RdRP ( IC50 = 341 nM )

Favipiravir (T 705) (30 mg/kg/day, orally) improves survival compare to placebo. At a dose of 33 mg/kg/day or more, favipiravir (T 705) offers considerable protection against the A/Duck/MN/1525/81(H5N1) virus, irrespective of the number of daily doses. Every mouse survives when fed four times a day[1].

Using the MTS-based CPE reduction assay in the MNV/RAW 264.7 cell line, the antiviral activity of Favipiravir (T 705) is assessed. Thus, 96-well plates containing 1×10⁴ cells/well of RAW 264.7 cells are seeded, and MNV is injected at a multiplicity of infection (MOI) of 0.01, either with or without a dilution series of Favipiravir (T 705) (3.13-200 μg/mL). Once the infected cells have shown full CPE after three days of incubation, cell culture supernatants are obtained and used for quantitative real-time RT-PCR (qRT-PCR) to measure the viral RNA load. A stock solution consisting of 2 mg/mL MTS and 46 g/mL PMS in PBS at pH 6-6.5 is diluted 1/20 in MEM for the MTS reduction assay. The optical density (OD) is measured at 498 nm two hours after 75 μL of MTS/PMS solution is added to each well. In order to determine the percentage of CPE reduction, one must calculate [(OD_treated)_MNW−OD_VC]/[OD_CC-OD_VC]×100. In this calculation, OD_CC denotes the OD of the untreated, uninfected cells, while OD_VC and (OD_treated)_CC stand for the treated, virus-infected cells and untreated, infected cells, respectively. The concentration of a compound that, in 50% of cases, prevented virus-induced CPE is known as the EC50. Favipiravir concentrations are applied to uninfected cells for three days in order to assess the molecule's detrimental effects on the host cell using the MTS-method. The percentage of viable cells is computed as (OD_treated/OD_CC)×100, where OD_treated refers to untreated uninfected cells treated with compound, and OD_CC is the OD of untreated uninfected cells. The concentration of a compound at which 50% fewer viable cells are present is known as the CC50. CC50/EC50 is the formula used to compute the selectivity index (SI)[2].

Absorption, Distribution and Excretion
The bioavailability of favipiravir is almost complete at 97.6%. The mean Cmax for the recommended dosing schedule of favipiravir is 51.5 ug/mL. Studies comparing the pharmacokinetic effects of multiple doses of favipiravir in healthy American and Japanese subjects are below: Japanese subjects First Dose: Cmax = 36.24 ug/mL tmax = 0.5 hr AUC = 91.40 ugxhr/mL American subjects First Dose: Cmax = 22.01 ug/mL tmax = 0.5 hr AUC = 44.11 ugxhr/mL Japanese Subjects Final Dose: Cmax = 36.23 ug/mL Tmax = 0.5 hr AUC = 215.05 ugxhr/mL American Subjects Final Dose: Cmax = 23.94 ug/mL Tmax = 0.6 hr AUC = 73.27 ugxhr/mL When favipiravir was given as a single dose of 400 mg 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.
Favipiravir's metabolites are predominantly renally cleared.
The apparent volume of distribution of favipiravir is 15 - 20 L.
The recommended oral dosing regimen for favipiravir is as follows: Day 1: 1600 mg twice daily; Days 2-5: 600 mg twice daily. The reported CL/F for favipiravir 1600 mg dosed once daily is 2.98 L/hr ±0.30 and the CL/F values for favipiravir 600 mg dosed twice daily on days 1-2 and once daily on days 3-7 were 6.72 L/hr ±1.68 on Day 1, and 2.89 L/hr ±0.91 on Day 7. There is currently no reported clearance data for favipiravir 1600 mg dosed twice daily.

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Metabolism / Metabolites
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.

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

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Favipiravir is an antiviral drug that is not approved in the United States by the US Food and Drug Administration. Information from one patient indicates that milk levels are low with a peak level at about 2 hours. One infant has reportedly been breastfed by a mother receiving favipiravir and pumping her breasts after doses with no adverse effects reported in the infant. Favipiravir has caused liver enzyme abnormalities, gastrointestinal symptoms, and serum uric acid elevations. If favipiravir is used in a nursing mother, these parameters should be monitored in the breastfed infant.
◉ Effects in Breastfed Infants
A nursing mother with a positive PCR for COVID-19 was prescribed favipiravir with a loading dose of 1600 mg twice on the first day, then 600 mg every 12 hours from day 2 to day 5. She breastfed her 15-month-old COVID-19-negative infant just before each dose of the drug. She pumped and discarded her milk between doses. No symptoms were observed in the baby during drug use and no abnormalities were detected in the baby’s hematological and biochemistry tests. The infant was followed for 6 months and was fed breastmilk and complementary feeding, did not develop any symptoms.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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

[1]. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013 Nov;100(2):446-54.

[2]. Favipiravir (T-705) inhibits in vitro norovirus replication. Biochem Biophys Res Commun. 2012 Aug 10;424(4):777-80.

Favipiravir is a member of the class of pyrazines that is pyrazine substituted by aminocarbonyl, hydroxy and fluoro groups at positions 2, 3 and 6, respectively. It is an anti-viral agent that inhibits RNA-dependent RNA polymerase of several RNA viruses and is approved for the treatment of influenza in Japan. It has a role as an antiviral drug, an anticoronaviral agent and an EC 2.7.7.48 (RNA-directed RNA polymerase) inhibitor. It is a primary carboxamide, a hydroxypyrazine and an organofluorine compound.
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.
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.

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Drug 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.

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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.

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Pharmacodynamics
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.

C5H4FN3O2

157.1

157.028

C, 38.23; H, 2.57; F, 12.09; N, 26.75; O, 20.37

259793-96-9

492405

White to off-white solid powder

1.6±0.1 g/cm3

552.6±50.0 °C at 760 mmHg

192 °C

288.0±30.1 °C

0.0±1.5 mmHg at 25°C

1.600

0.78

2

4

1

11

282

0

FC1=C([H])N([H])C(C(C(N([H])[H])=O)=N1)=O

ZCGNOVWYSGBHAU-UHFFFAOYSA-N

InChI=1S/C5H4FN3O2/c6-2-1-8-5(11)3(9-2)4(7)10/h1H,(H2,7,10)(H,8,11)

5-fluoro-2-oxo-1H-pyrazine-3-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (15.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (15.91 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (15.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.5 mg/mL (15.91 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2.5 mg/mL (15.91 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 6: 4.55 mg/mL (28.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)