Bioequivalence study of generic molnupiravir in healthy volunteers
- Authors: Vasilyuk V.B.1,2, Boroduleva A.Y.3, Sobolev P.D.4, Nikiforova A.G.4, Mozgovaya V.G.5, Filon O.V.5, Zinkovskaya A.V.5, Ignatiev V.G.5, Samsonov M.Y.5, Kozlova I.S.5, Khanonina E.K.5
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Affiliations:
- Limited Liability Company “Eco-Safety Scientific Research Center”
- North-Western State Medical University named after I.I. Mechnikov
- Limited Liability Company “Exacte Labs”
- Limited Liability Company “Exacte Labs”,
- Joint-Stock Company “R-Pharm”
- Issue: Vol 10, No 6 (2022)
- Pages: 562-572
- Section: ORIGINAL ARTICLES
- URL: https://ogarev-online.ru/2307-9266/article/view/132948
- DOI: https://doi.org/10.19163/2307-9266-2022-10-6-562-572
- ID: 132948
Cite item
Abstract
Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease.
The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers.
Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0–16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 – 125.00%.
Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0–16) and Cmax were 96.31% – 113.64% and 91.37% – 114.8%, respectively. These intervals fit within the established limits of 80.00–125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs.
Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.
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##article.viewOnOriginalSite##About the authors
Vasily B. Vasilyuk
Limited Liability Company “Eco-Safety Scientific Research Center”; North-Western State Medical University named after I.I. Mechnikov
Email: vasilyuk_vb@ecosafety.ru
ORCID iD: 0000-0003-2503-4402
Doctor of Sciences (Medicine), Managing Director of “Eco-Safety Scientific Research Center”, Professor of the Department of Toxicology, Extreme and Diving Medicine, North-Western State Medical University n.a. I.I. Mechnikov
Russian Federation, 65, Yuri Gagarin Ave., St. Petersburg, 196143; 41, Kirochnaya Str., St. Petersburg, 191015Anna Yu. Boroduleva
Limited Liability Company “Exacte Labs”
Email: anna.boroduleva@exactelabs.com
ORCID iD: 0000-0003-1074-5551
Senior Analytical Chemist
Russian Federation, Bldg 2, 20, Nauchny driveway, Moscow, 117246Pavel D. Sobolev
Limited Liability Company “Exacte Labs”,
Email: pavel.sobolev@exactelabs.com
ORCID iD: 0000-0003-3634-596X
Head of the Laboratory of Bioanalytics
Russian Federation, Bldg 2, 20, Nauchny driveway, Moscow, 117246Aiyyna G. Nikiforova
Limited Liability Company “Exacte Labs”,
Email: aiyyna.nikiforova@exactelabs.com
ORCID iD: 0000-0002-5719-0787
Head of the Bioanalytics Department
Russian Federation, Bldg 2, 20, Nauchny driveway, Moscow, 117246Valentina G. Mozgovaya
Joint-Stock Company “R-Pharm”
Email: mozgovay@rpharm.ru
ORCID iD: 0000-0002-8934-8884
Scientific Adviser
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154Olga V. Filon
Joint-Stock Company “R-Pharm”
Email: ov.filon@rpharm.ru
ORCID iD: 0000-0002-8735-7429
Department Director
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154Anna V. Zinkovskaya
Joint-Stock Company “R-Pharm”
Email: zinkovskaya@rpharm.ru
ORCID iD: 0000-0002-7028-0496
Head of the Biostatistics Group of the Department of Preclinical and Clinical Development
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154Vasily G. Ignatiev
Joint-Stock Company “R-Pharm”
Email: info@rpharm.ru
ORCID iD: 0000-0003-2818-6583
Candidate of Sciences (Medicine), General Director
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154Mikhail Yu. Samsonov
Joint-Stock Company “R-Pharm”
Email: samsonov@rpharm.ru
ORCID iD: 0000-0003-2685-1623
Candidate of Sciences (Medicine), Associate Professor, Medical Director
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154Irina S. Kozlova
Joint-Stock Company “R-Pharm”
Email: is.kozlova@rpharm.ru
ORCID iD: 0000-0002-2536-296X
Medical Writer
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154Elizaveta K. Khanonina
Joint-Stock Company “R-Pharm”
Author for correspondence.
Email: khanonina@rphapm.ru
ORCID iD: 0000-0001-5848-0869
Junior Specialist
Russian Federation, Bldg 1, 19, Berzarin Str., Moscow, 123154References
- Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054–62. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Erratum in: Lancet. 2020 Mar 28;395(10229):1038.
- Walsh KA, Spillane S, Comber L, Cardwell K, Harrington P, Connell J, Teljeur C, Broderick N, de Gascun CF, Smith SM, Ryan M, O’Neill M. The duration of infectiousness of individuals infected with SARS-CoV-2. J Infect. 2020 Dec;81(6):847–56. doi: 10.1016/j.jinf.2020.10.009
- Ng TI, Correia I, Seagal J, DeGoey DA, Schrimpf MR, Hardee DJ, Noey EL, Kati WM. Antiviral Drug Discovery for the Treatment of COVID-19 Infections. Viruses. 2022 May 4;14(5):961. doi: 10.3390/v14050961
- Rahmah L, Abarikwu SO, Arero AG, Essouma M, Jibril AT, Fal A, Flisiak R, Makuku R, Marquez L, Mohamed K, Ndow L, Zarębska-Michaluk D, Rezaei N, Rzymski P. Oral antiviral treatments for COVID-19: opportunities and challenges. Pharmacol Rep. 2022 Dec;74(6):1255–78. doi: 10.1007/s43440-022-00388-7
- Singh AK, Singh A, Singh R, Misra A. Molnupiravir in COVID-19: A systematic review of literature. Diabetes Metab Syndr. 2021 Nov-Dec;15(6):102329. doi: 10.1016/j.dsx.2021.102329
- Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, Höbartner C, Cramer P. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021 Sep;28(9):740–6. doi: 10.1038/s41594-021-00651-0
- Tian L, Pang Z, Li M, Lou F, An X, Zhu S, Song L, Tong Y, Fan H, Fan J. Molnupiravir and Its Antiviral Activity Against COVID-19. Front Immunol. 2022 Apr 4;13:855496. doi: 10.3389/fimmu.2022.855496
- Johnson MG, Puenpatom A, Moncada PA, Burgess L, Duke ER, Ohmagari N, Wolf T, Bassetti M, Bhagani S, Ghosn J, Zhang Y, Wan H, Williams-Diaz A, Brown ML, Paschke A, De Anda C. Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial. Ann Intern Med. 2022 Aug;175(8):1126–34. doi: 10.7326/M22-0729
- Amani B, Zareei S, Amani B. Rapid review and meta-analysis of adverse events associated with molnupiravir in patients with COVID-19. Br J Clin Pharmacol. 2022 Oct;88(10):4403–11. doi: 10.1111/bcp.15449
- Fischer WA 2nd, Eron JJ Jr, Holman W, Cohen MS, Fang L, Szewczyk LJ, Sheahan TP, Baric R, Mollan KR, Wolfe CR, Duke ER, Azizad MM, Borroto-Esoda K, Wohl DA, Coombs RW, James Loftis A, Alabanza P, Lipansky F, Painter WP. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med. 2022 Jan 19;14(628):eabl7430. doi: 10.1126/scitranslmed.abl7430
- Caraco Y, Crofoot GE, Moncada PA, Galustyan AN, Musungaie DB, Payne B, Kovalchuk E, Gonzalez A, Brown ML, Williams-Diaz A, Gao W, Strizki JM, Grobler J, Du J, Assaid CA, Paschke A, Butterton JR, Johnson MG, de Anda C. Phase 2/3 trial of molnupiravir for treatment of Covid-19 in non-hospitalized adults. NEJM Evidence. 2022;1(2). doi: 10.1056/EVIDoa2100043
- Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509–20. doi: 10.1056/NEJMoa2116044
- Abdelnabi R, Foo CS, De Jonghe S, Maes P, Weynand B, Neyts J. Molnupiravir Inhibits Replication of the Emerging SARS-CoV-2 Variants of Concern in a Hamster Infection Model. J Infect Dis. 2021 Sep 1;224(5):749–53. doi: 10.1093/infdis/jiab361
- Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schäfer A, Dinnon KH 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, Kolykhalov AA, Painter G, Harcourt J, Tamin A, Thornburg NJ, Swanstrom R, Denison MR, Baric RS. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020 Apr 29;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883
- Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol. 2021 Jan;6(1):11–8. doi: 10.1038/s41564-020-00835-2
- Wang Y, Li P, Solanki K, Li Y, Ma Z, Peppelenbosch MP, Baig MS, Pan Q. Viral polymerase binding and broad-spectrum antiviral activity of molnupiravir against human seasonal coronaviruses. Virology. 2021 Dec;564:33–8. doi: 10.1016/j.virol.2021.09.009
- Agostini ML, Pruijssers AJ, Chappell JD, Gribble J, Lu X, Andres EL, Bluemling GR, Lockwood MA, Sheahan TP, Sims AC, Natchus MG, Saindane M, Kolykhalov AA, Painter GR, Baric RS, Denison MR. Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. J Virol. 2019 Nov 26;93(24):e01348–19. doi: 10.1128/JVI.01348-19
- Pagliano P, Sellitto C, Ascione T, Scarpati G, Folliero V, Piazza O, Franci G, Filippelli A, Conti V. The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19). Expert Opin Drug Discov. 2022 Dec;17(12):1299–311. doi: 10.1080/17460441.2022.2153828
- Yoon JJ, Toots M, Lee S, Lee ME, Ludeke B, Luczo JM, Ganti K, Cox RM, Sticher ZM, Edpuganti V, Mitchell DG, Lockwood MA, Kolykhalov AA, Greninger AL, Moore ML, Painter GR, Lowen AC, Tompkins SM, Fearns R, Natchus MG, Plemper RK. Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses. Antimicrob Agents Chemother. 2018 Jul 27;62(8):e00766–18. doi: 10.1128/AAC.00766-18
- Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK. Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model. Transl Res. 2020 Apr;218:16–28. doi: 10.1016/j.trsl.2019.12.002
- Wahl A, Gralinski LE, Johnson CE, Yao W, Kovarova M, Dinnon KH 3rd, Liu H, Madden VJ, Krzystek HM, De C, White KK, Gully K, Schäfer A, Zaman T, Leist SR, Grant PO, Bluemling GR, Kolykhalov AA, Natchus MG, Askin FB, Painter G, Browne EP, Jones CD, Pickles RJ, Baric RS, Garcia JV. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021 Mar;591(7850):451–7. doi: 10.1038/s41586-021-03312-w
- Mali KR, Eerike M, Raj GM, Bisoi D, Priyadarshini R, Ravi G, Chaliserry LF, Janti SS. Efficacy and safety of Molnupiravir in COVID-19 patients: a systematic review. Ir J Med Sci. 2022 Sep 10:1–14. doi: 10.1007/s11845-022-03139-y
- Wen W, Chen C, Tang J, Wang C, Zhou M, Cheng Y, Zhou X, Wu Q, Zhang X, Feng Z, Wang M, Mao Q. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis. Ann Med. 2022 Dec;54(1):516–23. doi: 10.1080/07853890.2022.2034936
- Wong CKH, Au ICH, Lau KTK, Lau EHY, Cowling BJ, Leung GM. Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study. Lancet. 2022 Oct 8;400(10359):1213–22. doi: 10.1016/S0140-6736(22)01586-0
- Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrob Agents Chemother. 2021 Mar 1;65(5):e02428–20. doi: 10.1128/AAC.02428-20
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