u2010label in the first wave of COVID\u201019"],"prefix":"10.1111","volume":"14","author":[{"given":"Annie","family":"Delaunois","sequence":"first","affiliation":[{"name":"UCB Biopharma SRL Braine\u2010l\u2019Alleud 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