Generic drugs of direct antiviral action for the treatment of hepatitis C: features of bioequivalence studies

Introduction. In the last decade, approaches to the treatment of chronic viral hepatitis C (HCV) have undergone significant changes. The new WHO strategy aims to eliminate HCV by 2030 by reducing the number of new infections and deaths by simplifying hepatitis C therapy. The development of drugs for the treatment of patients with chronic HCV has a number of features, which requires compliance with special recommendations for conducting clinical bioequivalence studies.
Aim. The study was to analyze the guidelines and protocols of bioequivalence studies of drugs for HCV therapy.
Materials and methods. An information and analytical method was used to evaluate recommendations for conducting bioequivalence studies of HCV drugs according to the US Food and Drug Administration, the European Medicines Agency, and WHO. Separately, an analysis of permitted clinical trials was carried out according to the data of the GRLS of the Ministry of Health of the Russian Federation.
Results and discussions. According to the results of the study, it was noted that for the WHO guidelines on the bioequivalence of drugs for HCV therapy, it is common to develop common principles for planning and conducting research. Special attention is paid to the preferred design of the study. It is also necessary to analyze data on the variability of the pharmacokinetic parameters of the substance under study, which are used to calculate the required number of volunteers to be included in the study.
Conclusions. Direct antiviral drugs under development for HCV therapy, for which clinical bioequivalence studies are currently being conducted in the Russian Federation, cover a large list of INN. The entry of new reproduced drugs into the pharmaceutical market will improve patients’ access to effective treatment of hepatitis C. In order to conduct a high-quality bioequivalence study, it is necessary to thoroughly familiarize yourself with nosology manuals, critical assessment and analysis of information, which will allow you to choose the appropriate design of the study and correctly plan its conduct.

1. European Union HCV Collaborators. Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study. Lancet Gastroenterol Hepatol. 2017;2(5):325–336. https://doi.org/10.1016/S2468-1253(17)30045-6.

2. Negro F., Weis N., Lazarus J. Программное заявление Европейской Ассоциации по изучению болезней печени (EASL) о ликвидации гепатита С. Режим доступа: https://easl.eu/wp-content/uploads/2019/04/EASL_Policy_Statement_on_Hepatitis_C_Elimination_June2019_RU.pdf.

3. Cooke G.S., Andrieux-Meyer I., Applegate T.L., Atun R., Burry J.R., Cheinquer H. et al. Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol Hepatol. 2019;4(2):135–184. https://doi.org/10.1016/S2468-1253(18)30270-X.

4. Tang W., Tao Y., Fajardo E., Reipold E.I., Chou R., Tucker J.D., Easterbrook P. Diagnostic Accuracy of Point-of-Care HCV Viral Load Assays for HCV Diagnosis: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2022;12(5):1255. https://doi.org/10.3390/diagnostics12051255.

5. Ivashkin V.T., Yushchuk N.D., Bogomolov P.O., Volchkova E.V., Dmitriev A.S., Zharkova M.S. et al. Chronic hepatitis C infection (2021). Clinical guidelines. (In Russ.) Available at: https://medi.ru/klinicheskie-rekomendatsii/khronicheskij-virusnyj-gepatit-s-khvgs-u-vzroslykh_14028/.

6. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol. 2020;73(5):1170–1218. https://doi.org/10.1016/j.jhep.2020.08.018.

7. Salari N., Kazeminia M., Hemati N., Ammari-Allahyari M., Mohammadi M., Shohaimi S. Global prevalence of hepatitis C in general population: A systematic review and meta-analysis. Travel Med Infect Dis. 2022;46:102255. https://doi.org/10.1016/j.tmaid.2022.102255.

8. Carrat F., Fontaine H., Dorival C., Simony M., Diallo A., Hezode C. et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet. 2019;393(10179):1453–1464. https://doi.org/10.1016/S0140-6736(18)32111-1.

9. An J., Park D.A., Ko M.J., Ahn S.B., Yoo J.J., Jun D.W., Yim S.Y. Direct-Acting Antivirals for HCV Treatment in Decompensated Liver Cirrhosis Patients: A Systematic Review and Meta-Analysis. J Pers Med. 2022;12(9):1517. https://doi.org/10.3390/jpm12091517.

10. Majumdar A., Kitson M.T., Roberts S.K. Systematic review: current concepts and challenges for the direct‐acting antiviral era in hepatitis C cirrhosis. Aliment pharmacol Ther. 2016;43(12):1276–1292. https://doi.org/10.1111/apt.13633.

11. Yushchuk N.D., Klimova E.A. Treatment of chronic hepatitis C in Russia: modern possibilities and the immediate prospects. Infectious Diseases: News, Opinions, Training. 2017;(2):86–95. (In Russ.) https://doi.org/10.24411/2305-3496-2017-00039.

12. Martinello M., Orkin C., Cooke G., Bhagani S., Gane E., Kulasegaram R. et al. Short‐Duration Pan‐Genotypic Therapy With Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection. Hepatology. 2020;72(1):7–18. https://doi.org/10.1002/hep.31003.

13. Chappell C.A., Krans E.E., Bunge K., Macio I., Bogen D., Scarsi K.K. et al. A Phase 1 study of ledipasvir/sofosbuvir in pregnant women with hepatitis C virus. Conference on Retroviruses and Opportunistic Infections, Seattle (Washington), March 4–7, 2019. Available at: https://natap.org/2019/CROI/croi_69.htm.

14. Da B.L., Lourdusamy V., Kushner T., Dieterich D., Saberi B. Efficacy of sofosbuvir/velpatasvir/voxilaprevir in direct-acting antiviral experienced patients with hepatitis C virus. Eur J Gastroenterol Hepatol. 2021;33(6):859–861. https://doi.org/10.1097/MEG.0000000000001786.

15. El-Serag H.B., Christie I.C., Puenpatom A., Castillo D., Kanwal F., Kramer J.R. The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection. Aliment Pharmacol Ther. 2019;49(11):1442–1447. https://doi.org/10.1111/apt.15240.

16. Hajarizadeh B., Cunningham E.B., Reid H., Law M., Dore G.J., Grebely J. Directacting antiviral treatment for hepatitis C among people who use or inject drugs: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2018;3(11):754–767. https://doi.org/10.1016/S2468-1253(18)30304-2.

17. Narkevich I.A., Nemyatykh O.D., Siukaeva D.D., Tsitlionok E.A., Lisacenco V.O., Grinyuk A.S. Multi-vector analysis of the market for drugs used to treat hepatitis C. Pharmacy Formulas. 2020;2(4):8–17. (In Russ.) https://doi.org/10.17816/phf49892.

18. Zhdanov K.V., Kozlov K.V. Clinical benefits and cost-effectiveness of antiviral therapy for chronic hepatitis C under governmental funding of health care. HIV Infection and Immunosuppressive Disorders. 2016;8(2):77–83. (In Russ.) https://doi.org/10.22328/2077-9828-2016-8-2-77-83.