biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2021-21-2-97-107biopreparat-314Research ArticleОБЗОРЫREVIEWSЛекарственные препараты фактора VIII, актуальные вопросы разработки, клинического исследования и применения (часть 2)Factor VIII products: key aspects of development, clinical research and use (part 2)https://orcid.org/0000-0002-9377-1378АвдееваЖ. И.AvdeevaZh. I.

Авдеева Жанна Ильдаровна, доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051

Zhanna I. Avdeeva, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

Avd-cytok@yandex.ruhttps://orcid.org/0000-0001-6624-2692СолдатовА. А.SoldatovA. A.

Солдатов Александр Алексеевич, доктор медицинских наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Aleksandr A. Soldatov, Dr. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

Soldatov@expmed.ruhttps://orcid.org/0000-0001-6472-6386БондаревВ. П.BondarevV. P.

Бондарев Владимир Петрович, доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vladimir P. Bondarev, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

Bondarev@expmed.ruhttps://orcid.org/0000-0003-0269-8337МосягинВ. Д.MosyaginV. D.

Мосягин Вячеслав Дмитриевич,  доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vyacheslav D. Mosyagin, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

mosiagin@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051;Трубецкая ул., д. 8, стр. 2, Москва, 119991

Vadim A. Merkulov, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051;8/2 Trubetskaya St., Moscow 119991

merkulov@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации; Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И. М. Сеченова» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal Products; I. M. Sechenov First Moscow State Medical UniversityRussian Federation20210903202121297107Copyright © Авдеева Ж.И., Солдатов А.А., Бондарев В.П., Мосягин В.Д., Меркулов В.А., 20212021Авдеева Ж.И., Солдатов А.А., Бондарев В.П., Мосягин В.Д., Меркулов В.А.Avdeeva Z.I., Soldatov A.A., Bondarev V.P., Mosyagin V.D., Merkulov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/314

Постоянная заместительная терапия препаратами свертывания крови при гемофилии А может привести к серьезным осложнениям, одной из причин которых является развитие «нежелательного» иммунного ответа на лекарственный препарат фактора свертывания крови VIII (FVIII), что приводит к потере эффективности проводимой терапии. Цель работы — систематизация и обобщение сведений о проявлении нежелательной иммуногенности плазменных и рекомбинантных лекарственных препаратов FVIII, формировании иммунологической толерантности, о современных подходах к разработке программы проведения клинических исследований этих препаратов на основе данных литературы, а также международных и российских руководств, включая обновленный документ Европейского агентства по лекарственным средствам. В обзоре представлены данные об оценке в ходе клинических исследований препаратов FVIII фармакокинетики, эффективности и безопасности, в том числе проявлений нежелательной иммуногенности. Особое внимание уделено рассмотрению молекулярных механизмов взаимодействия ингибиторов и FVIII. Проанализированы основные факторы (генетические особенности, состояние иммунной системы пациента, режим дозирования препарата и др.), влияющие на частоту и выраженность иммунного ответа на препарат. Изложены подходы к дизайну клинических исследований, в том числе касающиеся отбора пациентов и выбора показателей для исследований. Обоснована необходимость пострегистрационных исследований с целью сбора дополнительных клинических данных, касающихся как эффективности, так и безопасности рутинного применения препарата, включая дополнительную оценку иммуногенности и других нежелательных реакций. Сделан вывод о том, что успешность внедрения в клиническую практику качественных лекарственных препаратов FVIII обеспечивается гармонизацией требований, изложенных в отечественных и международных нормативных документах.

Continuous replacement therapy with clotting factor products can lead to serious complications in haemophilia A patients. One of potential reasons of such complications is an undesirable immune response to a blood clotting factor VIII (FVIII) product, which undermines the treatment effectiveness. The aim of the study was to systematise and summarise data on undesirable immunogenicity of plasma-derived and recombinant FVIII products, formation of immunological tolerance, and modern approaches to the development of clinical trial programmes for such products. The analysis was based on scientific literature, as well as Russian and international guidelines, including the updated document of the European Medicines Agency. The paper presents clinical trial data on pharmacokinetics, efficacy, and safety of FVIII products, including data on manifestations of unwanted immunogenicity. It highlights molecular mechanisms of interaction between inhibitors and FVIII, and analyses the main factors (genetic characteristics, immune status of patients, dosage regimen, etc.) affecting the frequency and intensity of the immune response to the product. The authors summarised approaches to the clinical trial design, including selection of patients and studied parameters. They substantiate the need for post-authorisation studies to collect additional clinical data on both efficacy and safety of the routine use of the product, including additional assessment of immunogenicity and other adverse reactions. It is concluded that the successful use of high-quality FVIII products ensures by harmonisation of requirements of Russian and international regulatory documents.

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The authors declare that there are no conflicts of interest present.