Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19
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 erythromyc...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-05-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13011 |
| _version_ | 1818441130099867648 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Annie Delaunois |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T18:23:21Z |
| format | Article |
| id | doaj.art-d703d6568c29415c8e2d93ccf47af5d0 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-12-14T18:23:21Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-d703d6568c29415c8e2d93ccf47af5d02022-12-21T22:52:00ZengWileyClinical and Translational Science1752-80541752-80622021-05-011431133114610.1111/cts.13011Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19Annie Delaunois0Matthew Abernathy1Warren D. Anderson2Kylie A. Beattie3Khuram W. Chaudhary4Julie Coulot5Vitalina Gryshkova6Simon Hebeisen7Mark Holbrook8James Kramer9Yuri Kuryshev10Derek Leishman11Isabel Lushbough12Elisa Passini13Will S. Redfern14Blanca Rodriguez15Eric I. Rossman16Cristian Trovato17Caiyun Wu18Jean‐Pierre Valentin19UCB Biopharma SRL Braine‐l’Alleud BelgiumEli Lilly and Company Lilly Corporate Center Indianapolis Indiana USACenter for Public Health Genomics University of Virginia Charlottesville Virginia USAGlaxoSmithKline Stevenage UKGlaxoSmithKline Collegeville Pennsylvania USAB’SYS GmbH Witterswil SwitzerlandUCB Biopharma SRL Braine‐l’Alleud BelgiumB’SYS GmbH Witterswil SwitzerlandCertara UK Ltd Sheffield UKCharles River Cleveland Ohio USACharles River Cleveland Ohio USAEli Lilly and Company Lilly Corporate Center Indianapolis Indiana USAUCB Biopharma SRL Braine‐l’Alleud BelgiumDepartment of Computer Science University of Oxford Oxford UKCertara UK Ltd Sheffield UKDepartment of Computer Science University of Oxford Oxford UKGlaxoSmithKline Collegeville Pennsylvania USADepartment of Computer Science University of Oxford Oxford UKCharles River Cleveland Ohio USAUCB Biopharma SRL Braine‐l’Alleud BelgiumAbstract 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.https://doi.org/10.1111/cts.13011 |
| spellingShingle | 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 Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19 Clinical and Translational Science |
| title | Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19 |
| title_full | Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19 |
| title_fullStr | Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19 |
| title_full_unstemmed | Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19 |
| title_short | Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off‐label in the first wave of COVID‐19 |
| title_sort | applying the cipa approach to evaluate cardiac proarrhythmia risk of some antimalarials used off label in the first wave of covid 19 |
| url | https://doi.org/10.1111/cts.13011 |
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