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Do Clinical Trials Support the Use of Favipiravir Therapy for Covid-19 Management?

Dr. Khalid is a physician, a researcher, a health writer, and holds a Ph.D. in clinical research.

do-clinical-trials-support-the-use-of-favipiravir-therapy-for-covid-19-management

What is Favipiravir Therapy?

Favipiravir is a drug of choice for the systematic treatment of influenza cases (Shiraki & Daikoku, 2020). Favipiravir is known for its toxic effects on novel influenza strains. The viral load reduction capacity of Favipiravir relies on its potential to break the viral RNA chains. Clinical literature acknowledges Favipiravir for treating deadliest and lethal influenza infections. Preclinical studies have affirmed anti-RNA virus activities of Favipiravir that help to control a range of life-threatening RNA viruses. The in-vitro studies testify the therapeutic efficacy of Favipiravir against thrombocytopenia syndrome, severe fever, rabies, Lassa virus, and Ebola virus (Shiraki & Daikoku, 2020). Favipiravir does not trigger resistance in the strains of RNA viruses, while its broad-spectrum activity helps to contain their development inside the human host. Drug manufacturers continue recommending the use of Favipiravir for the treatment of debilitating viral infections that threaten human existence in the absence of standard therapies. Preclinical studies have also confirmed the therapeutic potential of Favipiravir against respiratory syncytial virus, rhinovirus, and poliovirus. However, Favipiravir fails to offer therapeutic advantage against adenovirus, cytomegalovirus, herpes simplex virus 1, and other DNA viruses. The influenza treatment potential of Favipiravir relies on its RdRp (RNA-dependent RNA polymerase) inhibition activity (Du & Chen, 2020). However, the prospective investigation of this purine nucleic-acid is highly warranted to investigate its therapeutic potential against specific RNA virus strains.

What is the Pharmacodynamics of Favipiravir?

Favipiravir actively challenges the proliferation cycle of RNA viruses; however, this drug fails to produce its therapeutic effects in many scenarios associated with competitive inhibition by purine nucleosides (Furuta et al., 2017). The interaction of Favipiravir with human host cell lines triggers the production of Favipiravir ribofuranosyl-5′-triphosphate that eventually inhibits the activity of the influenza virus RNA polymerase. The intracellular phosphorylation of Favipiravir facilitates it's active binding with RNA Polymerase. The locking of RNA polymerase domains by Favipiravir ceases the process of virus replication. The decrease in viral titer by Favipiravir triggers lethal mutagenesis that deactivates the replication capacity of the RNA viruses. Favipiravir induces transition mutations in RNA virus nucleoprotein that substantially reduces the overall viral resistance. Favipiravir is a drug of choice for treating a range of RNA virus infections due to its high anti-viral-index. Evidence-based clinical literature advocates the activity of Favipiravir against the H1N1 influenza virus in comparison to zanamivir and oseltamivir. The research studies have also demonstrated the therapeutic effects of oseltamivir and Favipiravir combination therapy against RNA viruses. This combination intervention requires further assessment to explore its therapeutic potential against the resistant strains of epidemic influenza virus. Several clinical trials claim the therapeutic efficacy of Favipiravir against arenaviruses, bunyaviruses, flaviviruses, picornaviruses, caliciviruses, filoviruses, and rhabdoviruses. Favipiravir facilitates postexposure prophylaxis of various RNA viruses in multiple clinical trials. A research study in China has revealed the therapeutic benefits of IFN-α1b 60 and Favipiravir combination treatment in COVID-19 cases (Coomes & Haghbayan, 2020). However, these benefits remain confined to the active clearance of the viral load rather than complete recovery from the COVID-19 infection.

What is the Pharmacokinetics of Favipiravir?

97.6% bioavailability and narrow therapeutic index of Favipiravir reveal the requirement of its dosage titration to minimize the risk of irreversible side effects (Pub Chem, 2020). 51.5 ug/mL is reportedly the C-max level of Favipiravir. The coadministration of food with 400mg of Favipiravir reduces its C-max to 22.01-36.23 ug/mL. The multiple or repeated administration of Favipiravir (with or without food) in high dosages irreversibly blocks the production of aldehyde oxide. Favipiravir encounters renal clearance following the distribution volume of 15-20 liters. Few clinical trials have recommended the oral administration of 600mg-1600mg of Favipiravir (Pub Chem, 2020). However, the clinical literature does not provide clearance data for this dose range. Favipiravir is metabolized extensively before its urinary clearance. The xanthine and aldehyde oxidase trigger the hydroxylation of Favipiravir that results in the production of its inactive metabolite. The elimination half-life of 2-5.5 hours substantiates the rapid action of Favipiravir against the RNA viruses (Pub Chem, 2020).

Is Favipiravir a Viable Treatment Option for COVID-19 Cases?

No pharmacotherapy so far has been formalized and approved for the treatment of COVID-19 cases (Yavuz & Unal, 2020). It is important to note that the need for antiviral therapy usually arises in 5-10% of COVID-19 patients who encounter life-threatening conditions. The preferred antiviral treatment options for COVID-19 management include Remdesivir, Favipiravir, ritonavir, lopinavir, hydroxychloroquine, chloroquine, ivermectin, and nitazoxanide. T-705; 6-fluoro-3-hydroxy-2-pyrazine carboxamide or Favipiravir is an RdRp (RNA-dependent RNA polymerase) inhibitor that transforms to Favipiravir-RTP (ribofuranosyl-5B-triphosphate) through intracellular phosphorylation. The inhibition of RdRp by Favipiravir substrate potentially restricts the activity of RNA polymerase. However, the half inhibitor concentration of Favipiravir (warranted for inhibiting RNA polymerase activity of COVID-19) is yet not known to the scientific community. The presumed half inhibitor concentration of Favipiravir for COVID-19 management (based on influenza virus data) is 0.022 micrograms per milliliters. 100 microgram per milliliters of Favipiravir fails to disrupt the alpha, beta, and gamma subunits of human DNA polymerases. Favipiravir, despite this pitfall, inhibits the development of filo/flavi/bunya/arenaviruses (Yavuz & Unal, 2020). The COVID-19 treatment candidature of Favipiravir relies on the single-stranded RNA beta structure of SARS-CoV-2. The structural similarity between RdRp genes of COVID-19, MERS-CoV, and SARS-CoV, and the potential of Favipiravir to block the functionality of these genes raises positive expectations for the use of this drug in COVID-19 management. So far, no clinical trial or preclinical studies have provided affirmatory evidence related to the therapeutic potential of Favipiravir against COVID-19. A recently conducted preclinical-study has testified the therapeutic efficacy of Favipiravir against COVID-19 at the half-maximal effective concentration of 61.88 micromoles. An open-labeled study has affirmed the COVID-19 treatment potential of aerosol-based combination therapy of interferon-alpha and Favipiravir. However, clinicians also require investigating the COVID-19 management potential of integrative-therapy, including ritonavir, lopinavir, interferon-alpha, and Favipiravir (Yavuz & Unal, 2020). The in-vitro studies have affirmed a reduced viral clearance time related to the systematic use of Favipiravir therapy as compared to other antiviral interventions. These studies have also testified the pneumonia management efficiency of Favipiravir in COVID-19 cases. The chest imaging improvement recorded after Favipiravir therapy in some clinical trials also reveals the scope of its utilization in COVID-19 cases. The clinical studies have not achieved much success in testifying the therapeutic benefits of Favipiravir over non-invasive mechanical ventilation and auxiliary oxygen administration (Yavuz & Unal, 2020). The presently recorded Favipiravir data does not substantiate its therapeutic use against COVID-19 cases in the absence of concrete therapeutic evidence. The approval for Favipiravir-based COVID-19 therapy in some countries could potentially threaten the health, wellness, and prognosis of the SARS-CoV-2 infected patients.

Is the Repurposing of Favipiravir for COVID-19 Management Clinically Justified?

The current body of medical literature contains unverified therapeutic claims of several antiviral drugs against COVID-19 mitigation. Limited clinical evidence substantiates the fever and cough reduction potential of Favipiravir in COVID-19 patients (Khambholja, 2020). The clinicians remain clueless regarding the use of Favipiravir in mild versus moderate or severe COVID-19 complications. Most importantly, researchers have not standardized any protocol or algorithm for COVID-19 treatment based on Favipiravir or other antiviral drugs. Accordingly, The personalized use of Favipiravir for COVID-19 management is not a workable and clinically justified option. The haste of acquiring economic benefit and fame at the cost of bypassing the clinical trial protocols is challenging the safety and efficacy of new treatments in human populations. The traditional system of medicine also offers several drugs for controlling COVID-19 manifestations. However, limited clinical evidence barricades their wide-scale use in COVID-19 cases. Integrative medicine also offers various treatment combinations for the management of COVID-19 infections. The scientists need to test the combination of allopathic and herbal remedies for reducing the viral load in COVID-19 infected patients. However, the concerned studies appear time-consuming, and so far, no rational solution is available for the mitigation of COVID-19 pandemic. The drug repositioning for coronavirus cases has not encountered the desired success until date. Scientists require testifying various treatment combinations to evaluate the scope of their successful utilization in COVID-19 management. The assessment of interferons, human immunoglobulin, and Favipiravir-based combination therapy for COVID-19 treatment might generate a lead for the scientific community (Rosa & Santos, 2020). Until date, the unsubstantiated use of Favipiravir for COVID-19 treatment could unprecedently increase the risk of patient adversities and safety events.

What are the Safety Risks of Favipiravir Therapy?

Clinical trials reveal the risk of the following complications that COVID-19 patients could encounter after receiving Favipiravir therapy (Pilkington et al., 2020) (Cai et al., 2020) (Wu et al., 2020) (Mehta et al., 2020).

  1. QTc prolongation
  2. Teratogenicity
  3. Hyperuricemia
  4. Kidney injury
  5. Liver injury
  6. Rash
  7. Nausea
  8. Vomiting
  9. Diarrhea
  10. Asthenia
  11. Serum uric acid elevation
  12. Gastrointestinal discomfort
  13. Psychiatric symptoms
  14. Abnormal serum transaminases
  15. Reduced red blood cell count
  16. Elevated serum alkaline phosphatase
  17. Elevation in total bilirubin
  18. Hepatocytes vacuolization
  19. Testis toxicity
  20. Teratogenic effects

What are the Contraindications of Favipiravir Therapy?

The clinical trial by Zhao et al. (2015) affirms the potential of Favipiravir to reduce the serum level of acetaminophen sulfate. Accordingly, the co-administration of Favipiravir with acetaminophen appears questionable and warrants further clinical investigation. Furthermore, pregnant women and lactating mothers must not receive Favipiravir due to the risk of embryonic deaths and clinical complications in infants (Hayden & Shindo, 2019). The individuals with a known history of antiviral nucleoside-analog hypersensitivity must not receive Favipiravir therapy in any situation. The patients affected with life-threatening chronic disease conditions and respiratory illnesses should also not receive Favipiravir therapy (Clinical Trials Gov, 2015). The co-administration of Favipiravir with attenuated influenza vaccine or other influenza treatment interventions is associated with potential safety risks and adversities. The patients affected with urinary tract infections, renal calculi, hypouricemia, hereditary xanthinuria, and gout or hyperuricemia are not the ideal candidates for Favipiravir therapy.

References

Cai, Q. et al., 2020. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing).

Clinical_Trials_Gov, 2015. Phase 3 Efficacy and Safety Study of Favipiravir for Treatment of Uncomplicated Influenza in Adults - T705US316. [Online] Available at: https://clinicaltrials.gov/ct2/show/NCT02026349 [Accessed 22 06 2020].

Coomes, E. A. & Haghbayan, H., 2020. Favipiravir, an antiviral for COVID-19?. J Antimicrob Chemother.

Du, Y. X. & Chen, X. P., 2020. Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection. Clinical Pharmacology and Therapeutics.

Furuta, Y., Komeno, T. & Nakamura, T., 2017. Favipiravir (T-705), a broad-spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci, 93(7), pp. 449-463.

Hayden, F. G. & Shindo, N., 2019. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis, 32(2), pp. 176-186.

Khambholja, K., 2020. Potential repurposing of Favipiravir in the COVID-19 outbreak based on current evidence. Travel Med Infect Dis.

Mehta, N., Mazer-Amirshahi, M., Alkindi, N. & Pourmand, A., 2020. Pharmacotherapy in COVID-19; A narrative review for emergency providers. Am J Emerg Med.

Pilkington, V., Pepperrell, T. & Hill, A., 2020. A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic?. Journal of Virus Eradication, 6(2), pp. 45-51.

Pub_Chem, 2020. Favipiravir. [Online] Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Favipiravir [Accessed 22 06 2020].

Rosa, S. G. V. & Santos, W. C., 2020. Clinical trials on drug repositioning for COVID-19 treatment. Rev Panam Salud Publica, Volume 44.

Shiraki, K. & Daikoku, T., 2020. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Europe PMC.

Shiraki, K. & Daikoku, T., 2020. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Search Results.

Wu, R. et al., 2020. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol Rep, pp. 1-15.

Yavuz, S. S. & Unal, S., 2020. Antiviral treatment of COVID-19. Turkish Journal of Medical Sciences, 50(3), pp. 611-619.

Zhao, Y. et al., 2015. Favipiravir Inhibits Acetaminophen Sulfate Formation but Minimally Affects Systemic Pharmacokinetics of Acetaminophen. Br J Clin Pharmacol, 80(5), pp. 1076-85.

This content is for informational purposes only and does not substitute for formal and individualized diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed medical professional. Do not stop or alter your current course of treatment. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.

© 2020 Dr Khalid Rahman

Discussion

Sarah Khalid on June 24, 2020:

Very nice and really important for all the people to understand what this medicine is. EXCELLENT!!! I really appreciate you and your article. Very important .