INTRODUCTION:

The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes. Not only does favipiravir inhibit replication of influenza A and B, but the drug has shown promise in the treatment of avian influenza, and may be an alternative option for influenza strains that are resistant to neuramidase inhibitors. Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.

Favipiravir functions as a prodrug and undergoes ribosylation and phosphorylation intracellularly to become the active favipiravir-RTP. Favipiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp), which ultimately prevents viral transcription and replication.

With regard to COVID-19, lay media have reported on a non-placebo, open-label trial in Shenzhen, China, of oral favipiravir (1600mg twice daily for 1 day, then 600mg twice daily) plus inhaled interferon compared with a historical cohort of patients receiving lopinavir/ritonavir for 14 days (Med News Today; 2020 Mar 27). Those receiving favipiravir and interferon had median shedding of virus of 4 days, compared with 11 days in the lopinavir/ritonavir group. Radiographic improvement was seen in 91% of favipiravir-interferon treated subjects compared with 62% of those on lopinavir/ritonavir. The results of this study have not been published in a peer-reviewed journal to date. A prospective, multicenter, open-label, randomized trial in China comparing favipiravir with umifenovir (Arbidol), a membrane-fusion inhibitor active against influenza viruses, was recently reported (MedRxiv 2020 Mar 27; [e-pub]). It demonstrated a higher clinical recovery rate at day 7 in those on favipiravir among moderately ill patients but not among mildly or severely ill patients. ^[1,2,3]

Structure

6-fluoro-3-hydroxypyrazine-2-carboxamide

IUPAC Name:

6-fluoro-3-hydroxypyrazine-2-carboxamide.

Indication:

In 2014, favipiravir was approved in Japan to treat cases of influenza that were unresponsive to conventional treatment. Given its efficacy at targetting several strains of influenza, it has been investigated in other countries to treat novel viruses including Ebola and most recently COVID-19^[2,3]

Pharmacodynamics:

Mechanism of action:

The mechanism of action of favipiravir is novel compared to existing influenza antivirals that primarily prevent entry and exit of the virus from cells. The active favipiravir-RTP selectively inhibits RNA polymerase and prevents replication of the viral genome.There are several hypotheses as to how favipiravir-RTP interacts with RNA dependent RNA polymerase (RdRp). Some studies have shown that when favipiravir-RTP is incorporated into a nascent RNA strand, it prevents RNA strand elongation and viral proliferation. Studies have also found that the presence of purine analogs can reduce favipiravir’s antiviral activity, suggesting competition between favipiravir-RTP and purine nucleosides for RdRp binding.

Although favipiravir was originally developed to treat influenza, the RdRp catalytic domain (favipiravir's primary target), is expected to be similar for other RNA viruses. This conserved RdRp catalytic domain contributes to favipiravir's broad-spectrum coverage^[1,2,3]

Absorption:

The bioavailability of favipiravir is almost complete at 97.6%. The mean Cmax for the recommended dosing schedule of favipiravir is 51.5ug/mL. When favipiravir was given as a single dose of 400mg with food, the Cmax decreased. It appears that when favipiravir is given at a higher dose or in multiple doses, irreversible inhibition of aldehyde oxidase (AO) occurs and the effect of food on the Cmax is lessened.

Volume of distribution:

The apparent volume of distribution of favipiravir is 15 - 20 L.^[1,2,3]

Protein binding:

avipiravir is 54% plasma protein-bound. Of this fraction, 65% is bound to serum albumin and 6.5% is bound to ɑ1-acid glycoprotein.

Metabolism:

Favipiravir is extensively metabolized with metabolites excreted mainly in the urine. The antiviral undergoes hydroxylation primarily by aldehyde oxidase and to a lesser extent by xanthine oxidase to the inactive metabolite, T705M1.^[2,3]

Route of elimination:

Favipiravir's metabolites are predominantly renally cleared

Half life:

The elimination half-life of favipiravir is estimated to range from 2 to 5.5 hours.

Toxicity:

Based on single-dose toxicity studies, the lethal dose for oral and intravenous favipiravir in mice is estimated to be >2000mg/kg. In rats, the lethal dose for oral administration is >2000mg/kg, while the lethal dose in dogs and monkeys is >1000mg/kg. Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.^[,3,4,5]

Uses:

Favipiravir has been approved to treat influenza in Japan. It is, however, only indicated for novel influenza (strains that cause more severe disease) rather than seasonal influenza. As of 2020, the probability of resistance developing appears low. Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.^[,7,8,9]

COVID-19:

In February 2020, favipiravir was being studied in China for experimental treatment of the emergent COVID-19. Trials are also being planned in Japan. A study on 80 people in comarison to lopinavir/ritonavir found that it reduced viral clearance time, and that 91% of people had improved CT scans with few side effects. The limitation of this study was that it was not randomized double-blinded and placebo-controlled.

The drug has been approved for use in clinical trials of coronavirus disease 2019 in China. In March 2020, Italy approved the drug for experimental use against COVID-19 and has begun conducting trials in three regions most affected by the disease. The Italian Pharmaceutical Agency, however, has reminded the public that the existing evidence in support of this drug is scant and preliminary. There are plans to study it in three hospitals in Massachusetts, USA as of April 20, 2020. As of early May 2020, a trial is starting in London, UK.^[,7,8,9]

The drug was approved for the treatment of COVID-19 in the hospital settings in Russia on May 29, 2020, after an ongoing open-label randomized clinical trial had recruited 60 subjects on favipiravir. According to the government clinical trial registry, this study COVID-FPR-01 is expected to recruit 390 subjects overall and finish by December 31, 2020. On May 30, 2020, the Russian Health Ministry approved a generic version of favipiravir named Avifavir. RDIF backed the development of Avifavir and found it highly effective in the first phase of clinical trials.^[7,8,]

Ebola:

Research in 2014 suggested that favipiravir may have efficacy against Ebola based on studies in mouse models; efficacy in humans was unaddressed. During the 2014 West Africa Ebola virus outbreak, a French nurse who contracted Ebola while volunteering for MSF in Liberia reportedly recovered after receiving a course of favipiravir. A clinical trial investigating the use of favipiravir against Ebola virus disease began in Guéckédou, Guinea, in December 2014. Preliminary results presented in 2016 at the Conference on Retroviruses and Opportunistic Infections (CROI), later published, showed a decrease in mortality in patients with low-to-moderate levels of virus in blood, but no effect on patients with high levels (the group at a higher risk of death). The trial design was concomitantly criticised for using only historical controls. ^[8,9,10,11]

Experimental Properties:

PROPERTY	VALUE
melting point (°C)	187℃ to 193℃
water solubility	slightly soluble in water
pKa	5.1

Predicted Properties:

PROPERTY	VALUE
Water Solubility	8.7 mg/mL
logP	.49
logP	0.25
pKa (Strongest Acidic)	9.39
Hydrogen Acceptor Count	4
Refractivity	33.98 m³·mol^-1

CONCLUSION:

Favipiravir is a pyrazinecarboxamide derivative with activity against RNA viruses. Favipiravir is converted to the ribofuranosyltriphosphate derivative by host enzymes and selectively inhibits the influenza viral RNA-dependent RNA polymerase. Favipiravir is a member of pyrazines and a primary carboxamide. Discovered by Toyama Chemical Co., Ltd. in Japan, favipiravir is a modified pyrazine analog that was initially approved for therapeutic use in resistant cases of influenza. The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes. Not only does favipiravir inhibit replication of influenza A and B, but the drug has shown promise in the treatment of avian influenza, and may be an alternative option for influenza strains that are resistant to neuramidase inhibitors. Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.

ACKNOWLEDGEMENT:

The authors would like to thanks Shree. Sureshadada Jain Institutes of Pharmaceutical Education and Reasearch, Jamner Maharashtra (India) for supporting the fulfillment of this work.

REFERENCES:

1. www.drug bank.com

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4. Gowen BB, Wong MH, Jung KH, Sanders AB, Mendenhall M, Bailey KW, Furuta Y, Sidwell RW: In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob Agents Chemother. 2007 Sep;51(9):3168-76. Epub 2007 Jul 2. [PubMed:17606691]

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6. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K: Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother. 2005 Mar;49(3):981-6. [PubMed:15728892]

7. Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Watanabe Y, Narita H, Shiraki K: In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother. 2002 Apr; 46(4):977-81. [PubMed:11897578]

8. 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(7):449-463. doi: 10.2183/pjab.93.027. [PubMed:28769016]

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11. Madelain V, Nguyen TH, Olivo A, de Lamballerie X, Guedj J, Taburet AM, Mentre F: Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clin Pharmacokinet. 2016 Aug;55(8):907-23. doi: 10.1007/s40262-015-0364-1. [PubMed:26798032]

Received on 21.06.2020 Revised on 19.09.2020

Asian J. Pharm. Res. 2021; 11(1):39-42.

DOI: 10.5958/2231-5691.2021.00008.3