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

Annie Delaunois,Vitalina Gryshkova,Cristian Trovato,Caiyun Wu,Elisa Passini,Blanca Rodriguez,Julie Coulot,Eric I Rossman,Isabel Lushbough,Kylie A Beattie,Mark Holbrook,Jean‐Pierre Valentin,James Kramer,Simon Hebeisen,Khuram W Chaudhary,William S Redfern ,Yuri A Kuryshev ,Matthew M Abernathy ,Derek J Leishman ,W T Anderson

doi:10.1111/cts.13011

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 I Kr (half‐maximal inhibitory concentration [IC50]: 1 µM and 3–7 µM, respectively) and I K1 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.

Highlights

The concept of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm was proposed jointly by the US Food and Drug Administration (FDA), the Health and Environmental Sciences Institute (HESI), and the Cardiac Safety Research Consortium (CSRC) in 2013 to improve on prediction of risk of Torsade de Pointes (TdP) for small molecule pharmaceuticals.1–4 It comprises both nonclinical and clinical components
The present work “road-tested” the new CiPA paradigm,1–4 aiming at assessing the proarrhythmic risk of drugs using human-based models, with CLQ and or hydroxychloroquine (OH-CLQ), two long- established antimalarials that were repurposed for treatment of COVID-1 9 during the first wave of the pandemic in 2020
The experiments consisted of a panel of in silico and in vitro assays

Summary

Introduction

The concept of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm was proposed jointly by the US Food and Drug Administration (FDA), the Health and Environmental Sciences Institute (HESI), and the Cardiac Safety Research Consortium (CSRC) in 2013 to improve on prediction of risk of Torsade de Pointes (TdP) for small molecule pharmaceuticals.1–4 It comprises both nonclinical and clinical components. Chloroquine (CLQ) and hydroxychloroquine (OH-CLQ) are long-established medicines used for prophylaxis and treatment of uncomplicated malaria or some autoimmune diseases. Their use has been associated with cardiovascular side effects, in particular QT interval prolongation and TdP.[5] CLQ and OH-C LQ were developed and marketed long before the introduction of the ICH S7B6 and E147 guidelines, which provide recommendations for the nonclinical and clinical assessment of the potential of a new drug to delay ventricular repolarization and prolong QT interval. A few former publications reported that CLQ inhibits IKr current with a half-maximal inhibitory concentration (IC50) value of 2.5 μM10 and prolongs QTc interval in ex vivo and in vivo rabbit models,[11] as well as in healthy subjects.[12]

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