Favipiravir

Identification

Summary

Favipiravir is an antiviral used to manage influenza, and that has the potential to target other viral infections.

Generic Name

Favipiravir

DrugBank Accession Number

DB12466

Background

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.^7,9 The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes.^7,12,13

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.^9,19 Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.^10,14,15

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Favipiravir (DB12466)

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Weight

Average: 157.104
Monoisotopic: 157.028754544

Chemical Formula

C₅H₄FN₃O₂

Synonyms

• Fapilavir
• Favilavir
• Favipiravir

External IDs

• T 705
• T-705
• T705

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Pharmacology

Indication

In 2014, favipiravir was approved in Japan to treat cases of influenza that were unresponsive to conventional treatment.⁹ 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.^7,10,17

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Treatment resistant novel influenza		••••••••••••
Treatment of	Treatment resistant reemerging influenza		••••••••••••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Favipiravir functions as a prodrug and undergoes ribosylation and phosphorylation intracellularly to become the active favipiravir-RTP.^7,10 Favipiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp), which ultimately prevents viral transcription and replication.^7,8

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.⁷ The active favipiravir-RTP selectively inhibits RNA polymerase and prevents replication of the viral genome.¹⁸ There are several hypotheses as to how favipiravir-RTP interacts with RNA dependent RNA polymerase (RdRp).⁷ Some studies have shown that when favipiravir-RTP is incorporated into a nascent RNA strand, it prevents RNA strand elongation and viral proliferation.⁷ 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.⁷

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.⁷ This conserved RdRp catalytic domain contributes to favipiravir's broad-spectrum coverage.⁷

Target	Actions	Organism
ARNA-directed RNA polymerase catalytic subunit	Not Available	Influenza A virus (strain A/Silky Chicken/Hong Kong/SF189/2001 H5N1 genotype A)

Absorption

The bioavailability of favipiravir is almost complete at 97.6%.¹⁸ The mean Cmax for the recommended dosing schedule of favipiravir is 51.5 ug/mL.¹⁸

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.¹⁸ 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.¹⁸

Volume of distribution

The apparent volume of distribution of favipiravir is 15 - 20 L.¹¹

Protein binding

Favipiravir is 54% plasma protein-bound.⁹ Of this fraction, 65% is bound to serum albumin and 6.5% is bound to ɑ1-acid glycoprotein.¹⁸

Metabolism

Favipiravir is extensively metabolized with metabolites excreted mainly in the urine.¹⁰ The antiviral undergoes hydroxylation primarily by aldehyde oxidase and to a lesser extent by xanthine oxidase to the inactive metabolite, T705M1.¹⁰

Hover over products below to view reaction partners

• Favipiravir
  • T705M1
  • M2 (favipiravir glucuronide conjugate)

Route of elimination

Favipiravir's metabolites are predominantly renally cleared.⁹

Half-life

The elimination half-life of favipiravir is estimated to range from 2 to 5.5 hours.⁹

Clearance

The recommended oral dosing regimen for favipiravir is as follows: Day 1: 1600 mg twice daily; Days 2-5: 600 mg twice daily.¹⁸

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 7.¹⁸ There is currently no reported clearance data for favipiravir 1600 mg dosed twice daily.

Adverse Effects

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Toxicity

Based on single-dose toxicity studies, the lethal dose for oral and intravenous favipiravir in mice is estimated to be >2000 mg/kg.¹⁸ In rats, the lethal dose for oral administration is >2000 mg/kg, while the lethal dose in dogs and monkeys is >1000 mg/kg.¹⁸ Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.¹⁸

In repeat-dose toxicity studies involving dogs, rats, and monkeys, notable findings after administration of oral favipiravir included: adverse effects on hematopoietic tissues such as decreased red blood cell (RBC) production, and increases in liver function parameters such as aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin, and increased vacuolization in hepatocytes.¹⁸ Testis toxicity was also noted.¹⁸

Favipiravir is known to be teratogenic; therefore, administration of favipiravir should be avoided in women if pregnancy is confirmed or suspected.^7,16

Toxicity information regarding favipiravir in humans is not readily available.

Pathways

Not Available

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Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Favipiravir.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Favipiravir.
Acetaminophen	Favipiravir may increase the hepatotoxic activities of Acetaminophen.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Favipiravir.
Adefovir dipivoxil	The excretion of Adefovir dipivoxil can be decreased when combined with Favipiravir.

Food Interactions

No interactions found.

Products

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International/Other Brands

Avigan

Categories

ATC Codes

J05AX27 — Favipiravir

• J05AX — Other antivirals
• J05A — DIRECT ACTING ANTIVIRALS
• J05 — ANTIVIRALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Anti-Infective Agents
• Antiinfectives for Systemic Use
• Antiviral Agents
• Antivirals for Systemic Use
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2E1 Inhibitors
• Cytochrome P-450 CYP2E1 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• Direct Acting Antivirals
• Experimental Unapproved Treatments for COVID-19
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• P-glycoprotein inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as pyrazinecarboxamides. These are compounds containing a pyrazine ring which bears a carboxamide.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazines

Sub Class

Pyrazines

Direct Parent

Pyrazinecarboxamides

Alternative Parents

2-heteroaryl carboxamides / Aryl fluorides / Vinylogous amides / Heteroaromatic compounds / Primary carboxylic acid amides / Lactams / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives

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Substituents

2-heteroaryl carboxamide / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Carboxamide group / Carboxylic acid derivative / Heteroaromatic compound / Hydrocarbon derivative / Lactam / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Primary carboxylic acid amide / Pyrazinecarboxamide / Vinylogous amide

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

EW5GL2X7E0

CAS number

259793-96-9

InChI Key

ZCGNOVWYSGBHAU-UHFFFAOYSA-N

InChI

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

IUPAC Name

6-fluoro-3-hydroxypyrazine-2-carboxamide

SMILES

NC(=O)C1=NC(F)=CN=C1O

References

General References

1. Beigel J, Bray M: Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102. doi: 10.1016/j.antiviral.2008.01.003. Epub 2008 Feb 4. [Article]
2. Hsieh HP, Hsu JT: Strategies of development of antiviral agents directed against influenza virus replication. Curr Pharm Des. 2007;13(34):3531-42. [Article]
3. 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. [Article]
4. Sidwell RW, Barnard DL, Day CW, Smee DF, Bailey KW, Wong MH, Morrey JD, Furuta Y: Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrob Agents Chemother. 2007 Mar;51(3):845-51. Epub 2006 Dec 28. [Article]
5. 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. [Article]
6. 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. [Article]
7. 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. [Article]
8. Venkataraman S, Prasad BVLS, Selvarajan R: RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. Viruses. 2018 Feb 10;10(2). pii: v10020076. doi: 10.3390/v10020076. [Article]
9. Hayden FG, Shindo N: Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019 Apr;32(2):176-186. doi: 10.1097/QCO.0000000000000532. [Article]
10. 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. [Article]
11. Nguyen TH, Guedj J, Anglaret X, Laouenan C, Madelain V, Taburet AM, Baize S, Sissoko D, Pastorino B, Rodallec A, Piorkowski G, Carazo S, Conde MN, Gala JL, Bore JA, Carbonnelle C, Jacquot F, Raoul H, Malvy D, de Lamballerie X, Mentre F: Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl Trop Dis. 2017 Feb 23;11(2):e0005389. doi: 10.1371/journal.pntd.0005389. eCollection 2017 Feb. [Article]
12. de Farias ST, Dos Santos Junior AP, Rego TG, Jose MV: Origin and Evolution of RNA-Dependent RNA Polymerase. Front Genet. 2017 Sep 20;8:125. doi: 10.3389/fgene.2017.00125. eCollection 2017. [Article]
13. Shu B, Gong P: Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation. Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):E4005-14. doi: 10.1073/pnas.1602591113. Epub 2016 Jun 23. [Article]
14. Nagata T, Lefor AK, Hasegawa M, Ishii M: Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep. 2015 Feb;9(1):79-81. doi: 10.1017/dmp.2014.151. Epub 2014 Dec 29. [Article]
15. Rosenke K, Feldmann H, Westover JB, Hanley PW, Martellaro C, Feldmann F, Saturday G, Lovaglio J, Scott DP, Furuta Y, Komeno T, Gowen BB, Safronetz D: Use of Favipiravir to Treat Lassa Virus Infection in Macaques. Emerg Infect Dis. 2018 Sep;24(9):1696-1699. doi: 10.3201/eid2409.180233. Epub 2018 Sep 17. [Article]
16. Delang L, Abdelnabi R, Neyts J: Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018 May;153:85-94. doi: 10.1016/j.antiviral.2018.03.003. Epub 2018 Mar 7. [Article]
17. Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]
18. Pharmaceuticals and Medical Devices Agency: Avigan (favipiravir) Review Report [Link]
19. World Health Organization: Influenza (Avian and other zoonotic) [Link]

External Links

PubChem Compound

492405

PubChem Substance

347828705

ChemSpider

431002

BindingDB

429507

ChEBI

134722

ChEMBL

CHEMBL221722

ZINC

ZINC000013915654

Wikipedia

Favipiravir

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
4	Unknown Status	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
3	Active Not Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
3	Completed	Treatment	Bacterial Pneumonia / Cold; Influenza / Coronavirus Disease 2019 (COVID‑19) / COVID-19 Pneumonia / COVID-19 Respiratory Infection / Flu caused by Influenza	1
3	Completed	Treatment	Coronavirus (SARS-CoV) / Coronavirus Disease 2019 (COVID‑19) / Infectious Diseases	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	200.00 mg
Tablet, film coated	Oral	200 mg
Tablet	Oral	200 mg
Tablet, film coated	Oral

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	187℃ to 193℃	https://www.pmda.go.jp/files/000210319.pdf
water solubility	slightly soluble in water	https://www.pmda.go.jp/files/000210319.pdf
pKa	5.1	https://www.pmda.go.jp/files/000210319.pdf

Predicted Properties

Property	Value	Source
Water Solubility	8.7 mg/mL	ALOGPS
logP	0.49	ALOGPS
logP	0.25	Chemaxon
logS	-1.3	ALOGPS
pKa (Strongest Acidic)	9.39	Chemaxon
pKa (Strongest Basic)	-3.7	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	89.1 Å2	Chemaxon
Rotatable Bond Count	1	Chemaxon
Refractivity	33.98 m3·mol-1	Chemaxon
Polarizability	12.12 Å3	Chemaxon
Number of Rings	1	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0a4l-9700000000-8e6268a2a95cda13e7b1
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0006-0900000000-16565f6b64e961605bc9
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0bt9-0900000000-3c08dbf0418b290a578c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00kf-0900000000-c30fff122d0f778e5d46
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-02mr-9400000000-985d584fb66033021e32
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-052v-9000000000-fa31ce96a20f7c3e423e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-9000000000-3f236023add364067245
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	130.38437	predicted	DeepCCS 1.0 (2019)
[M+H]+	132.78401	predicted	DeepCCS 1.0 (2019)
[M+Na]+	141.31496	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. RNA-directed RNA polymerase catalytic subunit

Kind

Protein

Organism

Influenza A virus (strain A/Silky Chicken/Hong Kong/SF189/2001 H5N1 genotype A)

Pharmacological action

Yes

General Function

RNA-dependent RNA polymerase which is responsible for replication and transcription of virus RNA segments. The transcription of viral mRNAs occurs by a unique mechanism called cap-snatching. 5' methylated caps of cellular mRNAs are cleaved after 10-13 nucleotides by PA. In turn, these short capped RNAs are used as primers by PB1 for transcription of viral mRNAs. During virus replication, PB1 initiates RNA synthesis and copy vRNA into complementary RNA (cRNA) which in turn serves as a template for the production of more vRNAs.

Specific Function

Nucleotide binding

Gene Name

PB1

Uniprot ID

Q809M3

Uniprot Name

RNA-directed RNA polymerase catalytic subunit

Molecular Weight

86420.48 Da

References

1. Hayden FG, Shindo N: Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis. 2019 Apr;32(2):176-186. doi: 10.1097/QCO.0000000000000532. [Article]

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Drug created at October 20, 2016 22:30 / Updated at October 07, 2021 12:09