In Vitro Safety “Clinical Trial” of the Cardiac Liability of Hydroxychloroquine and Azithromycin as COVID19 Polytherapy

  1. Bérénice Charrez
  2. Verena Charwat
  3. Brian Siemons
  4. Henrik Finsberg
  5. Evan Miller
  6. Andrew G. Edwards
  7. Kevin E. Healy

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Abstract

Despite global efforts, there are no effective FDA-approved medicines for the treatment of SARS-CoV-2 infection. Potential therapeutics focus on repurposed drugs, some with cardiac liabilities. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock clinical trial. The MPS contained human heart muscle derived from patient-specific induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements such as QT interval (action potential duration) and drug-biomarker pairing.

Chronic exposure to HCQ alone elicited early afterdepolarizations (EADs) and increased QT interval from day 6 onwards. AZM alone elicited an increase in QT interval from day 7 onwards and arrhythmias were observed at days 8 and 10. Monotherapy results closely mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4-8.. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Furthermore, biomarkers, most of them measurable in patients’ serum, were identified for negative effects of single drug or polytherapy on tissue contractile function, morphology, and antioxidant protection.

The cardiac MPS can predict clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe COVID-19 therapeutics.

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  1. Version published to 10.1101/2020.12.21.423869v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.12.21.423869: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    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:
    Limitations: Clinical QT interval values represent the summation of all the electrical activity in the ventricles. We used APD80 as a proxy for clinical QT prolongation, which is a credible and common approach to compare directional effects and provide some mechanistic insight, but is not sufficiently sensitive for precise prediction of instability thresholds [30]. COVID-19 patients with drug-induced QT interval changes of > 60 ms or QT interval values above 500ms are considered high risk, and treatment is suspended[32]. Our cardiac muscle exhibited unphysiologically high APD80 values in response to chronic drug exposure. The mechanism for these large responses is unclear, but likely related to a combination of the hiPSC source, well-known modest maturity of hiPSC-CMs relative to the adult human heart, and possibly due to the altered current source-sink relationship in these very small tissues. Additionally, we have used a single patient line to perform this study, albeit with a significant number of replicates. By screening more patient lines one can achieve a clinically relevant dataset; although anticipated patient variability will require further expansion of the data size. In future work, this study can be extended to diseased cell lines to better understand the arrhythmic risk of patients with cardiovascular complications or comorbidities (i.e., diabetes) who are most likely to be seriously affected by SARS-CoV2. Study highlight:

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2020.12.21.423869v1 on bioRxiv