Introduction
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.
Uses
Favipiravir is an antiviral used to manage influenza, and that has the potential to target other viral infections.
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.
Associated Conditions
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.
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.
Absorption
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.
Volume of Distribution
The apparent volume of distribution of favipiravir is 15 - 20 L.
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.
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.
Clearance
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.
Toxicity
Based on single-dose toxicity studies, the lethal dose for oral and intravenous favipiravir in mice is estimated to be >2000 mg/kg. In rats, the lethal dose for oral administration is >2000 mg/kg, while the lethal dose in dogs and monkeys is >1000 mg/kg. Symptoms of overdose appear to include but are not limited to reduced body weight, vomiting, and decreased locomotor activity.
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. Testis toxicity was also noted.
Favipiravir is known to be teratogenic; therefore, administration of favipiravir should be avoided in women if pregnancy is confirmed or suspected.
Toxicity information regarding favipiravir in humans is not readily available.
Food Interactions
No interactions found.
