Risk Assessment of Drug‐Induced Long QT Syndrome for Some COVID‐19 Repurposed Drugs

Abstract

The risk‐benefit ratio associated with the use of repurposed drugs to treat severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)‐related infectious coronavirus disease 2019 (COVID‐19) is complicated because benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID‐19. A risk assessment of drug‐induced long QT syndrome (LQTS) associated with COVID‐19 repurposed drugs was performed and compared with 23 well‐known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (I Kr ) encoded by the human ether‐a‐go‐go gene ( hERG ), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID‐19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug‐induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID‐19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients.

Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns

“…[ 14 ] In addition, pharmacovigilance investigations are still necessary for cardiac risk with remdesivir as a previous study reported the potential block of hERG (human ether‐a‐go‐go gene) and prolongation of cardiac repolarization with remdesivir. [ 15 ] Post hoc analyses of trials and additional observational studies are needed to corroborate our findings. Given the increased use of remdesivir and recent FDA recommendations, physicians should be aware of this cardiac safety signal.…”

In silico Exploration of Interactions Between Potential COVID-19 Antiviral Treatments and the Pore of the hERG Potassium Channel—A Drug Antitarget

“…This may be particularly important for remdesivir and favipiravir, given their potential as COVID-19 treatments. Indeed, the present study usefully complements a recent independent investigation that has used a combination of predictive indices for drug-induced LQTS (though not structural modeling as conducted here) to evaluate risks with potential COVID-19 treatments, on the basis of which it has recommended close monitoring of QT/QT c intervals in patients receiving both drugs (67). On the basis of our observations, we suggest that a direct in vitro experimental comparison would be informative of I hERG inhibitory potency between remdesivir, atazanavir, lopinavir, and ritonavir and favipiravir under a standardized set of conditions; this would aid further evaluation of likely I hERG safety margin.…”

Effect of COVID‐19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey

“…Repurposed drugs used in COVID-19 treatment cause QT prolongation by blocking the voltage-gated ion channel that mediates the rapid component of the delayed rectifier potassium current, IKr, resulting in lengthening of the ventricular action potential. 24 A timely early Afterdepolarisation, in the presence of a prolonged QT interval, may result in TdP. This risk increases in the presence of concomitant use of QT prolonging agents, loop diuretic, female gender, elderly people, structural heart disease, heart failure, myocardial infarction, electrolyte disturbances, bradycardia, renal disease and hepatic disease.…”