Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation

Background and Purpose Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID‐19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in...

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Bibliographic Details
Published in:British journal of pharmacology 2022-06, Vol.179 (11), p.2631-2646
Main Authors: TeBay, Clifford, McArthur, Jeffrey R., Mangala, Melissa, Kerr, Nicholas, Heitmann, Stewart, Perry, Matthew D., Windley, Monique J., Vandenberg, Jamie I., Hill, Adam P.
Format: Article
Language:English
Subjects:
Acidosis
Acidosis - chemically induced
Acidosis - drug therapy
Arrhythmia
Azithromycin
Azithromycin - adverse effects
cardiac pharmacology
Cardiomyocytes
Chloroquine
Chloroquine - adverse effects
Congestive heart failure
Coronaviruses
COVID-19
COVID-19 - drug therapy
Drugs
Electrophysiology
Environmental factors
Female
Humans
Hydroxychloroquine
Hydroxychloroquine - adverse effects
Hypokalemia
Hypokalemia - chemically induced
Induced Pluripotent Stem Cells
ion channels
mathematical modelling
Metabolism
Patients
Pluripotency
safety pharmacology
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Simulation
Stem cells
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Summary:Background and Purpose Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID‐19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles. Experimental Approach Potency of human ether‐à‐go‐go related gene (hERG) block was measured using high‐throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell‐derived cardiomyocytes from multiple individuals. Key Results Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47 ± 0.07 and 3.78 ± 0.17 μM, respectively, indicating proarrhythmic risk at concentrations effective against severe acute respiratory syndrome‐coronovirus‐2 (SARS‐CoV‐2) in vitro. Hypokalaemia and hypermagnesaemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure and identified specific genetic backgrounds associated with emergence of arrhythmia. Conclusion and Implications Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre‐existing disease. More broadly, the study acts as a blueprint for how high‐throughput in vitro screening, combined with in silico simulations, can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.15757