As states begin to relax the measures put in place to “flatten the curve” of coronavirus disease 2019 (COVID-19) infections and businesses across the country slowly reopen, the Institute for Health Metrics and Evaluation at the University of Washington projects that more than 137,000 Americans will die by early August.1
The National Institutes of Health (NIH) notes that a single, effective vaccine approach will likely be required to successfully protect the global community from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.2 This is, like everything else about the pandemic, an informational moving target. Every day there are new ideas, new evidence, old possibilities disproved, and clinicians and researchers on the front lines share the benefit of their experiences.
For those of us who work every day evaluating studies of different therapies, we believe it is essential that even as we monitor information and best practices about the most effective treatments for COVID-19, we must also pay attention to existing and emerging evidence about potentially dangerous drug interactions.
Remdesivir, hydroxychloroquine, and interleukin-6 (IL-6) pathway inhibitors are some of the most commonly-discussed medications being used to treat COVID-19 today, but they are not without potentially harmful adverse effects (AEs) or drug interactions. A close look at their potential to interact with other medications is required to limit the risk of adverse outcomes for patients.
Remdesivir (GS-5734) is an investigational nucleotide analogue with broad-spectrum activity against several coronaviruses that has been made available under an emergency use authorization (EUA) to treat suspected or laboratory confirmed COVID-19 in adults and children hospitalized with severe disease. Encouraging early data has prompted the National Institute of Allergy and Infectious Diseases (NIAID) to announce that it would be testing remdesivir in combination with the anti-inflammatory drug baricitinib.3 The clinical trial is the next iteration of NIAID’s Adaptive COVID-19 Treatment Trial (ACTT) and it will evaluate whether adding an anti-inflammatory agent to the remdesivir regimen can provide additional benefit for patients, including improving mortality outcomes.
Despite its EUA, there remains limited information about potential drug interactions with remdesivir, most of which is limited to in vitro data. Remdesivir appears to be a substrate for the drug metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, as well as a substrate for organic anion transporting polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. Additionally, in vitro, remdesivir is capable of inhibiting CYP3A4, OATP1B1/1B3, bile salt export pump (BSEP), multidrug resistance-associated protein-4 (MRP4), and sodium/bile acid cotransporter (NTCP).
The major drug interaction concern with hydroxychloroquine, another drug making headlines regarding its potential role in treating COVID-19, is its ability to prolong the QT interval, possibly increasing the risk for arrhythmias, a risk that may be greater in patients being treated for COVID-19.
Prior to the recent surge in hydroxychloroquine use as a possible treatment for COVID-19 infections, there was little published data supporting significant QT prolongation with hydroxychloroquine, and it mostly consisted of a small number of case reports in patients with a diverse set of risk factors.
However, many publications in the past weeks have described the potential cardiac risks of hydroxychloroquine in patients with COVID-19, particularly when combined with azithromycin, which itself is categorized as a moderate risk QT-prolonging drug.
There are several guideline panels, including the American College of Cardiology, that recommend that patients with COVID-19 who are being treated with hydroxychloroquine discontinue any non-critical drugs that can prolong the QT interval.4 In addition, these patients should be monitored closely for evidence of significant QT prolongation, particularly when used in conjunction with other agents that prolong the QT, such as azithromycin.
Another drug interaction concern with hydroxychloroquine is its potential to lower blood glucose concentrations, which could be a concern in patients who are receiving other blood glucose-lowering medications. This effect has been reported in both patients with and without diabetes, and hydroxychloroquine labeling states that patients taking hydroxychloroquine should be warned about the risk and signs/symptoms of hypoglycemia. The exact mechanism for this effect is not certain.
1. COVID-19 Projections: United States of America Institute for Health Metrics and Evaluation University of Washington; May 18, 2020. Accessed May 18, 2020. https://covid19.healthdata.org/united-states-of-america
2. Coordinated strategy to accelerate multiple COVID-19 vaccine candidates is key, NIH experts say. News Release. National Institutes of Health, US Department of Health and Human Services; May 11, 2020. Accessed May 11, 2020.
3. NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins. National Institutes of Health, US Department of Health and Human Services; May 8, 2020. Accessed May 8, 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib-covid-19-begins
4. Simpson TF, Kovacs RJ, Stecker EC. Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19. Cardiology Magazine. March 29, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19
5. Chinello P, Petrosillo N, Pittalis S, et al. QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis. 2017;11(12):e0006034. doi:10.1371/journal.pntd.0006034
6. Kumagai Y, Murakawa Y, Hasunuma T, et al. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015;53(10):866‐874. doi:10.5414/CP202388
7. Information for Clinicians on Investigational Therapeutics for Patients with COVID-19. CDC. Updated April 25, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html