Risk Assessment of Drug‐Induced Long QT Syndrome for Some COVID‐19 Repurposed Drugs
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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.
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SciScore for 10.1101/2020.04.21.20066761: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Although it presents some limitations, the appropriate adjustment of this data allows the capture of signals suggesting adverse drug events associated with a particular drug. On an individual and/or population basis, FAERS data can be used to identify patients who are at highest risk of adverse drug events using statistical approaches …
SciScore for 10.1101/2020.04.21.20066761: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Although it presents some limitations, the appropriate adjustment of this data allows the capture of signals suggesting adverse drug events associated with a particular drug. On an individual and/or population basis, FAERS data can be used to identify patients who are at highest risk of adverse drug events using statistical approaches such as relative odds. All of the sus-mentioned approaches are complementary while each having their own weaknesses and strengths. Recognizing the complexity of determining the risk of drug-induced LQTS noted by others 45, our team has developed the Long QT-JT index, which uses algorithms that consider IC50 for block of relevant ion channels (IKr, IKs, INa, ICa-L), inhibition of hERG trafficking, unbound Cmax at maximum dose, and most importantly the inhibition of the major metabolic pathway involved in the disposition or torsadogenic drugs.16 This last factor is considered to be a major determinant of risk associated with drug-induced LQTS when torsadogenic drugs are co-administered with other drugs in patients with polypharmacy. On one hand, it is often stated that combined administration of IKr blocking drugs (expected synergistic pharmacodynamic effects) could lead to increased QT prolongation. Although this appears to be the case, our studies have demonstrated that concomitant block of IKr was not necessarily associated with synergistic or potentiation of drug effects.46 However, our team has shown that a combined block of IKr and IKs was a...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04339634 Active, not recruiting Simulation of Risk of Adverse Drug Events Associated With th… NCT04378881 Active, not recruiting Simulation of Risk of Adverse Drug Events Associated With th… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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