EFFECTIVENESS AND SAFETY OF FAVIPIRAVIR INFUSION IN PATIENTS HOSPITALIZED WITH COVID-19

Research in the development of new therapeutic agents with a wide spectrum of the antiviral activity and a low ability to develop resistance remains the main dimension in combating the global threat to public health. The need for a parenteral form of favipiravir was dictated by the necessity to increase the efficacy of therapy in COVID-19 inpatients. This dosage form has expanded the possibilities of drug therapy in the inpatients, for whom a therapeutic effect acceleration and a high safety profile of the drugs used are especially important.

The aim of the article is the evaluation of the efficacy and safety of a medicinal product containing favipiravir for the parenteral administration against the background of pathogenetic and symptomatic therapy, in comparison with standard therapy in hospitalized COVID-19 patients.

Materials and methods. An open, randomized, multicenter comparative study was conducted in 6 research centers in the Russian Federation to evaluate the efficacy and safety of favipiravir, a lyophilisate for the preparation of a concentrate for the infusion solution administrated to the patients hospitalized with COVID-19. Screening procedures and randomization were completed in 217 patients, 209 of which had completed the study in accordance with the protocol.

Results. Between the study groups, statistically significant differences have been found out, making it possible to consider the hypothesis of the drug Areplivir (favipiravir) superiority for the parenteral administration over the standard therapy, which included favipiravir (p. o.) and remdesivir. A comparative analysis has shown that a course of therapy with the parenteral favipiravir drug leads to a significant improvement in the condition of patients with COVID-19, significant benefits in terms of the speed and frequency of improvement in the clinical status of patients, as well as a reduction in the hospital stay length. It has been proven that therapy with a drug containing favipiravir for the parenteral administration does not adversely affect the parameters of clinical and biochemical blood tests, urinalysis, coagulograms, vital signs and ECG, which indicates the therapy safety. The study drug is characterized by a high safety profile and tolerability.

Conclusion. The versatility and resistance to mutations of RNA-dependent RNA polymerase make it possible to consider it as the main target for combating the most common RNA viruses that cause ARVI, that determines the need  further studies of favipiravir to expand the range of its indications.

1. Zhu Z, Lian X, Su X, Wu W, Marraro GA, Zeng Y. From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir Res. 2020 Aug 27;21(1):224. DOI: 10.1186/s12931-020-01479-w.

2. Gavriatopoulou M, Ntanasis-Stathopoulos I, Korompoki E, Fotiou D, Migkou M, Tzanninis IG, Psaltopoulou T, Kastritis E, Terpos E, Dimopoulos MA. Emerging treatment strategies for COVID-19 infection. Clin Exp Med. 2021 May;21(2):167–79. DOI: 10.1007/s10238-020-00671-y.

3. Şimşek Yavuz S, Ünal S. Antiviral treatment of COVID-19. Turk J Med Sci. 2020 Apr 21;50(SI-1):611–9. DOI: 10.3906/sag-2004-145.

4. Collie S, Champion J, Moultrie H, Bekker LG, Gray G. Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa. N Engl J Med. 2022 Feb 3;386(5):494–6. DOI: 10.1056/NEJMc2119270.

5. Nemet I, Kliker L, Lustig Y, Zuckerman N, Erster O, Cohen C, Kreiss Y, Alroy-Preis S, Regev-Yochay G, Mendelson E, Mandelboim M. Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 Omicron Infection. N Engl J Med. 2022 Feb 3;386(5):492–4. DOI: 10.1056/NEJMc2119358.

6. Planas D, Saunders N, Maes P, Guivel-Benhassine F, Planchais C, Buchrieser J, Bolland WH, Porrot F, Staropoli I, Lemoine F, Péré H, Veyer D, Puech J, Rodary J, Baele G, Dellicour S, Raymenants J, Gorissen S, Geenen C, Vanmechelen B, Wawina-Bokalanga T, Martí-Carreras J, Cuypers L, Sève A, Hocqueloux L, Prazuck T, Rey FA, Simon-Loriere E, Bruel T, Mouquet H, André E, Schwartz O. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022 Feb;602(7898):671–5. DOI: 10.1038/s41586-021-04389-z.

7. Embi PJ, Levy ME, Naleway AL, et al. Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19–Associated Hospitalizations Among Immunocompromised Adults — Nine States, January–September 2021. MMWR Morb Mortal Wkly Rep 2021;70:1553–9. DOI: 10.15585/mmwr.mm7044e3external icon.

8. Scobie HM, Johnson AG, Suthar AB, et al. Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status – 13 U.S. Jurisdictions, April 4-July 17, 2021. MMWR Morb Mortal Wkly Rep. 2021 Sep 17;70(37):1284–90. DOI: 10.15585/mmwr.mm7037e1.

9. Chen J, Qi T, Liu L, Ling Y, Qian Z, Li T, Li F, Xu Q, Zhang Y, Xu S, Song Z, Zeng Y, Shen Y, Shi Y, Zhu T, Lu H. Clinical progression of patients with COVID-19 in Shanghai, China. J Infect. 2020 May;80(5):e1-e6. DOI: 10.1016/j.jinf.2020.03.004.

10. Wu J, Li W, Shi X, Chen Z, Jiang B, Liu J, Wang D, Liu C, Meng Y, Cui L, Yu J, Cao H, Li L. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19). J Intern Med. 2020 Jul;288(1):128–38. DOI: 10.1111/joim.13063.

11. Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, Patil S, Barkate H. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2021 Jan;102:501–8. DOI: 10.1016/j.ijid.2020.10.069.

12. Sulaiman I, Chung M, Angel L, et al. Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome. Nat Microbiol. 2021 Oct;6(10):1245–58. DOI: 10.1038/s41564-021-00961-5.

13. Petrov VI, Amosov AA, Gerasimenko AS, Shatalova OV, Ponomareva AV, Akinchits AN, Kulakova IS, Gorbatenko VS. Mechanisms of cytokine storm development in COVID-19 and new potential targets of pharmacotherapy. Pharmacy & Pharmacology. 2020;8(6):380–91. DOI: 10.19163/2307-9266-2020-8-6-380-391.

14. Balykova LA, Granovskaya MV, Zaslavskaya KYa, Simakina EN, Agaf’ina AS, Ivanova AYu, Kolontarev KB, Pushkar DYu. New possibilities for targeted antiviral therapy for COVID-19. Results of a multicenter clinical study of the efficacy and safety of using the drug Areplivir. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2020; 9 (3): 16–29. DOI: 10.33029/2305-3496-2020-9-3-16-29. Russian

15. Pilkington V, Pepperrell T, Hill A. A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic? J Virus Erad. 2020 Apr 30;6(2):45–51. DOI: 10.1016/S2055-6640(20)30016-9.

16. Kumagai Y, Murakawa Y, Hasunuma T, Aso M, Yuji W, Sakurai T, Noto M, Oe T, Kaneko A. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015 Oct;53(10):866–74. DOI: 10.5414/CP202388.

17. Zhao Y, Harmatz JS, Epstein CR, Nakagawa Y, Kurosaki C, Nakamura T, Kadota T, Giesing D, Court MH, Greenblatt DJ. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br J Clin Pharmacol. 2015 Nov;80(5):1076–85. DOI: 10.1111/bcp.12644.

18. Balykova LA, Radaeva OA, Zaslavskaya KY, Kostina YuA, Iskandyarova MS, Negodnova EV, Eremeev VV, Sabirov LF, Semeleva EV. Study of clinical and pathogenetic effects of anti-viral drug based on favipiravir in comorbid patients with COVID-19 at the outpatient stage of treatment. Pharmacy & Pharmacology. 2021;9(6):454–64. DOI: 10.19163/2307-9266-2021-9-6-454-464.

19. Balykova LA, Pavelkina VF, Shmyreva NV, Pyataev NA, Selezneva NM, Shepeleva OI, Almyasheva RZ Efficacy and safety of some etiotropic therapeutic schemes for treating patients with novel coronavirus infection (COVID-19). Pharmacy & Pharmacology. 2020;8(3):150–9. DOI: 10.19163/2307-9266-2020-8-3-150-159.

20. Bojkova D, Widera M, Ciesek S, et al. Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant of SARS-CoV-2 isolates. Cell Res. 2022;32:319–21. DOI: 10.1038/s41422-022-00619-9.

21. Drapkina OM, Maev IV, Bakulin IG, Nikonov EL, Chulanov VP, Belousova EA, Veselov AV, Saiganov SA, Simanenkov VI, Bakulina NV, Avalueva EB, Oganezova IA, Skalinskaya MI, Skazayeva EV, Kashin SV, Kuvaev RO. Interim guidelines: “Diseases of the digestive organs in the context of a new coronavirus infection pandemic (COVID-19)”. Profilakticheskaya Meditsina. 2020;23(3):2120–52. DOI: 10.17116/profmed202023032120. Russian

22. Irie K, Nakagawa A, Fujita H, Tamura R, Eto M, Ikesue H, Muroi N, Tomii K, Hashida T. Pharmacokinetics of Favipiravir in Critically Ill Patients With COVID-19. Clin Transl Sci. 2020 Sep;13(5):880–5. DOI: 10.1111/cts.12827.

23. Jacobs JJL. Persistent SARS-2 infections contribute to long COVID-19. Med Hypotheses. 2021 Apr;149:110538. DOI: 10.1016/j.mehy.2021.110538.

24. Kushakova KA., Konakova A. V. Lekarstvennye dozy i ih puti vvedeniya v organizm cheloveka [Medicinal doses and their routes of administration into the human body]. E-Scio. 2020;10(49):17–23. Russian

25. Raj GM, Raveendran, R. Introduction to basics of pharmacology and toxicology: Volume 1. Springer, 2019.

26. Talevi, A., Quiroga P. ADME Processes in Pharmaceutical Sciences: Dosage, Design, and Pharmacotherapy Success. Switzerland AG: Springer, 2018.

27. WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020 Aug;20(8):e192-e197. DOI: 10.1016/S1473-3099(20)30483-7. Epub 2020 Jun 12. Erratum in: Lancet Infect Dis. 2020 Oct;20(10):e250.

28. Chen F, Dai Z, Huang C, Chen H, Wang X, Li X. Gastrointestinal Disease and COVID-19: A Review of Current Evidence. Dig Dis. 2021 Sep 10:1–9. DOI: 10.1159/000519412.