Pharmacological Effects of Favipiravir on Coronavirus: An Update

The coronavirus pandemic is the worst health crisis of our time. There is a massive upsurge of the cases and no specific treatment options for this novel virus (SARS-CoV-2).Due to no time for research and development of a new drug or a vaccine, old and existing broad spectrum antiviral drugs were tried and tested. Favipiravir showed promising results in mild to moderate COVID-19 infection in small studies. The drug is approved with precaution under emergency use, as its safety profile is still not clear. We have considered every aspect of favipiravir and compiled all the latest information about the drug in this review article.

The world is facing the worst health crisis of our time. The Coronavirus Disease (COVID - 19) has hit us hard. According to the current record, total incidence of COVID-19 cases till 31-10-2020 was 45,921,794 and mortality was 1,193,912. 1 The causative agent of this COVID-19 infection is a new coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2, (SARS-CoV-2). 2 New virus requires new therapeutic options but due to lack of time for research and development of a new drug, there is no choice but to test and treat the disease with existing medicines. Many broad spectrum antiviral drugs are trialled but there is hardly any drug which is found to be potent against coronavirus disease. Favipiravir is one drug which has shown encouraging results in an open label control study done on 80 patients in China. 3 There was significant reduction in the duration of viral clearance. 3 There are many ongoing randomized and non-randomized controlled trials being conducted on favipiravir to evaluate its efficacy and safety against SARS-CoV-2. 4 Presently, there are 40 clinical trials registered (clinicaltrail. gov) for evaluation of favipiravir in treatment of COVID-19. 4 The central drugs standard control organization approved the restricted emergency use of favipiravir tablets for mild to moderate COVID -19 infection based on the little evidence from small studies.5 The permission to manufacture and market favipiravir tablets was given to Glenmark Pharmaceuticals by Drugs Controller General of India on 19.06.2020. 5 Since the literature available on favipiravir is scant, we aim to fill this knowledge gap through this article.

History and Outbreak of Coronavirus
It has been reported that SARS-CoV-2 originated in human from zoonotic reservoirs like bats, Himalayan palm civets and raccoon dogs in China. [6][7][8] Clinical presentation of COVID-19 disease was similar to MERS-COV epidemic of 2012, but unlike COVID-19 disease MERS-COV was limited to the middle eastern countries only 9 ,10 In 1965 scientist 'Tyrell & Bynoe' found and isolated coronavirus (HCoVs) from respiratory tract of an adult suffering from common cold. The most distinguishing feature of the coronavirus seen under the electron microscope was its spikes, giving it a crown like appearance. 9,11,12 Thus, Tyrell and group of other virologists named it coronavirus in 1968. 9,11,12,13 The disease coronavirus causes in human host and their cellular receptors are summarized in Table 1. 13 The first human case of COVID-19 disease was reported in Wuhan, China in December 2019. 14 The novel coronavirus causing this outbreak was later named SARS-COV-2.14 The number of cases reported in January 2020 was 9692 and by 31 st October, 2020 , it was raised to its 45,921,794. 1,9 The common clinical manifestations found are of lower respiratory tract like pneumonia, dry cough, fever, dyspnea and diarrhea. 15 The confirmed modes of transmission of SARS-CoV-2 infection is from person to person through contact or through larger respiratory droplets and smaller aerosols. 15,16 Treatment of COVID-19 is based on the severity of the infection and thus it is classified from asymptomatic to critical disease ( Table 2). 17

Favipiravir
A favipiravir is structurally 6-fluoro-3hydroxy-2pyrazenecarboxamide and a broad spectrum antiviral drug showing in vitro activity against RNA viruses including influenza virus, respiratory syncytial virus and measles virus. 18 The chemical structure of favipiravir is shown Figure  1. 19 Chemical substitution of pyrazine compound was found to show strong anti-influenza virus activity in vitro and in vivo. 19 Favipiravir was discovered as an anti-influenza drug originally.

Pharmacodynamics and Mechanism of Action
The mechanism of action of Favipiravir is special as other marketed influenza drugs either inhibit entry or release of the virus . For replication of RNA viruses RNA dependent RNA polymerase (RdRp) is needed as it controls the rate of replication and mutation of the virus to adapt within the host surroundings. 20 Favipiravir is a prodrug which enters the infected cells through endocytosis and it is transformed to active metabolites favipiravir ribofuranosyl triphosphate (Favipiravir-RTP) through phosphorylation and phosphoribosylation. [21][22][23][24] This active favipiravir -RTP competes with purine nucleoside. It binds to and selectively blocks RdRp which in turn prevents viral transcription and replication. 25 The disruption in viral RNA replication leads to increased number and frequency of translation mutations which replaces Guanine (G) by Adenine (A) and Cytosine (C) by Thymine (T) or Uracil (U), thereby producing devastating mutagenesis in RNA viruses. 17,25   Illustrative diagram of intracellular activation and mechanism of action of favipiravir is shown in Figure 2. 25

Phamacokinetics
On oral administration favipiravir is absorbed well, having bioavailability of 97.6% and plasma protein binding capacity of 54%. 24 The volume of distribution of favipiravir is 15-20 liters. 24 Considered oral dose in adults on day 1 at 1600 mg twice , then 600 mg twice daily for 4 days followed by 600 mg once daily for 1 day (1600-1day BID+600-4days BID+ 600-1day once). The estimated AUC on day 1 and day 6 was 446.09 and 553.98 µg hr/ml, Cmax was 64.56 and 64.69 µg/ml, tmax was 1.5 hours and t½ of 4.8 ± 1.1 hrs and 5.6 ± 2.3 hrs respectively. Favipiravir is metabolized in liver predominately by Aldehyde Oxidase (AO) and partly by Xanthine Oxidase (XO). It is eliminated by kidney in hydroxylated form. 24

Indications of favipiravir
Favipiravir is found to be effective against the following RNA viruses.

Influenza
Favipiravir was discovered during chemical modification of a pyrazine analogue in cells showing anti-influenza virus activity in vitro. 25 The drug is selective and powerful blocker of influenza viral RNA polymerase and works well against all strains of influenza virus and its subtypes. Favipiravir is also found to be effective against influenza viruses sensitive or resistant to neuraminidase and M2 inhibitors including Oseltamivir in vitro. 25,26

COVID-19
Many clinical trials with favipiravir are underway for testing its efficacy and safety on SARS-CoV-2. Few studies with favipiravir are shown in Table 3. 27 Now the drug is approved in several countries including India. In India, DCGI has allowed restricted emergency use in mild to moderate cases. Thus, currently the drug can only be prescribed after getting informed consent from the patient or their representative for emergency use in prescribed form. Recommended dose on Day 1 is 1800 mg or 9 tablets of 200 mg twice a day followed by 800 mg or 4 tablets of 200 mg twice a day for a maximum of 14 days. Others Favipiravir has also been promising in the treatment of Ebola and Norovirus infection. 21,23 Drug Interactions As there is no specific potent drug for COVID-19, multiple therapies are unavoidable considering the complications, severity and preexisting co-morbidities like cardiovascular disease, diabetes, bronchial asthma, hypertension and so Table 2. The severity of SARS-CoV-2 infection with typical characteristics. 17 on. Therefore, potential drug-drug interactions should be considered as favipiravir is new in the market. So far few confirmed and significant drug interactions are known. Cytochrome P-450 (CYP) does not metabolize favipiravir. 28 Pyrazinamide when co-administered with favipiravir increases blood uric acid level as reabsorption of uric acide in renal tubules is increased. 28 Favipiravir with repaglinide increases the blood level of repaglinide by inhibition of CYPZC8. 28 When favipiravir is used along with theophylline, blood concentration of favipiravir is raised due to the interaction of theophylline with xanthine oxidase (XO). 28 Efficacy of famciclovir and sulindac is reduced when co-administered with favipiravir due to inhibition of aldehyde oxidase (AO). 28

Contraindications of favipiravir Pregnancy
Favipiravir is found to be teratogenic in animal studies . Early embryonic death was seen in rats and teratogenicity was detected in mouse, rat, rabbit and monkey at doses similar or lower than clinical dose. 28

Fertility
Histopathological changes in testis of rats and young dogs were observed after exposure to favipiravir. 28 In rats, changes on the testis and sperm along with low fertility were reported. Thus, in general low fertility may occur due to changes in testis and sperm in male and markable anestrus in females at high doses. 28

Severe Renal and hepatic impairment
Since favipiravir is heavily metabolized in liver and excreted in urine, it is contraindicated in severe hepatic and renal failure. 28

Gout and hyperuricemia
Favipiravir has shown to increase blood uric acid loads which is reversed on drug discontinuation. 29

Undesirable effects and adverse drug reactions
Favipiravir observational study was conducted in Japan in 2,158 patients and subsequently adverse effects were reported in 24.65% of the subjects. The most prominent adverse events was hyperuricemia in 15.52 % of  34 10 days and all patients received significantly improved conventional therapy. the latency to relief Upon results, clinical improvement for pyrexia and cough at day 7 (primaryend point), did not significantly different between two groups. Whereas, in post-hoc analysis for moderateCOVID-19 patients showed a significant higher clinical improvement in the Arbidol group (62/111, 55.86%) compared to Favipiravir group (70/98, 71.43%). Favipiravir led to shorter latencies to relief for both pyrexia and cough. Whereas, no significant differences were found between both groups in the rate of auxiliary oxygen therapy (AOT) or non invasive mechanical ventilation (NMV). An Open-80 confirmed mild to moderate Favipiravir showed Only mild to Label severity cases of COVID-19 significantly better moderate cases were Control were assigned to receive treatment effects on included in the study. Study. 3 either Favipiravir(n = 35) COVID-19 in terms or Lopinavir /ritonavir of disease progression (n = 55) (control and viral clearance. group)for 14 days and both groups received interferon (IFN)-aby aerosol inhalation. FPV arm showed preferable outcomes compared to control arm, including shorter viral clearance (4 (2.5-9) d vs 11 (8)(9)(10)(11)(12)(13)  (day 2-day 10). 50 patients and could be used clinical trial 35 received hydroxychloroquine 800 safely during mg at day 1 followed by 200 mg home isolation in mild twice (day 2-10) and oral oseltamivir to moderate cases 75 mg/12 h/day for 10 days. PCR negativity for SARS-CoV-2 was 8.1 and 8.3 days in HCQ-arm and favipiravir-arm respectively, difference was not statistically significant (p= 0.7),. Fever and dry cough were reported more frequently in favipiravir arm (36% and 38% respectively) than HCQ -based therapy (24% and 30% respectively) but this was not statistically significant (p > 0.05). In the favipiravir-arm 4 patients (8%) experienced elevated liver transaminases 3-5 times the upper normal limit between Day 7 and Day 14, but improvement was seen within 2 weeks after the end of therapy. In the HCQ-based arm there was one death due to an acute heart failure resulting from myocarditis on Day 8. individuals followed by impaired liver function test (7.37%), rash (1.44%), diarrhea (0.74%) and acute renal injury with elevated blood creatinine level was found in 0.74% of the patients treated with favipiravir. 30 Common adverse reactions of Favipiravir are summarized in Table 4. 28

Cost Analysis
Glenmark Pharmaceuticals was the 1st company to lunch favipiravir in India under brand name Fabiflu (200 mg tablet) at Rupees (Rs) 103 per tablet in June, 2020. 31 However, a month later the company reduced the price by 27% to Rs 75 per tablet. At present 5 other companies

CONCLUSION
The COVID-19 disease does not seem to disappear anytime soon. Currently, a second wave of this pandemic has hit the European Union Countries. Scientists have predicted massive rise in infections this winter in India. Favipiravir has shown unique account and broad spectrum of antiviral activity against RNA viruses which has driven the researchers to carry out multiple clinical trials on it against the devastating SARS-CoV-2. It was found that favipiravir shortens the time for viral clearance and shows improvement in chest findings. It is considered to be relatively safe for short term use. However, we need more substantial evidence confirming its efficacy and safety. Favipiravir is the drug of choice at present for mild to moderate cases until a new efficient antiviral drug or vaccine is found for COVID-19. Health care providers must monitor and report any unfavourable outcomes related to its use on COVID-19 patients. Large scale studies are required for corroboration of existing data. As there is continuous upsurge of cases and frequent changes in the treatment protocols physicians should be updated from time to time about new progress in treatment of COVID-19.

ACKNOWLEDGEMENT
Authors would like to thank Dr. Arvind Kumar for his valuable suggestions and assistance in the preparation of this manuscript.

Conflicts of Interest
None to declare.

Funding
No funding resource was required for this review.