Daniel S. Streetman, PharmD, MS, and Carrie W. Nemerovski, PharmD 

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 

 that more than 137,000 Americans will die by early August.

 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.

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 

 that it would be testing remdesivir in combination with the anti-inflammatory drug baricitinib.

 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 clinical relevance of these in vitro assessments has not been established, and whether remdesivir would be a clinically relevant victim or perpetrator of drug interactions is still unknown. Because remdesivir is rapidly distributed into peripheral blood mononuclear cells where it is converted to the active nucleotide triphosphate metabolite (GS-443902), the potential for clinically meaningful CYP or transporter mediated drug interaction is low. However, due to a lack of drug interaction studies in humans, pharmacokinetic interactions cannot be completely ruled out, and it seems prudent to minimize the concurrent use of any nonessential medications whenever possible. This is important information that must be considered when prescribing the drug and should be clearly communicated to patients.


	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.

 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.

IL-6 pathway inhibitors such as tocilizumab, sarilumab, and siltuximab are being studied for their potentially beneficial ability to limit the cytokine response that may be seen in some patients with COVID-19.

One unique drug interaction consideration with these drugs is their effect on drug metabolism. Inflammation itself has been shown to impair hepatic drug metabolism, so drugs that can substantially reduce the systemic inflammation could restore normal levels of drug metabolism. Indeed, studies of IL-6 inhibitors have reported 36% to 57% reductions in exposure to some CYP3A4 substrates following just 1 dose. Exposure to CYP2D6 and CYP2C19 substrates has been reduced by 5% to 28%, respectively. Although these effects are thought to reflect remediation of cytokine-associated reductions in drug metabolism, the precise etiology of these changes is not certain. This raises some question about whether these effects would apply to all disease states-including COVID-19. In addition to these effects on drug metabolism, all these drugs impair immune function to such a degree that live vaccines should not be given to patients who are being treated with an IL-6 pathway inhibitor.

Several other medications are also being investigated or discussed as possible treatments for COVID-19 infections. Drugs with the most significant interaction concerns, those most widely discussed, or the newer agents are highlighted below.

An IL-1 receptor antagonist, anakinra causes notable immunosuppression. Due to these immunosuppressive effects, anakinra may affect the safety and effectiveness of vaccines, and concomitant use with other immunosuppressants may be concerning.

Baricitinib is a Janus Kinase inhibitor with anti-inflammatory actions that may also impair SARS-CoV endocytosis. Encouraging findings in a small pilot study have led to increased interest in its potential value as a part of a combination treatment. Baricitinib is a substrate of OAT3, and inhibition of OAT3 by potent inhibitors like probenecid may significantly increase exposure to baricitinib. Baricitinib dose reductions are recommended if used with probenecid. Additionally, like anakinra, baricitinib has immunosuppressive effects, and concomitant use with other immunosuppressants may result in additive immunosuppression and AEs. Live vaccines should not be given to patients who are being treated with baricitinib.

This antimalarial medication that is closely related to hydroxychloroquine also has the potential to cause dangerous QT interval prolongation (with more clinical evidence of harm than is available for hydroxychloroquine) and has been shown to lower blood glucose concentrations, similar to the effect seen with hydroxychloroquine. Thus, there is concern with any concurrent use of medications that can prolong the QT interval (ie, azithromycin), or drugs capable of lowering blood glucose concentrations.

Convalescent plasma; anti-COVID-19 human or equine antibodies

As immunoglobulins generally have very few drug interactions, anti-COVID-19 antibodies from recovered patients are not expected to have significant drug interaction concerns. However, because several different antibodies are often contained in immunoglobin products or plasma, they may inactivate live vaccines and diminish vaccine effectiveness.

Darunavir/cobicistat; Lopinavir/ritonavir

These agents are anti-HIV protease inhibitors and have a large number of significant drug interaction concerns, primarily related to their ability to strongly inhibit CYP3A4. These are also substrates for CYP3A4, raising drug interaction concerns when combined with enzyme inducers such as the rifamycins or enzyme-inducing antiepileptic drugs.

Favipiravir is an RNA polymerase inhibitor. Most drug interaction concerns with favipiravir are of minimal or uncertain clinical significance. 

 describes significant QT-prolongation, but the patient had several other risk factors for QT interval prolongation that call into question the role of favipiravir.

 Favipiravir is also a weak CYP2C8 inhibitor, but this is unlikely to result in many clinically significant interactions.

Interferons have a diverse set of actions in the body, and several different interferons are being evaluated as possible treatments based on their activity against a wide variety of viruses and in vitro activity against SARA-CoV and MERS-CoV. Although both alpha and beta interferons are of interest, encouraging results with interferon beta-1b in one clinical study has increased interest in beta interferons. Interferons have been associated with increased hematologic and other side effects when combined with zidovudine, and alpha interferons are potentially myelosuppressive and are weak CYP1A2 inhibitors. Other than these, interferons have relatively few significant drug interaction concerns.

Umifenovir (Arbidol) is a broad-spectrum antiviral that appears to inhibit viral entry but may also have other antiviral actions. In vitro studies have concluded CYP3A4 and FMO3 are the primary enzymes responsible for umifenovir metabolism, suggesting that inhibitors and inducers of CYP3A4 may cause potentially significant interactions.

Drug treatments for COVID-19 will evolve with our understanding of the virus. Currently, there are no drugs or other therapeutics approved by the FDA to prevent or treat COVID-19.  However, as more evidence emerges and literature is published to support decision making during this critical time, we will move closer to developing a treatment for widespread use in the United States and beyond. Until then, we must remain vigilant in considering drug interactions as we explore our options.

Dr Daniel S. Streetman, PharmD, MS, is the manager of referential content in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health. He completed a research fellowship in clinical pharmacology, with an emphasis in pharmacogenomics, at Bassett Healthcare in Cooperstown, NY, and was a clinical faculty member at the University of Michigan for several years prior to joining Wolters Kluwer. Dr Streetman continues to maintain an academic relationship with several schools, lecturing on pharmacogenomics and other topics.

Dr Carrie W. Nemerovski, PharmD, is a senior clinical content specialist in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health. She completed her PharmD, a PGY1 residency, and PGY2 residency in cardiology at the University of Michigan. She worked as a clinical faculty member at Wayne State University and as a clinical pharmacy specialist at Henry Ford Hospital prior to joining Wolters Kluwer. Dr Nemerovski continues to maintain an academic relationship with the University of Michigan, serves as a regular peer reviewer, and is active in professional pharmacy organizations.

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. 

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. 

. 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. 

. 2015;53(10):866â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

Articles

A close look at their potential to interact with other medications is required to limit the risk of adverse outcomes for patients.

Author | Daniel S. Streetman, PharmD, MS, and Carrie W. Nemerovski, PharmD

Articles

Drug Interaction Concerns for Potential COVID-19 Treatments