Favipiravir: A new and emerging antiviral option in COVID-19

Abstract

With over 16 million cases reported from across the globe, the SARS-CoV-2, a mere 125 microns in diameter, has left an indelible impact on our world. With the paucity of new drugs to combat this disease, the medical community is in a race to identify repurposed drugs that may be effective against this novel coronavirus. One of the drugs which has recently garnered much attention, especially in India, is an anti-viral drug originally designed for influenza, called favipiravir. In this article, we have tried to provide a comprehensive, evidence-based review of this drug in the context of the present pandemic to elucidate its role in the management of COVID-19.

Introduction

Six months and more than 16 million confirmed cases later, the COVID-19 pandemic has become the worst public-health crisis in a century. The Discovery of a new and specific antiviral agent against the SARS-CoV-2 would involve a long and arduous timeline. Hence, by default, repurposed drugs, already in use against other viral infections, have been pressed into quick service. One such drug is favipiravir, initially marketed as an anti-influenza agent in Japan. This drug has just received emergency approval by the Drug Controller General of India (DCGI) and hence this comprehensive review of favipiravir comes at a timely juncture.

Favipiravir was first used against SARS-CoV-2 in Wuhan at the very epicenter of the pandemic. Then, as the pandemic spread to Europe, this drug received approval for emergency use in Italy, and currently has been in use in Japan, Russia, Ukraine, Uzbekistan, Moldova, and Kazakhstan. Approval has also recently been granted in Saudi Arabia and the UAE. Thereafter, Turkey, Bangladesh, and most recently Egypt have also seen recent commercial launches. In June 2020, favipiravir received the DCGI approval in India for mild and moderate COVID-19 infections.

Pharmacology

Favipiravir (T-705) is a synthetic prodrug, first discovered while assessing the antiviral activity of chemical agents active against the influenza virus in the chemical library of Toyoma chemicals. A lead compound, A/PR/8/34, was later designated as T-1105, and its derivatives were found to have antiviral activities. Favipiravir is derived by chemical modification of the pyrazine moiety of T-1105 (Above Fig 1). It has been approved in Japan for the management of emerging pandemic influenza infections in 2014.

Pharmacokinetics and pharmacodynamics

Favipiravir is administered as a prodrug. It has an excellent bioavailability (∼94%), 54% protein binding, and a low volume of distribution (10–20 L). It reaches Cmax within 2 h after a single dose. Both Tmax and half-life increase after multiple doses. Favipiravir has a short half-life leading to rapid renal elimination in the hydroxylated form. Elimination is mediated by aldehyde oxidase and marginally by xanthine oxidase. Favipiravir exhibits both, dose-dependent and time-dependent pharmacokinetics. It is not metabolized by the cytochrome P450 system but inhibits one of its components (CYP2C8). Thus, it needs to be used with caution when coadministered with drugs metabolized by the CYP2C8 system.

Mechanism of action

Within the tissue, the molecule undergoes phosphoribosylation to favipiravir-RTP, which is the active form of this drug. It exerts its antiviral effect through the following mechanisms:

A: This molecule acts as a substrate for the RNA-dependent RNA-polymerase (RdRp) enzyme, which is mistaken by the enzyme as a purine nucleotide, thus inhibiting its activity leading to the termination of viral protein synthesis.

B.It gets incorporated in the viral RNA strand, preventing further extension. This mechanism of action, along with the preservation of the catalytic domain of the RdRp enzyme across various RNA viruses, explains the broad spectrum of activity of this drug.

C.It has recently been shown that favipiravir induces lethal mutagenesis in vitro during influenza virus infection, making it a virucidal drug. Whether a similar activity is demonstrated against SARS-CoV-2 or not is uncertain.

Spectrum of antiviral activity

A)Influenza: Favipiravir inhibits 53 types of influenza viruses including seasonal strains A (H1N1), A (H3N2), and influenza B; the A (H1N1)pdm09 pandemic virus; highly pathogenic avian influenza virus A (H5N1) isolated from humans; A (H1N1) and A (H1N2) isolated from swine; and A (H2N2), A (H4N2), and A (H7N2). It is also active against drug-resistant strains of the virus, including M2 and NA inhibitors.7

B)Ebola: During the Ebola virus outbreak in 2014, favipiravir was one of the drugs short-listed for trials by the WHO. Although in vitro studies showed encouraging results for this drug, with a trend toward survival benefit showed by clinical studies, conclusive evidence of benefit was never found. In the JIKI multicenter trial conducted in 126 patients with Ebola, favipiravir in an initial loading dose of 6000 mg followed by 2400 mg/day for 9 days was shown to have some effect in patients with a medium to high viremia but not in those with more severe viremia (Ct value < 20). This large dose seemed to have been well-tolerated as well. A subsequent retrospective study also found favipiravir-treated patients had a trend toward improved survival times against the Ebola virus, although this effect was not statistically significant.

C)Activity against other pathogenic RNA viruses: In addition to its activity against influenza and Ebola viruses, favipiravir has been found to have therapeutic efficacy in cell culture and mouse models of arenavirus, bunyavirus, filovirus, West Nile virus, yellow fever virus, foot-and-mouth disease virus, and Lassa virus including agents causing viral hemorrhagic fevers and encephalitis.

Role in SARS-CoV-2

Shannon et al. found that the SARS-CoV-2–RDRp complex is at least 10-fold more active than any other viral RdRp known. Favipiravir acts by inhibiting this viral RdRp enzyme, allowing facile insertion of favipiravir into viral RNA while sparing human DNA. They concluded that nucleoside analogs (such as favipiravir) are promising candidates for the treatment of COVID-19. The optimal dose of favipiravir is difficult to establish from the limited preclinical, in vitro data. For instance, the higher dosing of favipiravir used in Ebola was based on preclinical studies showing the target concentrations needed to inhibit the Ebola virus (EC50: 67 mM) were higher than that in influenza (EC50: 0.48 mM). Despite these high doses, the predicted target concentrations could not be achieved when PK studies were performed on 66 patients in the JIKI trial. Wang et al. found that high concentrations of favipiravir (EC50: 61.88uM) were needed to inhibit SARS-CoV-2 infection in Vero cells. Thus, it is difficult to ascertain the basis on which the current dose of this drug has been established in SARS-CoV-2. Despite this uncertainty, the dose in clinical use in most countries, including India, is 1800 mg bid on day 1, followed by 800 mg bid on days.