INTRODUCTION:

Favipiravir is a well-known influenza medicine that is now being investigated further for its use in the treatment of COVID-19. It's the first antiviral medication for COVID-19 that's been licenced for mild to moderate cases. Favipiravir has been demonstrated to be a promising therapy for this condition in tests conducted in China, Japan, and Russia. Favipiravir is a pyrazine carboxamide derivative created by Toyama Chemical in Japan that works against several RNA viruses. It was initially described as a cytotoxic, selective inhibitor of influenza virus replication. Favipiravir, a medication that has been found to exhibit antiviral action in vitro and/or in vivo against a wide range of human-infecting RNA viruses, including ss(–)RNA viruses, is thought to directly target the RdRp catalytic site, blocking virus reproduction in cells and suppressing infection. T-705 shows in vivo antiviral efficacy against Zaire EBOV in a mouse model, according to Oestereich et al. (2014). Under the experimental circumstances employed, no cytotoxicity was observed: the therapy began six days after infection and provided 100 percent protection. The evidence suggests that it has a wide range of medicinal applications. Notably, investigations show that favipiravir has no resistance and has wide antiviral action, which is a driving force for clinical trials for distressing coronavirus infections. It comes in an oral formulation and has a large therapeutic safety margin for a high dosage. Because % of COVID- 19 patients have a mild to severe infection, oral formulation is more convenient. ^1,2,3,4

FAV was authorised in Japan in 2014 for treatment in outbreaks of new or recurring influenza virus infections when existing antiviral medicines used in influenza are ineffective. The positive impact of influenza has been linked to a decrease in pulmonary viral load and TNF- alpha levels in the airways.⁵ Patients with Ebola virus infections were also given FAV as a post-exposure prophylactic and therapy.⁶ The first instances of COVID-19 viral infection (also known as SARS-Cov-2) were reported in Wuhan, China, in December 2019. This infection has now spread over the entire planet. As of September 1, 2020, 25327,098 cases had been diagnosed globally, and 848,255 people had died as a result of the pandemic. Like MERS (Middle East respiratory syndrome)-Cov and SARS (severe acute respiratory syndrome)-Cov, SARS-Cov-2 is an enveloped positive strand RNA virus.⁷ The viral genome codes for sixteen nonstructural proteins (Nsps) and four structural proteins necessary for virus replication and pathogenesis in SARS-Cov-2.⁸ Unfortunately, no particular therapeutic medication for the treatment of SARS-Cov-2 has yet been authorised. However, a number of commercially available antiviral medicines that have been shown to be safe and effective against other viruses are being investigated for SARS-Cov-2 action. Inhibitors of RNA dependent RNA polymerase (RdRp) are of particular importance. Favipiravir (FAV), also known as T-705, is one of these medicines. 6-fluoro-3-oxo-3,4-dihydropyrazine 2-carboxamide is its chemical name. The Design of Tests (DoE) method allows for the optimization of experimental settings once a small number of experiments have been carried out. Furthermore, it investigates interactions between components that are impossible to identify using typical One Factor at a Time methods (OFAT). When compared to other three-level designs such as three-level factorial design and Central Composite Design, Box Behnken Design (BBD) is one of the designs that is used to arrive at optimal conditions by studying the factors at three levels with a less number of experimental runs (CCD).⁹

The goal of this study was to create a simple, fast, and reliable spectrofluorimetric technique for measuring FAV in pure form and pharmaceutical formulations. To get a robust technique, Box Behnken Design was used to optimise experimental parameters. The spectrofluorimetric approach was used to quantify FAV in spiked human plasma, and the findings were good. Furthermore, the suggested approach used water as a diluent, which meets green chemistry standards.

Fig.1. Chemical Structure of Favipiravir (FVR)

Synthesis of Favipiravir:

Scheme 1:

Regioselective chlorination of the pyrazine ring, bromination, palladium-catalyzed cyanation, diazotation, and Sandmeyer chlorination were used to make favipiravir (1) from pyrazin-2- amine (6). The target product 1 was obtained in 12–18 percent yield after nucleophilic fluorination, nitrile hydrolysis, and substitution of the fluorine atom with a hydroxy group, depending on the reaction conditions for the first stage of the synthesis.¹⁰

Fig.2. Synthesis of Favipiravir- Scheme 1

Scheme 2:

A Chinese research team developed a technique to synthesise favipiravir (1) that used methyl 3-amino-6-bromopyrazine-2-carboxylate as a crucial step (4). The purity of this chemical, they claim, was critical for the effective production of 3,6-dichloropyrazine-2-carbonitrile (5). In addition, a one-pot method comprising fluorine substitution, hydrolysis, and aminolysis of the nitrile group was shown.¹¹

Fig.3. Synthesis of Favipiravir- Scheme 2

Pharmacology:

Favipiravir (T-705) is a synthetic prodrug that was identified while evaluating the antiviral activity of chemical agents active against the influenza virus in the Toyoma chemicals chemical library. Antiviral activity was discovered in a lead chemical, A/PR/8/34, subsequently identified as T-1105, and its derivatives. T-1105's pyrazine moiety is chemically modified to produce favipiravir. (Fig.4.)¹² It has been approved in Japan for the management of emerging pandemic influenza infections in 2014.

Pharmacokinetics and Pharmacodynamics:

Favipiravir is given in the form of a prodrug. It has a high bioavailability (94%) and protein binding (54%) as well as a limited volume of distribution (10–20 L). After a single dosage, it achieves Cmax after 2 hours. After several doses, both Tmax and half-life increase. The hydroxylated version of favipiravir has a short half-life (2.5–5 hours), resulting in fast renal clearance. Aldehyde oxidase and, to a lesser extent, xanthine oxidase are involved in elimination. The pharmacokinetics of favipiravir are dose-dependent as well as time- dependent. The cytochrome P450 system does not metabolise it, but it does block one of its components (CYP2C8). As a result, it should be taken with caution when combined with medications that are processed by the CYP2C8 system.^13,14

The maximal plasma concentration of favipiravir was found 2 hours after oral treatment in healthy Japanese participants, and thereafter quickly declined with a short half-life duration of 2–5.5 hours.¹⁵ In humans, favipiravir bound to 54 % of plasma proteins.¹⁶ He found that favipiravir bound to 65.0 percent of human serum albumin and 6.5 percent of 1-acid glycoprotein, respectively.¹⁷ The parent drug is broken down in the liver by aldehyde oxidase (AO) and xanthine oxidase (XO), resulting in the inactive oxidative metabolite T-705M1, which is eliminated via the kidneys.¹⁵ The quick presence of favipiravir in the liver following venous injection in mice, followed by the gall bladder and parts of the digestive system, indicating that favipiravir is rapidly excreted by the liver in mice.¹⁸ In cynomolgus macaques, pharmacokinetic examination of intravenous favipiravir after repeated doses reveals apparent nonlinear pharmacokinetics across time and across a variety of dosages, as well as a persistent drop in plasma concentration after 7 days of continuous dosing. The steady-state trough concentration of favipiravir for EVD was significantly lower on day 4 (25.9g/mL) than on day 2 (46.1g/mL), indicating a drop in drug concentration with continued usage, according to data acquired from 66 patients for the JIKI study.^19,20

Mechanism of Action:

The molecule is phosphoribosylated within the tissue, resulting in favipiravir-RTP, the drug's active form. Its antiviral properties are mediated by the following mechanisms:

Fig.4. Favipiravir (T-705antiviral )'s mechanism of action. Host cells absorb favipiravir and convert it to favipiravir ibofuranosyl-5′-triphosphate (favipiravir-RTP). Favipiravir- RTP, the triphosphate form, inhibits the function of RNA viruses' RNA dependent RNA polymerase (RdRp). RMP stands for ribosyl monophosphate while AO stands for aldehyde oxidase.

A. This molecule works as a substrate for the RNA-dependent RNA-polymerase (RdRp) enzyme, which misinterprets it as a purine nucleotide, causing the enzyme's activity to be inhibited and viral protein synthesis to be stopped.¹²

B. It becomes integrated into the viral RNA strand, stopping it from extending further. The broad range of activity of this medicine is explained by this method of action, as well as the preservation of the catalytic domain of the RdRp enzyme across numerous RNA viruses.²¹

C. Favipiravir, a virucidal medication, has recently been demonstrated to trigger deadly mutagenesis in vitro during influenza virus infection. It's unclear whether SARS-CoV- 2 has a similar pattern of action.²²

Potential Drug–Drug Interaction in Pharmacokinetics:

Multiple drug treatment is unavoidable in the treatment of COVID-19, particularly in patients with basic diseases (hypertension, diabetes, and cardiovascular disease) and complications (such as acute respiratory distress syndrome, shock, arrhythmia, and acute kidney injury) that are common in COVID-19 patients.^[23,24] In clinical practise, DDI is a subject that has to be addressed. At this time, there is little information on DDI induced by favipiravir. Favipiravir is metabolised by AO in the cytosol in the liver, but not by microsomal enzymes. There are no published studies that show how favipiravir and its active metabolite T-705-RTP alter the activity of hepatic drug-metabolizing enzymes. Concomitant administration of favipiravir increased the area under the curve (AUC) of acetaminophen and acetaminophen glucuronide by 20% and 23–34 percent, respectively, whereas the AUC of acetaminophen sulphate decreased by 29–35 percent, and the excretion of acetaminophen and acetaminophen glucuronide increased in urine in healthy volunteers.²⁵

1. Pyrazinamide:

The usage of pyrazinamide and favipiravir together raises uric acid levels. When these medicines are taken combined, it is necessary to check uric acid levels on a regular basis.

2. Repaglinide:

Favipiravir prevents repaglinide from being metabolized through the CYP2C8 route, increasing the risk of toxicity (hypoglycemia, headache, increase incidence of upper respiratory tract infections, etc.). Concomitant usage should be done with caution.

3. Theophylline:

Theophylline raises favipiravir levels in the blood, which might lead to favipiravir side effects.

4. Famciclovir, Sulindac:

Efficacy of these drugs may be reduced when co-administered with favipiravir

5. Acyclovir:

Acyclovir may reduce the antiviral activity of favipiravir by delaying its conversion to the active moiety.³²

Antiviral Activity Spectrum of Favipiravir:

1. Influenza:

Favipiravir inhibits 53 different 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 pigs; and A (H2N2), A (H4N2), and A (H5N2) isolated from humans (H7N2). It also works against drug-resistant viral types, such as M2 and NA inhibitors.²⁶

2. Ebola:

Favipiravir was one of the medications short-listed for testing by the WHO during the 2014 Ebola virus epidemic. Although in vitro research indicated promising findings for this medicine, and clinical trials revealed a tendency toward survival benefit, clear proof of benefit was never identified. Favipiravir in an initial loading dosage of 6000 mg followed by 2400mg/day for 9 days was proven to have some impact in patients with medium to high viremia but not in those with more severe viremia (Ct value 20) in the JIKI multicenter study, which included 126 Ebola patients. This huge dose also appeared to be well tolerated. A second retrospective analysis indicated that patients who received favipiravir had a trend toward longer Ebola virus survival periods, however this impact was not statistically significant.^27,28

3. Effectiveness against other RNA 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, in addition to its activity against influenza and Ebola viruses.

Consequences of Favipiravir:

According to the previously mentioned Japanese study, roughly 20% of individuals who got favipiravir had side effects (at a dose lower than approved for COVID-19)²⁹. Hyperuricemia and diarrhoea were experienced by 5% of the individuals, whereas lower neutrophil count and transaminitis were experienced by 2% of the subjects. Favipiravir was linked to the incidence of mental symptoms in one research³⁰. The effect of favipiravir on QTc prolongation is still unknown, with some pharmacodynamic studies pointing to a favourable relationship but another Japanese research pointing to the opposite. A major systematic evaluation revealed that favipiravir had a favourable safety profile³¹. The following sections provide a quick overview of this drug's adverse effect profile:

1. Teratogenicity:

Favipiravir has been shown to have teratogenic and embryotoxic properties. The Japanese drug safety bureau recommends that favipiravir be labelled with a strong warning against using it in women of reproductive age, as well as cautionary comments on the box and prescription notifications. Favipiravir should also be avoided when other medicines are available, according to the agency. Men who have received this therapy should be taught how to use effective contraception during treatment and for the next 7 days afterward. It is critical to rule out pregnancy with a negative urine pregnancy test before prescribing favipiravir to women of childbearing age.²⁹

2. Hyperuricemia:

The use of favipiravir causes a dose-dependent increase in the occurrence of hyperuricemia. Similar findings were discovered across many research in a systematic review. This, on the other hand, has nothing to do with clinical signs. There is no indication that favipiravir-induced hyperuricemia causes clinical symptoms; nevertheless, extended follow-up periods are needed to completely examine this risk.^29,31

Toxicity:

The fatal dosage of oral and intravenous favipiravir in mice is predicted to be >2000mg/kg based on single-dose toxicity studies. The fatal dosage for oral administration in rats is >2000 mg/kg, whereas it is >1000mg/kg in dogs and monkeys. Over dosage symptoms include, but are not limited to, weight loss, vomiting, and decreased locomotors activity.³²

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, as well as increased vacuolization in hepatocytes, were observed in repeat-dose toxicity studies involving dogs, rats, and monkeys. Toxicity of the testes was also discovered. ^[32] Because favipiravir is known to cause teratogenicity, it should be avoided in women who are pregnant or fear they are pregnant. There isn't a lot of information on favipiravir's toxicity in people.

Clearance:

The following is the recommended oral dosage schedule for favipiravir day 1; 1600mg twice day. For next 5 days; 600mg twice daily on days two through five.

The CL/F values for favipiravir 600mg 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 are currently no clearance data available for favipiravir 1600mg twice day.³²

Expert Advice for Favipiravir:

· Favipiravir is used for the treatment of mild to moderate Covid-19 symptoms.

· Inform your doctor if you have gout, uric acid, liver, or kidney disease.

· Favipiravir should be administered with care to elderly patients by monitoring their general conditions.

· Seek immediate medical attention if you see signs of allergic reactions like red or blistering rash, difficulty swallowing or breathing, swelling of the eyelids, lips, face, throat, or tongue.

· Favipiravir can be taken on an empty or full stomach. However, taking it with food might reduce the possibility of nausea and vomiting.

· It is advisable to use contraceptive methods while taking Favipiravir and for 7 days after the completion of the treatment.

· Let your doctor know if you are pregnant or breastfeeding.

DISCUSSION:

SARS-CoV-2, an acute respiratory illness caused by COVID-19, is quickly spreading and has already resulted in a pandemic with fatal consequences within a few months of November 2019. The number of people infected with the virus, as well as the fatality rate connected with it, has skyrocketed over the world. The lack of licenced medication and immunisation, as well as the lack of evidence for acceptable treatment alternatives, are the key challenges of COVID-19. Despite the fact that different medications are undergoing clinical trials, scientists have been forced to repurpose antiviral drugs due to the urgency of the issue.³³ As a ribonucleotide analogue and selective inhibitor of the viral RNA polymerase enzyme, favipiravir has a wide range of antiviral action against RNA-carrying viruses, blocking viral genome replication and transcription. In Japan and China, it has been licenced for the treatment of novel influenza viruses. It's also been found to work against Ebola and the RNA viruses that cause viral hemorrhagic fever.^34,35 Given the variable findings of available clinical trial data, none of the society and organisational guidelines (IDSA guidelines, World Health Organization guidelines, National Institutes of Health guidelines) support utilising Favipiravir in the therapy of COVID-19. Furthermore, numerous clinical studies on COVID-19 demonstrated mixed results for this medicine. As a result, we decided to test Favipiravir's safety and effectiveness in the treatment of COVID-19. Our meta-analysis included nine trials with a total of 827 subjects.³⁶ Overall, Favipiravir treatment caused minimal manageable side effects such as nausea, vomiting, diarrhoea, and increased serum transaminases. After therapy with Favipiravir, there were no major life-threatening adverse effects. The possibility of adverse effects could not be linked solely to the use of Favipiravir. In all three studies, patients in the Favipiravir groups were given additional medications.³⁷ According to the findings of the study, patients who received Favipiravir had a lower all- cause death rate than those who took control medicines. Dabbous' study found that one patient in the hydroxychloroquine group died. However, no death was reported in the Favipiravir group.³⁵ Given the importance of treating COVID-19 patients, more research into the function of Favipiravir in COVID-19 patient treatment is required. Despite its limitations, the current research offered important information for treating COVID-19, indicating that Favipiravir is linked with considerable clinical and laboratory improvement in the majority of patients and is a safe treatment with no serious adverse effects.³⁸ Favipiravir's safety and tolerability in short-term dosing is supported by some data. More research is needed, however, to determine the precise long-term implications of this intervention. Because of the lack of proof and other unique safety issues, caution should be exercised while using Favipiravir to combat the COVI D-19 pandemic.³⁹

Limitations:

The studies that were included had certain limitations. For starters, each research had a small sample size. Second, there was a danger of altering the effectiveness and safety of Favipiravir intervention in patients with COVID-19 in the most included trial due to multiple medication pharmacotherapy. Third, the dosage and duration of Favipiravir treatment differed amongst the trials considered. Fourth, it’s difficult to compare the clinical outcomes of individuals treated with Favipiravir who had varying degrees of illness severity, ages, and medical conditions across trials.

CONCLUSION:

In the general group of individuals with mild to moderate COVID-19, favipiravir may not have had a substantial favorable effect in terms of mortality. We should explore if using antivirals once a patient has developed symptoms is too late, which would explain their poor clinical effectiveness. Following that, further clinical trials with a bigger sample size will be required to determine the precise effectiveness and safety of this intervention. Favipiravir is a compassionate use substitute in COVID-19 because to its method of action in reducing viral RdRp and safety proof from previous clinical studies. Data from influenza treatment and a proof-of-concept clinical trial in EVD are utilized in COVID-19 to help select the dose regimen in clinical trials or experimental medication use. However, further clinical data is needed to assess favipiravir's true usefulness. Potential DDIs due to AO inhibition should not be neglected in the therapeutic setting.

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Received on 03.06.2022 Modified on 09.07.2022

Research J. Science and Tech. 2022; 14(4):253-260.

DOI: 10.52711/2349-2988.2022.00041