Favipiravir Other names: T-705

Chemical formula: C₅H₄FN₃O₂  Molecular mass: 157.104 g/mol  PubChem compound: 492405

Mechanism of action

Favipiravir (originally known as T-705) is an orally administered novel anti-viral compound with a unique mechanism of action that is active against a wide range of RNA-based viruses in laboratory tests. Favipiravir is a viral RNA polymerase inhibitor with a new mechanism of action, inhibiting viral gene replication within infected cells to prevent the propagation. Favipiravir is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5'- triphosphate (RTP). Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. With regards to the activity against human DNA polymerases α, β and γ, favipiravir RTP (1000 μmol/L) showed no inhibitory effect on α, 9.1-13.5% inhibitory effect on β and 11.7-41.2% inhibitory effect on γ. Inhibitory concentration (IC50) of favipiravir RTP on human RNA polymerase II was 905 μmol/L.

Pharmacodynamic properties

In vitro antiviral activity

Favipiravir showed antiviral activity against type A and type B influenza virus laboratory strains with an EC50 of 0.014-0.55 μg/mL.

The EC50 against seasonal type A and type B influenza viruses including strains resistant to adamantane (amantadine and rimantadine), oseltamivir or zanamivir was 0.03-0.94 and 0.09-0.83 μg/mL, respectively.

The EC50 against type A influenza viruses (including strains resistant to adamantane, oseltamivir or zanamivir) such as swine-origin type A and avian-origin type A including highly-pathogenic strains (including H5N1 and H7N9) was 0.06–3.53 μg/mL.

The EC50 against type A and type B influenza viruses resistant to adamantane, oseltamivir and zanamivir was 0.09-0.47 μg/mL, and no cross resistance was observed.

Therapeutic effect in animal models

In mouse infection models inoculated with influenza viruses A (H7N9), A (H1N1) pdm09 or A (H3N2), decrease of virus titers in lung tissues was observed by a 5-day oral administration of favipiravir with a dose of ≤60 mg/kg/day.

In mouse infection models inoculated with influenza viruses A (H3N2) or A (H5N1), therapeutic effect was observed by a 5-day oral administration of favipiravir with a dose of 30 mg/kg/day.

In a SCID mouse infection model inoculated with an influenza virus A (H3N2), therapeutic effect was observed by a 14-day oral administration of favipiravir with a dose of 30 mg/kg/day.

Resistance

No change of susceptibility of type A influenza viruses to favipiravir was observed after 30 passages in the presence of favipiravir, and no resistant viruses have been selected. In clinical studies including the global phase III study, information about emergence of favipiravir-resistant influenza viruses has not been obtained.

Pharmacokinetic properties

Blood Concentrations

The following table shows pharmacokinetic parameters of favipiravir after an oral administration in 8 healthy adults at 1600 mg twice daily for 1 day, then 600 mg twice daily for 4 days followed by 600 mg once daily for 1 day (1600 mg/600 mg BID).

Pharmacokinetic parameters of favipiravir:

Dosage CmaxNote2 (μg/mL) AUCNote2,3 (μg·hr/mL) TmaxNote4 (hr) T1/2Note5 (hr)
1600 mg/600 mg BIDDay 164.56 (17.2) 446.09 (28.1) 1.5 (0.75, 4) 4.8±1.1
Day 664.69 (24.1) 553.98 (31.2) 1.5 (0.75, 2) 5.6±2.3

Note 2: Geometric mean (CV%)
Note 3: Day 1: AUC0-∞, Day 6: AUCτ
Note 4: Median (minimum, maximum)
Note 5: Mean±SD

Figure 1. Time course of plasma concentration of favipiravir (mean±SD):

Following multiple oral administration of favipiravir for 7 daysNote6 to an healthy adult who appeared to have little AO activity, the estimated AUC of unchanged drug was 1452.73 μg·hr/mL on Day 1 and 1324.09 μg·hr/mL on Day 7.

Note 6: 1200 mg + 400 mg on Day 1, then 400 mg twice daily on Days 2 to 6 followed by 400 mg once daily on Day 7. The approved dosage of favipiravir is “1600 mg orally twice daily for 1 day followed by 600 mg orally twice daily for 4 days”.

Distribution

When favipiravir was orally administered to 20 healthy adult male subjects at 1200 mg twice daily for 1 day followed by 800 mg twice daily for 4 days (1200 mg/800 mg BID)Note7, the geometric mean concentration of the drug in semen was 18.341 μg/mL on Day 3, and 0.053 μg/mL on the second day after the treatment. The semen levels became below the limit of quantification (0.02 μg/mL) in all subjects in 7 days after the end of the treatment. The mean ratio of the drug concentration in semen to that in plasma was 0.53 on Day 3 and 0.45 on the second day after the treatment.

The serum protein binding ratio was 53.4 to 54.4% (in vitro, centrifugal ultrafiltration) at 0.3 to 30 μg/mL.

Note 7: The approved dosage of favipiravir is “1600mg orally twice daily for 1 day followed by 600 mg orally twice daily for 4 days”.

Reference: Animal data

When a single dose of 14C-favipiravir was orally administered to monkeys, it was distributed broadly in tissues. Radioactivity of each tissue peaked in 0.5 hours after the administration and changed in parallel with the radioactivity in plasma. The ratio of radioactivity in lung tissues to that in plasma was 0.51 in 0.5 hours after the administration, and the drug was distributed rapidly to respiratory tissues which were considered infection site. Radioactivity in kidney was higher than that in plasma, with a ratio of 2.66. Radioactivity in each tissue, except bones, decreased to ≤2.8% of the peak within 24 hours after the administration.

Metabolism

Favipiravir was not metabolized by cytochrome P-450 (CYP), mostly metabolized by aldehyde oxidase (AO), and partly metabolized to a hydroxylated form by xanthine oxidase (XO). In studies using human liver microsomes, formation of the hydroxylate ranged from 3.98 to 47.6 pmol/mg protein/min, with an inter-individual variation of AO activity by 12 times at maximum. A glucuronate conjugate was observed in human plasma and urine as a metabolite other than the hydroxylated form.

Excretion

Favipiravir was mainly excreted as a hydroxylated form into the urine, and little amount unchanged drug was observed. In an oral 7 day multiple dose studyNote8 with 6 healthy adults, cumulative urinary excretion ratio of the unchanged drug and the hydroxylated form was 0.8% and 53.1%, respectively, during 48 hours after the last administration.

Note 8: 1200 mg + 400 mg on Day 1, then 400 mg twice daily on Days 2 to 6 followed by 400 mg once daily on Day 7. The approved dosage of favipiravir is “1600 mg orally twice daily for 1 day followed by 600 mg orally twice daily for 4 days”.

Patients with liver function impairment

When favipiravir was orally administered to subjects with mild and moderate liver function impairment (Child-Pugh classification A and B, 6 subjects each) at 1200 mg twice daily for 1 day followed by 800 mg twice daily for 4 days (1200 mg/800 mg BID)Note9, compaired to healthy adult subjects, Cmax and AUC at day 5 were approximately 1.6 fold and 1.7 fold, respectively in subjects with mild liver function impairment, and 1.4 fold and 1.8 fold, respectively in subjects with moderate liver function impairment. When favipiravir was orally administered to subjects with severe liver function impairment (Child-Pugh classification C, 4 subjects) at 800 mg twice daily for 1 day followed by 400 mg twice daily for 2 days (800 mg/400 mg BID)Note9, compaired to healthy adult subjects, Cmax and AUC at day 3 were approximately 2.1 fold and 6.3 fold, respectively.

Note 9: The approved dosage of favipiravir is “1600mg orally twice daily for 1 day followed by 600 mg orally twice daily for 4 days”.

Drug Interactions

In vitro

Favipiravir inhibited irreversibly AO in a dose and time dependent manner, and inhibited CYP2C8 in a dose dependent manner. There were no inhibitory activity to XO, and weak inhibitory activity to CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. The hydroxylated metabolite showed weak inhibitory activity to CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Inductive effect of favipiravir on CYP was not observed.

Drug-drug Interaction Clinical Studies

Effects of co-administered drugs on pharmacokinetics of favipiravir:

Co-administrated drug and dosageFavipiravir dosagenTime of dosingParameter ratio for favipiravir (90% CI) (Co-administered/single administered)
CmaxAUC
Theophylline 200mg twice daily on Days 1 to 9, 200mg once daily on Day 10600mg twice daily on Day 6, 600mg once daily on Days 7 to 1010Day 61.33 [1.19, 1.48] 1.27 [1.15, 1.40]
Day 7 1.03 [0.92, 1.15] 1.17 [1.04, 1.31]
Oseltamivir 75mg twice daily on Days 1 to 5, 75mg once daily on Day 6600mg twice daily on Day 5, 600mg once daily on Day 610Day 60.98 [0.87, 1.10] 1.01 [0.91, 1.11]
Raloxifene 60mg once daily on Days 1 to 3Note101200mg twice daily on Day 1, 800mg twice daily on Day 2, 800mg once daily on Day 317Day 11.00 [0.90, 1.10] 1.03 [0.95, 1.12]
Day 30.90 [0.81, 0.99] 0.85 [0.79, 0.93]
Hydralazine 5mg once daily on Day 1 and Day 51200mg/400mg on Day 1, 400mg twice daily on Days 2 to 4, 400mg once daily on Day 514Day 10.99 [0.92, 1.06] 0.99 [0.92, 1.07]
Day 3 0.90 [0.81, 0.99] 0.85 [0.79, 0.93]
Hydralazine 5mg once daily on Day 1 and Day 51200mg/400mg on Day 1, 400mg twice daily on Days 2 to 4, 400mg once daily on Day 514Day 10.99 [0.92, 1.06] 0.99 [0.92, 1.07]
Day 50.96 [0.89, 1.04] 1.04 [0.96, 1.12]

Note 10: Results in non-Japanese

Effects of favipiravir on pharmacokinetics of co-administered drugs:

Co-administrated drug and dosageFavipiravir dosagenTime of dosingParameter ratio for co-administered drug [90% CI] (Co-administered/single administered)
CmaxAUC
Theophylline 200mg twice daily on Days 1 to 9, 200mg once daily on Day 10600mg twice daily on Day 6, 600mg once daily on Days 7 to 1010Day 70.93 [0.85, 1.01] 0.92 [0.87, 0.97]
Day 100.99 [0.94, 1.04] 0.97 [0.91, 1.03]
Oseltamivir 75mg twice daily on Days 1 to 5, 75mg once daily on Day 6600mg twice daily on Day 5, 600mg once daily on Day 610Day 61.10 [1.06, 1.15] 1.14 [1.10, 1.18]
Acetaminophen 650mg once daily on Day 1 and Day 5Note111200mg twice daily on Day 1, 800mg twice daily on Days 2 to 4, 800mg once daily on Day 528Day 11.03 [0.93, 1.14] 1.16 [1.08, 1.25]
Day 5 1.08 [0.96, 1.22] 1.14 [1.04, 1.26]
No orethindrone/Ethhinylestradiol commbination 1mmg/0.035mg once daily on Days 1 to Day 5Note111200mg twice daily on Day 1, 800mg twice daily on Days 2 to 4, 800mg once daily on Day 525Day 12Note121.23 [1.16, 1.30] 1.47 [1.42, 1.52]
Day 12Note131.48 [1.42, 1.54] 1.43 [1.39, 1 1.47]
Repaglinide 0.5 once daily on Day 13Note111200mg twice daily on Day 1, 800mg twice daily on Days 2 to 4, 800mg once daily on Day 517Day 131.28 [1.16, 1.41] 1.52 [1.37, 1.68]
Hydralazine 5mg once daily on Day 1 and Day 51200mg/400mg on Day 1, 400mg twice daily on Days 2 to 4, 400mg once daily on Day 514Day 10.73 [0.67, 0.81] 0.87 [0.78, 0.97]
Day 50.79 [0.71, 0.88] 0.91 [0.82, 1.01]

Note 11: Results in non-Japanese
Note 12: Norethindrone
Note 13: Ethinylestradiol

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