Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA)

Seung-Hyun Yoon; Hyun-Lee Lee; Da Un Jeong; Ki Moo Lim; Seong-Jun Park; Ki-Suk Kim

doi:10.3389/fphar.2023.1220796

Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA)

Front Pharmacol. 2023 Aug 15:14:1220796. doi: 10.3389/fphar.2023.1220796. eCollection 2023.

Authors

Seung-Hyun Yoon^{1

2}, Hyun-Lee Lee¹, Da Un Jeong³, Ki Moo Lim⁴, Seong-Jun Park², Ki-Suk Kim¹

Affiliations

¹ R&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, Republic of Korea.
² College of Veterinary Medicine, Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
³ Intelligent Human Twin Research Center, Electronics and Telecommunications Research Institute, Daejeon, Republic of Korea.
⁴ Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, Republic of Korea.

Abstract

Due to the outbreak of the SARS-CoV-2 virus, drug repurposing and Emergency Use Authorization have been proposed to treat the coronavirus disease 2019 (COVID-19) during the pandemic. While the efficiency of the drugs has been discussed, it was identified that certain compounds, such as chloroquine and hydroxychloroquine, cause QT interval prolongation and potential cardiotoxic effects. Drug-induced cardiotoxicity and QT prolongation may lead to life-threatening arrhythmias such as torsades de pointes (TdP), a potentially fatal arrhythmic symptom. Here, we evaluated the risk of repurposed pyronaridine or artesunate-mediated cardiac arrhythmias alone and in combination for COVID-19 treatment through in vitro and in silico investigations using the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. The potential effects of each drug or in combinations on cardiac action potential (AP) and ion channels were explored using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Chinese hamster ovary (CHO) cells transiently expressing cardiac ion channels (Nav1.5, Cav1.2, and hERG). We also performed in silico computer simulation using the optimized O'Hara-Rudy human ventricular myocyte model (ORd model) to classify TdP risk. Artesunate and dihydroartemisinin (DHA), the active metabolite of artesunate, are classified as a low risk of inducing TdP based on the torsade metric score (TMS). Moreover, artesunate does not significantly affect the cardiac APs of hiPSC-CMs even at concentrations up to 100 times the maximum serum concentration (C_max). DHA modestly prolonged at APD₉₀ (10.16%) at 100 times the C_max. When considering C_max, pyronaridine, and the combination of both drugs (pyronaridine and artesunate) are classified as having an intermediate risk of inducing TdP. However, when considering the unbound concentration (the free fraction not bound to carrier proteins or other tissues inducing pharmacological activity), both drugs are classified as having a low risk of inducing TdP. In summary, pyronaridine, artesunate, and a combination of both drugs have been confirmed to pose a low proarrhythmogenic risk at therapeutic and supratherapeutic (up to 4 times) free C_max. Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity.

Keywords: COVID-19; CiPA; antimalarials; cardiotoxicity; electrophysiology.

Grants and funding

This work was supported by a grant (22213MFDS391) from the Ministry of Food and Drug Safety and the Ministry of Trade, Industry and Energy, Republic of Korea (20009748).