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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 2  |  Page : 51-54

Remdesivir and Favipiravir for COVID-19: An update


1 Department of Cardiology, Badr Al Samaa Hospital, Muscat, Oman
2 Department of Medicine, Badr Al Samaa Hospital, Muscat, Oman

Date of Submission02-Aug-2020
Date of Decision02-Aug-2020
Date of Acceptance25-Aug-2020
Date of Web Publication07-Oct-2020

Correspondence Address:
Dr. Suman Omana Soman
Simi Bhavan, Azhoor.P.O, Perumguzhi, Trivandrum
Oman
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2666-6979.297511

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  Abstract 


COVID-19 pandemic due to SARS-CoV-2 infection has already resulted in more than 6 lakhs death worldwide. Various drugs like hydroxychloroquine, lopinavir/ritonavir, dexamethasone, ivermectin etc are examples of drugs currently used to treat COVID-19 with varying results. Remdesivir is a broad spectrum anti-viral agent, which is active against Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-1, Ebola virus etc. Favipiravir had been widely used for treating influenza pandemics in Japan in 2014 .Studies showed that it was effective for treating many RNA viruses like arenavirus, bunyavirus, flavivirus, and filoviruses causing hemorrhagic fever and Ebola virus. Remdesivir and favipiravir are anti-viral agents tried in patients with COVID-19 with varying results. Currently Remdesivir is recommended in hospitalized patients with COVID-19 requiring supplemental oxygen and favipiravir in patients with mild to moderate disease. In this article we are reviewing the pharmacological features and clinical use of Remdesivir and favipiravir in COVID-19.

Keywords: COVID-19, favipiravir, remdesivir


How to cite this article:
Soman SO, Raveendran A V. Remdesivir and Favipiravir for COVID-19: An update. Ann Clin Cardiol 2020;2:51-4

How to cite this URL:
Soman SO, Raveendran A V. Remdesivir and Favipiravir for COVID-19: An update. Ann Clin Cardiol [serial online] 2020 [cited 2020 Dec 5];2:51-4. Available from: http://www.onlineacc.org/text.asp?2020/2/2/51/297511




  Introduction Top


COVID-19 pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has already resulted in more than 6 lakhs death worldwide. The search for an effective anti-viral agent and vaccines to control the disease is a prime issue in front of the health professionals and researchers. The development of new drugs or repurposing of available agents is the option available. Various drugs such as hydroxychloroquine (HCQS), lopinavir/ritonavir, dexamethasone, ivermectinetc are examples of drugs currently used to treat COVID-19 with varying results. Remdesivir is a broad-spectrum antiviral agent, which is active against the Middle East respiratory syndrome CoV, SARS-CoV-1, Ebola virus, Nipah virus, and respiratory syncytial virus.[1],[2],[3] Favipiravir had been widely used for treating influenza pandemics in Japan in 2014.[4] Studies showed that it was effective for treating many RNA viruses such as arenavirus, flavivirus, bunyavirus, and filoviruses, causing hemorrhagic fever and Ebola virus.[5],[6],[7] It is tried in patients with COVID-19 and is in this article, we are reviewing the pharmacological features and clinical use of remdesivir and favipiravir in COVID-19.


  Remdesivir Top


Remdesivir, an adenosine nucleotide prodrug, is found to be effective in SARS-CoV-2 infection.


  Mechanism of Action Top


Remdesivir is an adenosine nucleotide prodrug. After entering into the cells, it is metabolized into pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an adenosine triphosphate analog and it competes for RNA chain incorporation by the SARS-CoV-2 RNA-dependent RNA polymerase. Incorporation of remdesivir triphosphate into the nascent RNA chain inhibits viral replication by inducing delayed termination of RNA chain [8] [Figure 1].
Figure 1: Mechanism of action of Remdesivir

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  Indication in COVID-19 Top


Remdesivir is indicated for “compassionate use” in hospitalized patients with COVID-19 who require supplemental oxygen but who are not on high-flow oxygen, noninvasive ventilation, extracorporeal membrane oxygenation, or mechanical ventilation.[9]


  Dose Recommendation Top


The recommended dose of remdesivir is 200 mg intravenous (IV) infused over 30–120 min on day 1, followed by maintenance dose of 100 mg IV once daily for days 2–5. The duration of treatment is usually 5 days. Those who do not improve after 5 days of receiving remdesivir consider extending the total treatment duration to up to 10 days.[10]


  Dose Adjustment of Remdesivir in Renal and Hepatic Dysfunction Top


The dose adjustment in patients with renal impairment is given in [Table 1]. In patients with renal impairment if the estimated glomerular filtration rate (eGFR) falls to >50% from baseline, it has to be discontinued.[11]
Table 1: Renal dose modification of remdesivir

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Remdesivir not to be used in patients with baseline alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN). If, during treatment, ALT increases ≥5 times the ULN, it has to be discontinued till ALT becomes <5 times the ULN.[11] Associated with ALT elevation if there are signs or symptoms of liver inflammation or increasing levels of conjugated bilirubin, alkaline phosphatase, or international normalized ratio, discontinue remdesivir.


  In Pregnancy Top


The safety of remdesivir during pregnancy and lactation is not known. During the Ebola virus infection, significant number of pregnant ladies received remdesivir without much issue.[12]


  Adverse Effects Top


Remdesivir can cause transaminase elevations, hence advised to perform liver function tests at baseline and daily during remdesivir administration. During intravenous administration, infusion-related reactions can occur. These include diaphoresis, nausea and vomiting, hypotension, and shivering. Other adverse effects include phlebitis, headache, ecchymosis, transient increase in prothrombin time, and blood sugar.[11]


  Drug Interaction Top


Remdesivir should not be combined with chloroquine and HCQS, as this may diminish the anti-viral effect of remdesivir.


  Monitoring Parameters Top


During treatment with remdesivir look for features of the infusion reaction and manage accordingly. Obtain baseline and daily liver function tests; hematology; renal function tests and serum chemistries.


  Clinical Evidence Top


There are case series suggesting beneficial effects of remdesivir. In one study, treatment with remdesivir is associated with 68% clinical improvement in severe cases and 100% and 71% improvement with mild and moderate disease, respectively.[13] Another randomized controlled trial (RCT) showed that remdesivir treatment is associated with 31% faster time to recovery.[14] It is also showed that the results are better if remdesivir is started early in the course of illness, within 10 days of illness.[15] Another trial of patients with severe COVID-19 showed that remdesivir treatment duration of 5 days and 10 days had similar clinical benefit.[16] Another RCT showed no improvement, and it adds to the confusion regarding the clinical benefits of remdesivir in COVID-19.[17]


  Favipiravir Top


Favipiravir, a pyrazinecarboxamide derivative prodrug, is also used to treat COVID-19.


  Mechanism of Action Top


Favipiravir is a pyrazinecarboxamide derivative prodrug, which isribosylated and phosphorylated inside the cell and forms favipiravir ibofuranosyl-5′-triphosphate, which is an active metabolite. It inhibits the enzyme RNA-dependent RNA polymerase (RdRp inhibitor) of RNA virus and it prevents elongation and proliferation of viral genome [Figure 2].[18],[19]
Figure 2: Mechanism of action of favipiravir

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  Indication in COVID-19 Top


Favipiravir is indicated for mild-to-moderate COVID-19 patients.


  Dose Recommendation Top


The estimated half-life of favipiravir is around 2–5.5 h.[20] It undergoes hydroxylation primarily by aldehyde oxidase and by xanthine oxidase. Favipiravir can start with an initial dose of 1600 mg twice a day, followed by 600 mg twice for a period of 7–10 days.[21]


  Dose Adjustment of Favipiravir in Renal and Hepatic Dysfunction Top


In people with eGFR 30–50 mL/min, the plasma level of favipiraviris was found to be about three times higher. Still, it is safe, but not preferred in people with eGFR >20 mL/min. Usually, no dose adjustment is required in renal impairment.


  In Pregnancy Top


Favipiravir is not recommended for usage in pregnancy because of its teratogenicity.[5]


  Drug Interaction Top


Favipiravir can cause potential drug interactions with pyrazinamide, theophylline, famciclovir, and sulindac.


  Monitoring Parameters Top


During treatment with favipiravir, look for features of drug reaction and manage accordingly. Obtain baseline and daily liver function tests; hematology; renal function tests, uric acid, and serum chemistries.


  Clinical Evidence Top


A randomized prospective study conducted by Chen et al. in Wuhan, China, showed that favipiravir is superior to umifenovir for treating COVID-19 patients.[22] In a nonrandomized trial by Cia et al. found that patients who received favipiravir had a faster recovery and improvement in radiological imaging compared with lopinavir/ritonavir treated COVID-19 patients.[23]


  Conclusion Top


Remdesivir and favipiravir are anti-viral agents tried in patients with COVID-19 with varying results. Currently, remdesivir is recommended in hospitalized patients with COVID-19 requiring supplemental oxygen and favipiravir in patients with mild-to-moderate disease. The on-going trials are expected to through more light into its role in patients with COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.  Back to cited text no. 1
    
2.
Brown AJ, Won JJ, Graham RL, Dinnon KH 3rd, Sims AC, Feng JY, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res 2019;169:104541.  Back to cited text no. 2
    
3.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71.  Back to cited text no. 3
    
4.
Shiraki K, Daikoku T. “Favipiravir, an anti-influenza drug against life-threatening RNA virus infections”. Pharmacol Ther 2020;209:107512.  Back to cited text no. 4
    
5.
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 2017;93:449-63.  Back to cited text no. 5
    
6.
Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, et al. Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLOS Medicine 2016;13(4):e1002009.  Back to cited text no. 6
    
7.
Bai CQ, Mu JS, Kargbo D, Song Y.B, Niu WK, Nie WM. et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone 2014. Clin. Infect Dis 2016;63: 1288-94.  Back to cited text no. 7
    
8.
Gordon CJ, Tchesnokov EP, Woolner E, Perry JK, Feng JY, Porter DP, et al. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem 2020;295:6785-97.  Back to cited text no. 8
    
9.
NIHCOVID-19 treatment guidelines. What's New in the Guidelines. Available from: https://www.covid19treatmentguidelines.nih.gov/whats-new/. [Last accessed on 2020 Sep 12].  Back to cited text no. 9
    
10.
Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA)of remdesivir (GS-5734™). 2020. Available from: https://www.fda.gov/media/137566/download. [Last accessed on 2020 Jul 23].  Back to cited text no. 10
    
11.
Singh AK, Singh A, Singh R, Misra A. Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies. Diabetes Metab Syndr 2020;14:641-8.  Back to cited text no. 11
    
12.
Mulangu S, Dodd LE, Davey RT Jr, Mbaya OT, Proschan M, Mukadi D, et al. A randomized, controlled trial of ebola virus disease therapeutics. N Engl J Med 2019;381:2293-2303.  Back to cited text no. 12
    
13.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med 2020;382:2327-36.  Back to cited text no. 13
    
14.
NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19. Available from: https://www.nih.gov/news-events/news-releases/nih-clinical- trial-shows-remdesivir-accelerates-recovery-advanced- covid-19. [Last accessed on 2020 Sep 12].  Back to cited text no. 14
    
15.
Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19.  Back to cited text no. 15
    
16.
Goldman JD, Lye DCB, Hui DS, Marks K.M, Bruno R, Montejano R et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459919. May 27, 2020 DOI: 10.1056/NEJMoa2015301.  Back to cited text no. 16
    
17.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78.  Back to cited text no. 17
    
18.
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B 2017;93:449-63.  Back to cited text no. 18
    
19.
Du YX, Chen XP. Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection. Clin Pharmacol Ther 2020;108:242-7.  Back to cited text no. 19
    
20.
Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis 2019;32:176-86.  Back to cited text no. 20
    
21.
Pharmaceuticals and Medical Devices Agency: Avigan (favipiravir) Review Report.  Back to cited text no. 21
    
22.
Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. MedRxiv 2020. (18) (PDF) Favipiravir in Covid-19. Available from: https://www.researchgate.net/publication/340781703_Favipiravir_in_Covid-19 [Last accessed on 2020 Jul 29].  Back to cited text no. 22
    
23.
Cai, Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering 2020  Back to cited text no. 23
    


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  In this article
Abstract
Introduction
Remdesivir
Mechanism of Action
Dose Recommendation
In Pregnancy
Adverse Effects
Drug Interaction
Clinical Evidence
Favipiravir
Mechanism of Action
Dose Recommendation
In Pregnancy
Drug Interaction
Clinical Evidence
Conclusion
References
Article Figures
Article Tables

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