OVERVIEW OF FAVIPIRAVIR AND REMDESIVIR TREATMENT FOR COVID-19

OVERVIEW OF FAVIPIRAVIR AND REMDESIVIR TREATMENT FOR COVID-19

Ezgi Eroglu ^{* 1} and Cigdem Toprak ²

Department of Pharmacology ¹, Faculty of Pharmacy, Lokman Hekim University, 06530, Ankara, Turkey.

Department of Anesthesia ², Vocational School of Health Services, Bursa Uludag University, 16240, Bursa, Turkey.

ABSTRACT: The current coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the wholesale market in Wuhan, China in the last months of 2019 and spread to almost all countries of the world. Although several vaccines have already been developed in different countries of the world, there is currently no specific treatment for COVID-19. Some agents are used all over the world based on in-vitro, in-vivo studies, and randomized controlled studies. The number of studies on antiviral therapy has been increasing day by day. However, the efficacy of antiviral drugs for COVID-19 remains controversial. In this review, brief information about antiviral drugs favipiravir and remdesivir used for the treatment of COVID-19, the results of the conducted studies, and the possible adverse effects of these drugs are summarized. We hope that this review will provide an impression of favipiravir and remdesivir used to treat and control COVID-19 patients until the approval of specific drugs that target SARS-CoV-2.

COVID-19, Coronavirus, SARS-CoV-2, Favipiravir, Remdesivir

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the main factor of coronavirus disease 2019 (COVID-19) announced a global epidemic by the World Health Organization (WHO) on March 11, 2020 ¹. SARS-CoV-2 first appeared in Wuhan, China in December 2019. The source of the virus was initially unknown, but it was later discovered that newly diagnosed cases were linked to the Huanan Seafood Wholesale Market, where people could buy wild animals such as bats ². After the first cases emerged in China, the virus is known to spread rapidly throughout the world ³.

SARS-CoV-2 has been reported to have phylogenetic similarity with the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) ⁴. SARS-CoV-2 is associated with human SARS-CoV showing 82% nucleotide similarity ⁵. Early studies on COVID-19 have reported that SARS-CoV-2 may be transmitted from animal to human by droplets or from person to person by direct contact ⁶.

In addition, SARS-CoV-2 has been reported to be transmitted from human angiotensin. Studies have also shown that it encodes the spike S protein, which allows binding to transforming enzyme 2 (ACE2), and by supporting the membrane fusion of this protein, it enables the virus to enter human cells such as the lung by endocytosis. After entering human cells, SARS-CoV-2 uses the protein synthesis mechanism of human cells to synthesize viral proteins and subsequently provide viral replication ⁷. Once in the human body, viruses generally trigger a range of responses, such as autophagy, apoptosis, and stress response ⁸. Approximately 20% of individuals infected with SARS-CoV-2 who suffer from health problems such as lung disease have serious respiratory symptoms causing to acute respiratory distress syndrome (ARDS) and even death. A key point to note is that the disease the onset of ARDS in the early stages and preceding acute lung injury ⁹. Currently, there is no specific antiviral drug used for the treatment of COVID-19. Therefore, deciding which treatment regimen to apply to prevent and treat severe COVID-19 cases remains a major challenge ¹⁰. As of now, many studies are being carried out to develop vaccines that can be effective against COVID-19 worldwide. Until the discovery of specific vaccines or therapeutic drugs targeting SARS-CoV-2, medications approved by the FDA for other indications are used to treat COVID-19 patients ¹¹. In this review, we synthesized the available information regarding two of the most important antiviral drugs favipiravir and remdesivir for SARS-CoV-2 therapy.

Favipiravir: Favipiravir, also known as T-705, is a pyrazine analog Fig. 1 and potent inhibitor of influenza viral RNA polymerase ¹². Favipiravir is converted intracellularly into its ribofuranosyl 5′-triphosphate (favipiravir-RTP) metabolite, and the antiviral activity of this drug is decreased in the existence of the purine nucleotides ATP and GTP, implying that favipiravir-RTP can be recognized as a pseudo-purine by the viral RNA-dependent RNA polymerase (RdRp) ¹³. For influenza a virus polymerase it was demonstrated that favipiravir-RTP was known as an effective substrate for incorporation in the RNA ¹⁴. Incorporation of favipiravir-RTP in the viral RNA could eventuate in lethal mutagenesis ¹⁵.

The results of several studies have suggested that one of favipiravir's mechanisms of action for different viruses is lethal mutagenesis ^{16, 17}. Otherwise, there are some studies that have indicated that incorporation of favipiravir-RTP into the viral RNA strand prevented further, RNA strand extension is the mechanism of action of this antiviral drug ^{18, 19}.

Favipiravir was priorily presented to be an effective antiviral against influenza virus infections; it has also been shown to be efficient against a large number of RNA viruses ²⁰.

FIG 1: CHEMICAL STRUCTURE OF FAVIPIRAVIR

An in-vitro study investigating seven potential anti-SARS-CoV-2 drugs has shown that favipiravir has exhibited efficacy in Vero E6 cells infected with SARS-CoV-2 with half-maximal effective concentration (EC₅₀) of 61.88 μM and half-cytotoxic concentration (CC₅₀) at over 400 μM, indicating the high concentration is required for effective and safe treatment ²¹. Favipiravir is also an antiviral agent that has been demonstrated to be effective for Ebola virus disease. In a retrospective analysis of patients with Ebola virus disease treated with favipiravir had a remarkably higher survival rate compared to receiving supportive therapy (56.4% vs. 35.3%; P=0.027) ²². Favipiravir is currently being investigated for the novel coronavirus disease COVID-19. In an open-label non-randomized study of 80 patients with COVID-19 in China, a significant decrease in SARS-CoV-2 viral clearance was observed in patients treated with favipiravir compared to those treated with lopinavir/ritonavir ²³. In another multicentered randomized clinical trial in China, favipiravir treatment has been demonstrated to increase the 7-day clinical recovery rate (from 55.86% to 71.43%) and significantly reduce fever and cough relief time in COVID-19 patients ²⁴. Clinical trials testing favipiravir for COVID-19 have been conducted in different countries worldwide Table 1 and 2.

Several studies have indicated that the maximum plasma concentration of favipiravir occurred at two hours after oral administration and then reduced quickly with a short half-life time of 2–5.5 h, and the fraction of its metabolites excreted in the urine increases overtime to reach 80–100% after seven days ²⁵.

Favipiravir exhibits dose and time-dependent pharmacokinetics. It is not metabolized by the cytochrome P450 system, however, it inhibits one of its components (CYP2C8). Therefore, it needs to be used with caution when co-administered with drugs metabolized by the CYP2C8 system ²⁶. The most common side effects of favipiravir are gastrointestinal discomfort, abnormal trans-aminases, elevated serum uric acid, and psychiatric symptoms.

TABLE 1: THE ONGOING AND UPCOMING CLINICAL TRIALS WITH FAVIPIRAVIR FOR THE TREATMENT OF COVID‐19

*A registry and results database of privately and publicly supported clinical studies of human participants conducted around the world. Available online: www.ClinicalTrials.gov

In addition, other existing safety concerns, such as the potential for QTc prolongation, are still unresolved ²⁷. Furthermore, there is proof that favipiravir has teratogenic potential. When the doses equivalent to the recommended human regimens were tested in animal models, retarded development of embryonic death was observed in four different animal species in the first trimester ²⁸. There is no information about the use of favipiravir during breastfeeding or its excretion into breast milk. However, since favipiravir is a small molecule that is approximately 60% protein-bound in plasma, it may be expected to appear in breast milk and be absorbed by the infant slightly. Therefore, the breastfed infant should be monitored in terms of some parameters such as gastro-intestinal symptoms, liver enzyme abnormalities, and serum uric acid elevations ²⁹. Favipiravir seems to be safe and tolerable in short-term use, but more evidence is needed to evaluate the longer-term effects of COVID-19 treatment. The clinical application of favipiravir is being researched for clear information about its effectiveness and safety.

Remdesivir: Remdesivir (GS-5734) is a monophosphoramidate prodrug, a C-adenosine nucleoside analog Fig. 2 and a new antiviral drug with broad antiviral action against zoonotic and human pathogens from multiple virus families. It was developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections ³⁰. Remdesivir terminates viral RNA synthesis by inhibiting viral RNA-dependent RNA polymerase (RdRp) ³¹. The active form, remdesivir triphosphate, compete for the inclusion of the native adenosine triphosphate chain, resulting in chain termination ³². Remdesivir is a broad-spectrum antiviral drug with effects on ribonucleic acid (RNA) viruses, including Coronaviridae (such as SARS-CoV, MERS-CoV, and bat coronavirus strains), Filoviridae (such as EBOV), and Paramyxoviridae (Nipah virus, Hendra virus) ³³. Laboratory tests show that remdesivir is effective against a wide variety of viruses such as SARS-CoV and MERS-CoV.

FIG. 2: CHEMICAL STRUCTURE OF REMDESIVIR

In previous studies, it has been tested on RNA viruses such as MERS coronavirus and SARS coronavirus but has not been fully approved as a treatment drug. Remdesivir was originally developed for Hepatitis C, then it was tried in Ebola and Marburg virus, but its effectiveness was not proven in all these infections. Although the drug has proven to be safe, its effect against filoviruses such as the Ebola virus has not been observed ³³. After the COVID-19 pandemic, treatment protocols have begun to be tried on patients, and finally. Remdesivir has been approved for emergency use in the USA and for the treatment of patients with severe symptoms in Japan ³³. A number of factors have led to increased public and medical interest in remdesivir for SARS-CoV-2 treatment recently.

First, its in-vitro activity against SARS-CoV-2 was confirmed. Researchers studied the effect of seven drugs: ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine, favipiravir, and rem-desivir against SARS-CoV-2 in non-human Vero E6 cells. The EC50 was the lowest for remdesivir (0.77 µM), followed by chloroquine (1.13 µM).

The simulated molecular insertion experiment also predicted that remdesivir could bind high-affinity SARS-CoV-2 RdRp ²¹. The first clinical efficacy data for remdesivir in COVID-19 focused on case reports of patients. All cases described received 200 mg of remdesivir intravenously on day 1 followed by 100 mg for up to 9 days ³³. The first patient, a 35-year-old man with a limited past medical history and recent travel to Wuhan, diagnosed with COVID-19 in the United States, was treated with remdesivir.

Remdesivir was initiated on day 7 due to increased oxygen requirements and ongoing pyrexia, and was generally asymptomatic in the following days ³⁴. The largest report included 61 patients from centers in Europe, North America, and Japan. All patients were hospitalized with COVID-19. After 8 patients were excluded for a number of reasons, 53 patients were received remdesivir at a median of 12 days following symptom onset, and clinical improve-ment was detected in 36 of these 53 patients (68%) ³⁵. In the first randomized, placebo-controlled, double-blind study with remdesivir for COVID-19, Wang and colleagues matched patients receiving remdesivir (n=158) and placebo (n=78) in hospitalized patients with severe COVID-19. Remdesivir was given a dose of 200 mg on day 1, followed by a dose of 100 mg on days 2-10. In most of the patients with medical comorbidities, the basic characteristics were detected to be balanced, and a higher respiratory rate was found after 10 days ³⁶. In another open observational study of patients having received a 10-day remdesivir therapy, these patients not requiring mechanical ventilation, the trial did not demonstrate a significant difference between a 5-day course and a 10-day course of remdesivir ³⁷. Clinical trials testing remdesivir for COVID-19 have been carried out in different countries of the world Table 3 and 4.

TABLE 2: THE ONGOING AND UPCOMING CLINICAL TRIALS WITH FAVIPIRAVIR FOR THE TREATMENT OF COVID‐19 (CONTINUE)

*A registry and results database of privately and publicly supported clinical studies of human participants conducted around the world. Available online: www.ClinicalTrials.gov

Remdesivir is a substrate of several cytochrome P450 enzymes in-vitro, but clinical implications are still unclear since the pro-drug is rapidly metabolized by plasma hydrolases ³⁸. Remdesivir has linear pharmacokinetics and an extended intracellular half-life (>35 h for active parent triphosphate). Remdesivir triphosphate accumulates in peripheral blood mononuclear cells and therefore recommending a loading dose may accelerate the stable success situation ³⁹. Detailed information on remdesivir metabolism and elimination is not available. In remdesivir studies, the most common side effects were reported as respiratory failure, organ failure, low albumin, low potassium, reduction in red blood cells and platelet counts leading to clotting and yellowing of the skin.

TABLE 3: THE ONGOING AND UPCOMING CLINICAL TRIALS WITH REMDESIVIR FOR THE TREATMENT OF COVID‐19

*A registry and results database of privately and publicly supported clinical studies of human participants conducted around the world. Available online: www.ClinicalTrials.gov

Other side effects have been defined as gastrointestinal disorders, increased liver enzymes, and reactions in the treated vessel. During the drug's intravenous administration, patients may experience low blood pressure, nausea, vomiting, sweating, and tremor ³³.

Because remdesivir is slightly absorbed orally, infants are unlikely to absorb clinically significant amounts of the drug from the milk. Given the limited information on infants, it does not appear that mothers taking remdesivir should avoid breastfeeding, but until more data are available, remdesivir should be used with careful infant monitoring during breastfeeding ⁴⁰.

Although the use of remdesivir in COVID-19 seems safe, more studies are needed regarding its efficacy and safety.

TABLE 4: THE ONGOING AND UPCOMING CLINICAL TRIALS WITH REMDESIVIR FOR THE TREATMENT OF COVID‐19 (CONTINUE)

*A registry and results database of privately and publicly supported clinical studies of human participants conducted around the world. Available online: www.ClinicalTrials.gov

CONCLUSION: To summarize, favipiravir and remdesivir have been suggested as a promising alternative for COVID-19 therapy based on the findings of in vitro tests, case reports, and clinical trials, but their safety and effects have not yet been fully understood. While vaccine and drug research is still ongoing, various studies on the relationship between antiviral drugs and coronavirus have been conducted at the same time. The use of favipiravir and remdesivir for COVID-19 treatment has not been clarified yet, and more detailed studies are needed on these drugs. The ongoing studies will provide more high-quality evidence on the benefit and harmful effects of favipiravir and remdesivir.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: The author has no conflicts of interest in the present review.

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    Eroglu E and Toprak C: Overview of favipiravir and remdesivir treatment for Covid-19. Int J Pharm Sci & Res 2021; 12(4): 1950-57. doi: 10.13040/IJPSR.0975-8232.12(4).1950-57.

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