What is Favipiravir? How Does It Work for COVID-19?
Date of publication：2020/4/10 16:41:24
Coronavirus continues to wreak havoc worldwide and no drug has been found or manufactured that can cope with it. Some people, such as US President Donald Trump, have been promoting the "possible" virtue of hydroxychloroquine, but another drug is attracting scientific attention – Favipiravir.
What is Favipiravir?
Favipiravir (CAS No.259793-96-9, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, T-705) is a new type of RNA polymerase inhibitor, acting on viral genetic copying to prevent its reproduction. As another weapon for anti-viral treatment of influenza A and B, it was approved for marketing in Japan in March 2014. Studies have shown that, in addition to influenza viruses, Favipiravir may also exhibit good antiviral effects on a variety of RNA viruses, such as Ebola virus, sand virus, Bunia virus, and rabies virus, etc. The COVID-19 is a coronavirus, a positive-stranded single-stranded RNA virus with a coat, and from a mechanical perspective, Favipiravir also has a potential antiviral effect on it.
Mechanisms of Action of Favipiravir
The mechanism by which favipiravir exerts a broad-spectrum antiviral activity has not been fully elucidated, but the existing evidence supports that it can selectively and potently inhibit RNA-dependent RNA polymerase (RdRp) of RNA viruses. Favipiravir undergoes an intracellular phosphoribosylation to be an active form, favipiravir-RTP (favipiravir ribofuranosyl-5′-triphosphate), which is recognized as a substrate by RdRp, and inhibits the RNA polymerase activity. The structure of favipiravir RTP is similar to that of purine, which can compete with purine for viral RNA polymerase, causing it to be mistakenly recognized by viral RNA polymerase, and inserted into the viral RNA chain or combined with the viral RNA polymerase domain to induce fatal mutations, thus preventing incorporation of nucleotides for viral RNA replication and transcription.
There are two published trials for favipiravir for the treatment of COVID-19:
· An open-label, non-randomised trial in Shenzhen (N=80)5 examined the efficacy of favipiravir (n=35) versus lopinavir/ritonavir (n=45) for treating COVID-19. Significantly shorter viral clearance time (primary endpoint) was found for favipiravir versus lopinavir/ritonavir (median 4 days versus 11 days; p<0.001). Patients receiving favipiravir also showed significant improvement in chest imaging compared with those receiving lopinavir/ritonavir, with an improvement rate of 91.43% versus 62.22% (p = 0.004). Fewer adverse reactions were reported for favipiravir (11.43%) compared to lopinavir/ritonavir (55.56%) (p><0.01).
· An open-label, randomised trial in Wuhan (N=240)6 examined the efficacy of favipiravir (n=120) versus arbidol (n=120) for treating COVID-19. There was no difference in the 7-day clinical recovery rate (primary endpoint) for favipiravir versus arbidol in the overall population (61.21% versus 51.67%; p=0.14). However, for a sub-population of non-critical patients without hypertension or diabetes, the 7-day clinical recovery rate was significantly better with favipiravir (71.43%; 70/98) versus arbidol (55.86%; 62/111) (p = 0.02).
According to other news reports:
· A Japanese health ministry source suggested that favipiravir was not as effective in patients with more severe symptoms, from their clinical studies of 70 to 80 participants.
· One medical center in South Korea started administration of favipiravir on 22 February and, while the drug has not been approved for treating COVID-19, the Ministry of Food and Drug Safety (MFDS) in South Korea is considering a fast-track approval to import favipiravir.
Recommendations from Professional Bodies
The US Food and Drug Administration (FDA) has not specifically approved any drugs used to treat COVID-19. The World Health Organization (WHO), the UK National Health Service (NHS) and the Australian health authorities have not provided any advice on the use of favipiravir. It is also not included in the 7 th edition of Chinese Guidelines for the Prevention, Diagnosis, and Treatment of Novel Coronavirus-induced Pneumonia for tentative treatment of COVID-19.
According to reports, no significant adverse reactions have been seen since the listing of favipiravir. In the clinical study of COVID-19, no obvious adverse reactions were found.
In the phase III clinical trial of favipiravir in Japan and internationally, a total of 501 patients participated in the evaluation, including 100 cases of adverse reactions (19.96%). The main adverse reactions included 24 cases of increased uric acid (4.79%) and 24 cases. Diarrhea (4.79%), 9 cases of neutropenia (1.80%), 9 cases of aspartate aminotransferase increase (1.80%), 8 cases of alanine aminotransferase increase (1.60%).
When applying piriravir clinically, attention should be paid to the interaction with other drugs:
1. When combined with oseltamivir, the plasma concentrations of the two drugs were not affected.
2. When combined with famciclovir and sulindac, favipiravir may reduce the efficacy of these drugs.
3. When combined with theophylline, the blood concentration of favipiravir increases, and adverse drug reactions may occur.
4. When used in combination with repaglinide, the blood concentration of repaglinide increases due to the inhibition of CYP2C8, which may cause side effects.
5. When combined with pyrazinamide, it can promote the reabsorption of uric acid by the renal tubules and increase uric acid.
6. When combined with acetaminophen, the risk of liver injury is low, but liver function needs to be monitored.
7. When used in combination with a substrate for transport protein, favipiravir has a weak inhibitory effect on P-glycoprotein (P-gp).
Given that favipiravir's public evidence is limited to two open-label trials, further research is needed to determine its efficacy and safety in patients with COVID-19. Three clinical trials are planned and the results may be reported in the coming months. These findings will determine whether favipiravir should be used more widely in this situation. At present, there is no international professional body recommending the treatment of COVID-19 with favipiravir.
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