Interleukin-6 Pathway Inhibitors
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.
Other Potential Treatments
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. One case report describes significant QT-prolongation, but the patient had several other risk factors for QT interval prolongation that call into question the role of favipiravir.5 Additionally, a single-dose controlled study showed no significant QT prolongation.6 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. 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