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The ongoing COVID-19 pandemic crisis has been complicated and worsened by the lack of recognized and/or FDA-approved drug therapies for the novel coronavirus. Concerted efforts to evaluate existing antiviral therapies for COVID-19 patients are now underway. Two drugs currently of significant interest and under investigation are favipiravir (“FAVI”) and remdesivir. As noted in our March 27, 2020 APSF Newsletter post, we cannot comment on the overall appropriateness, advisability, and/or efficacy of any specific COVID-19 therapy. However, reviews of the currently available online information and peer-review literature indicate that these drugs may be relatively uninvolved in significant drug-drug interactions (DDIs), especially compared to other antivirals such as CQ/HCQ and lopinavir/ritonavir.
(T705 or Avigan) does not hold approval in the US for any indication but is currently approved in Japan and China for the treatment of influenza and/or novel influenza. The primary package insert is in Japanese but English language drug information for FAVI is readily available online.1,2,3 It has been approved for experimental use and/or is in clinical trials in the US, Italy, Japan, and China to treat patients with the novel coronavirus.
FAVI is a pro-drug. It requires in vivo conversion via human hypoxanthine guanine phosphoribosyltransferase (HGPRT) to an active metabolite in order to exert an antiviral effect. Because acyclovir is known to be an in vitro inhibitor of HGPRT, it is a theoretical concern that co-administration of these two drugs could impair the efficacy of FAVI. The problematic drug pair of FAVI and acyclovir is not at all unlikely, since latent viral herpetic reactivation can occur with other viral or bacterial concomitant infections in medically challenged and critically ill COVID-19 patients.4,5. Thus, clinicians prescribing acyclovir for a patient already receiving FAVI must consider the possibility of decreased FAVI efficacy against the novel coronavirus due to decreased prodrug conversion.
Final metabolism of FAVI is not thought to be primarily mediated by microsomal enzymes (i.e., the cytochrome P450 system), but rather by aldehyde oxidase (AO) and xanthine oxidase in the hepatocyte cytosol.6 There are no direct reports of the effect of AO inhibition on FPV, however the literature contains at least one reported in vitro DDI between a different AO substrate-inhibitor pair, namely zaleplon (an oral sedative-hypnotic) and cimetidine, respectively.7 So, although the literature lacks any definitive reports directly involving FAVI, clinicians should note that co-administration of the drug with AO inhibitors such as cimetidine, tamoxifen, phenothiazines, verapamil, amlodipine, nifedipine, loratidine, cyclobenzaprine, ondansetron, ketoconazole, and could theoretically raise blood levels of active FAVI metabolites.
Clinicians should also be aware that FAVI is associated with alterations in acetaminophen metabolism, specifically inhibition of acetaminophen sulfate formation.8 In order to avoid accumulation of toxic acetaminophen metabolites (such as NAPQI) while taking FAVI, the maximum acetaminophen dosage should not exceed 3000 mg per day.
Finally, per the drug sheets, please note that FAVI, although not a CYP450 substrate, is a possible CYP2C8 inhibitor. Therefore, co-administration with CYP2C8 substrates such as paclitaxel, repaglinide and rosiglitazone (oral hypoglycemics), torasemide (loop diuretic), and buprenorphine may pose a risk for increased drug effects of these co-administered drugs.
Remdesivir is an investigational drug, now in clinical trials in the US. Because COVID -19 is a RNA virus and remdesivir resembles an RNA subunit, incorporation of this drug into the viral RNA halts replication.9 Because this is not an FDA-approved drug, fully-developed US package insert information is unfortunately not available. Therefore, a distinct lack of rigorously verified DDI information is available to clinicians.
Remdesivir is apparently an in vitro substrate of CYP2C8, 2D6, and 3A4. However, the most current understanding is that in vivo remdesivir metabolism is dominated by hydrolase activity, which would suggest that the range of possible DDIs with clinically relevant CYP2C8/2D6/3A4 inhibitors and inducers is unlikely to occur.10
As part of our online search for remdesivir DDIs, we reviewed a website entitled “Interactions with Experimental COVID-19 Therapies”, compiled by the Liverpool Drug Interaction Group. This compilation contains tables that detail potential DDIs for , (as well as FAVI and other possible COVID-19 antiviral therapies), with numerous other medications spanning a wide range of therapeutic classes. However, in our brief acquaintance with this website, we have so far found it to be quite sensitive but rather non-specific. This reflects the mechanism-driven nature of the tabular content, which has not necessarily been rigorously validated by a search for empirically-verified findings.
For example, the database indicates that the combination of remdesivir with carbamazepine would yield significantly decreased remdesivir levels, when this has never been empirically demonstrated, and the quite minor contribution of CYP3A4 to remdesivir metabolism renders this much less likely than it might theoretically seem at first glance.8 So, while we cannot conclude that the specified DDI information pertaining to remdesivir has been rigorously verified, it seems that the website might be useful as an adjunct to direct targeted inquiries into potential DDIs involving remdesivir (and other possible COVID-19 therapeutic agents) as well as a potential, although we believe over-inclusive, reference for the clinician prescribing anti-viral therapies for the novel coronavirus.
Because FAVI and remdesivir are so new, not all possible DDIs will have been anticipated in pre-marketing studies. The fact that there are few, if any, substantiated reports of DDIs in the peer-reviewed literature at present should not lull prescribing physicians into a false sense of security. Notwithstanding the lack of pre-existing clinical confirmation, problems may arise when these drugs are combined with other agents in complex regimens and seemingly inexplicable reactions can occur. These deleterious events may be a result of unexpected and previously undescribed DDIs as well as idiosyncratic side-effects. Clinical vigilance is warranted at all times when administering FAVI and remdesivir.
- https://www.drugbank.ca/drugs/DB12466. Last accessed April 16, 2020.
- https://www.pmda.go.jp/files/000210319.pdf. Last accessed April 16, 2020.
- https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.1844. Last accessed April 16, 2020.
- Ansari MY, Dikhit MR, Sahoo GC, Das P. Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP. Int J Biol Macromol. 2012 Apr 1;50(3):637-49. Epub 2012 Feb 3.
- Campbell J, Trgovcich J, Kincaid M, Zimmerman PD, Klenerman P, Sims S, Cook CH. Transient CD8-memory contraction: a potential contributor to latent cytomegalovirus reactivation. J Leukoc Biol, 2012 Jun;92(5):933-937.
- Madelain V, Nguyen T, Olivo A, De Lamballerie X, Guedj J, Taburet A-M, Mentre F. Ebola Virus Infection: a review on the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials. Clin Pharmacokinet. 2016 Aug; 55(8):907-923
- Renwick AB, Ball SE, Tredger JM, Price RJ, Walters DG, Kao J, Scatina JA, Lake BG. Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro studies with subcellular fractions and precision-cut liver slices. 2002 Oct;32(10):849-62
- Zhao Y, Harmatz JS, Epstein CR, Nakagawa Y, Kurosaki C, Nakamura T, Kadota T, Giesing D, Court MH, Greenblatt DJ. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br J Clin Pharmacol. 2015 Nov;80(5):1076-85. Epub 2015 Jun 8.
- Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. 2020 Apr 10;295(15):4773-4779. Epub 2020 Feb 24.
- McCreary EK, Pogue JM. Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options. Open Forum Infectious Diseases, Volume 7, Issue 4, April 2020. https://doi.org/10.1093/ofid/ofaa105. Last accessed April 16, 2020.