Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19

Autor: Annie Delaunois, Matthew Abernathy, Warren D. Anderson, Kylie A. Beattie, Khuram W. Chaudhary, Julie Coulot, Vitalina Gryshkova, Simon Hebeisen, Mark Holbrook, James Kramer, Yuri Kuryshev, Derek Leishman, Isabel Lushbough, Elisa Passini, Will S. Redfern, Blanca Rodriguez, Eric I. Rossman, Cristian Trovato, Caiyun Wu, Jean‐Pierre Valentin
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Clinical and Translational Science, Vol 14, Iss 3, Pp 1133-1146 (2021)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.13011
Popis: Abstract We applied a set of in silico and in vitro assays, compliant with the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm, to assess the risk of chloroquine (CLQ) or hydroxychloroquine (OH‐CLQ)‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin (ERT) and azithromycin (AZI), drugs repurposed during the first wave of coronavirus disease 2019 (COVID‐19). 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‐risk cell populations, and in human‐induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes. In each assay, concentration‐response curves encompassing and exceeding therapeutic free plasma levels were generated. Both CLQ and OH‐CLQ showed blocking activity against some potassium, sodium, and calcium currents. CLQ and OH‐CLQ inhibited IKr (half‐maximal inhibitory concentration [IC50]: 1 µM and 3–7 µM, respectively) and IK1 currents (IC50: 5 and 44 µM, respectively). When combining OH‐CLQ with AZI, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC50 > 300–1000 µM). Using Virtual Assay, both antimalarials affected several TdP indicators, CLQ being more potent than OH‐CLQ. Effects were more pronounced in the high‐risk cell population. In hiPSC‐derived cardiomyocytes, all drugs showed early after‐depolarizations, except AZI. Combining CLQ or OH‐CLQ 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‐label use in COVID‐19, CLQ and OH‐CLQ use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.
Databáze: Directory of Open Access Journals
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