vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2021-11-4-228-238vedomostiregmed-380Research ArticleОБЗОРЫREVIEWSСовременные подходы к подтверждению терапевтической эквивалентности лекарственных препаратов локального действия в желудочно-кишечном трактеCurrent Approaches to Demonstration of Therapeutic Equivalence of Locally-Acting Gastrointestinal Drugshttps://orcid.org/0000-0001-6433-9781ГорбуноваЕ. В.GorbunovaE. V.

Горбунова Екатерина Владимировна

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

Ekaterina V. Gorbunova

8/2 Petrovsky Blvd, Moscow 127051

gorbunova@expmed.ruhttps://orcid.org/0000-0001-8583-2372ГорячевД. В.GoryachevD. V.

Горячев Дмитрий Владимирович, доктор медицинских наук

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

Dmitry V. Goryachev, Dr. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

gorachev@expmed.ruhttps://orcid.org/0000-0002-5430-6975ГорскаяТ. Е.GorskayaT. E.

Горская Татьяна Евгеньевна

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

 

Tatiana E. Gorskaya

8/2 Petrovsky Blvd, Moscow 127051

gorskayate@expmed.ruhttps://orcid.org/0000-0002-8930-4689БогдановА. Н.BogdanovA. N.

Богданов Александр Николаевич, доктор медицинских наук

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

Aleksandr N. Bogdanov, Dr. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

bogdanov@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202115112021114228238Copyright © Горбунова Е.В., Горячев Д.В., Горская Т.Е., Богданов А.Н., 20212021Горбунова Е.В., Горячев Д.В., Горская Т.Е., Богданов А.Н.Gorbunova E.V., Goryachev D.V., Gorskaya T.E., Bogdanov A.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/380

Развитие знаний об особенностях фармакокинетики и фармакодинамики лекарственных препаратов, действующих локально, увеличение количества разрабатываемых и воспроизведенных препаратов стало основанием для разработки новых научных подходов к выбору методик организации и проведения исследований терапевтической эквивалентности лекарственных препаратов, действующих локально в желудочно-кишечном тракте (ЛЖК-препараты). На сегодняшний день обновлены многие международные рекомендации по планированию и проведению исследований биоэквивалентности (БЭ) ЛЖК-препаратов, в Российской Федерации и Евразийском экономическом союзе (ЕАЭС) подобные рекомендации отсутствуют. Таким образом, создание единых методологических подходов к планированию клинических исследований подобных препаратов, проводимых на территории ЕАЭС, является актуальным. Цель работы — анализ зарубежных подходов к планированию, проведению и экспертной оценке исследований терапевтической эквивалентности ЛЖК-препаратов. Проведен анализ руководств Европейского агентства по лекарственным средствам и Управления по контролю за качеством продуктов питания и лекарственных средств США по планированию, проведению и оценке исследований биоэквивалентности ЛЖК-препаратов. Сделан вывод о вытеснении клинических исследований при выборе метода исследования БЭ экспериментальными подходами, обеспечивающими чувствительную и точную оценку различий тестируемого ЛЖК-препарата и референтного препарата in vitro с применением индивидуального подхода с учетом механизма действия, лекарственной формы и места действия. Приведены примеры процедур исследований препаратов, имеющих сложный биофармацевтический профиль и демонстрирующих сложности при проведении исследований их биоэквивалентности, большое внимание уделено исследованиям препаратов месалазина. Результаты проведенного анализа могут служить основой создания единого методологического подхода к организации и проведению исследований терапевтической эквивалентности ЛЖК-препаратов в Российской Федерации и ЕАЭС.

Evolution of knowledge about pharmacokinetics and pharmacodynamics of locally acting products, and an increase in the number of generics and medicines under development have laid the ground for the development of new scientific approaches to planning and conducting of therapeutic equivalence studies of medicinal products acting locally in the gastrointestinal (GI) tract. To date, many international guidelines on planning and conducting of bioequivalence (BE) studies of locally acting GI products have been updated, however, there are still no such guidelines in the Russian Federation and the Eurasian Economic Union (EAEU). Therefore, elaboration of common methodological approaches to the planning of clinical studies of these products is of particular relevance for the EAEU. The aim of the study was to analyse foreign approaches to planning, conducting, and evaluation of therapeutic equivalence studies of locally acting GI products. The paper analyses the guidelines of the European Medicines Agency and the US Food and Drug Administration on the planning, conduct, and evaluation of BE studies of locally acting GI products. The analysis demonstrated that BE clinical trials are giving way to in vitro studies providing a sensitive and accurate assessment of the differences between a locally acting GI product and the reference product, based on careful consideration of the medicine’s mechanism of action, dosage form, and site of action. The paper gives examples of test methods applied to medicinal products with a complex biopharmaceutical profile whose bioequivalence assessment is challenging, with a special focus on mesalazine products. The results of the analysis may be used for elaboration of a harmonised methodological approach to planning and conducting therapeutic equivalence studies of locally acting GI products in the Russian Federation and EAEU.

клиническое исследованиерегистрация лекарственных средствлокально действующие лекарственные препараты в желудочно-кишечном трактемесалазинбиоэквивалентностьтерапевтическая эквивалентностьреферентный препаратin vitroтест кинетики растворенияclinical studymedicinal product authorisationlocally acting gastrointestinal productsmesalazinebioequivalencetherapeutic equivalencereference productin vitrodissolution kinetics testРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00005-21-00 на проведение прикладных научных исследований (номер государственного учета НИР 121021800098-4).The study reported in this publication was carried out as part of a publicly funded research project No. 056-00005-21-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121021800098-4).ReferencesVetchy D, Frybortova K, Rabiskova M, Daneckova H. Bioequivalence studies of pharmaceutical preparations. Cas Lek Cesk. 2007;146(5):431–3. PMID: 175549632.Vetchy D, Frybortova K, Rabiskova M, Daneckova H. Bioequivalence studies of pharmaceutical preparations. Cas Lek Cesk. 2007;146(5):431–3. PMID: 175549632.Горячев ДВ, Уварова НЕ. Обоснование возможности проведения исследований терапевтической эквивалентности. Ведомости Научного центра экспертизы средств медицинского применения. 2019;9(2):79–84. [Goryachev DV, Uvarova NE. Substantiation of the possibility of conducting therapeutic equivalence studies. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2019;9(2):79–4 (In Russ.)] https://doi.org/10.30895/1991-2919-2019-9-2-79-84.Горячев ДВ, Уварова НЕ. Обоснование возможности проведения исследований терапевтической эквивалентности. Ведомости Научного центра экспертизы средств медицинского применения. 2019;9(2):79–84. [Goryachev DV, Uvarova NE. Substantiation of the possibility of conducting therapeutic equivalence studies. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2019;9(2):79–4 (In Russ.)] https://doi.org/10.30895/1991-2919-2019-9-2-79-84.Jiang X, Yang Y, Stier E. Bioequivalence for drug products acting locally within gastrointestinal tract. In: Yu LX, Li BV, eds. FDA Bioequivalence Standards. New York – Heidelberg – Dordrecht – London: Springer; 2014. P. 297–334.Jiang X, Yang Y, Stier E. Bioequivalence for drug products acting locally within gastrointestinal tract. In: Yu LX, Li BV, eds. FDA Bioequivalence Standards. New York – Heidelberg – Dordrecht – London: Springer; 2014. P. 297–334.Yu A, Sun D, Li BV, Yu LX. Bioequivalence history. In: Yu LX, Li BV, eds. FDA Bioequivalence Standards. New York – Heidelberg – Dordrecht – London: Springer; 2014.P. 1–27.Yu A, Sun D, Li BV, Yu LX. Bioequivalence history. In: Yu LX, Li BV, eds. FDA Bioequivalence Standards. New York – Heidelberg – Dordrecht – London: Springer; 2014.P. 1–27.Zhang X, Zheng N, Lionberger RA, Yu LX. Innovative approaches for demonstration of bioequivalence: the US FDA perspective. Ther Deliv. 2013;4(6):725–40. https://doi.org/10.4155/tde.13.41Zhang X, Zheng N, Lionberger RA, Yu LX. Innovative approaches for demonstration of bioequivalence: the US FDA perspective. Ther Deliv. 2013;4(6):725–40. https://doi.org/10.4155/tde.13.41Chen ML, Shah V, Patnaik R, Adams WA, Hussain A, Conner D, et al. Bioavailability and bioequivalence: an FDA regulatory overview. Pharm Res. 2001;18(12):1645–50. https://doi.org/10.1023/a:1013319408893Chen ML, Shah V, Patnaik R, Adams WA, Hussain A, Conner D, et al. Bioavailability and bioequivalence: an FDA regulatory overview. Pharm Res. 2001;18(12):1645–50. https://doi.org/10.1023/a:1013319408893Zou P, Yu LX. Pharmacodynamic endpoint bioequivalence studies. In: Yu LX, Li BV, eds. FDA Bioequivalence Standards. New York – Heidelberg – Dordrecht – London: Springer; 2014.P. 217–41.Zou P, Yu LX. Pharmacodynamic endpoint bioequivalence studies. In: Yu LX, Li BV, eds. FDA Bioequivalence Standards. New York – Heidelberg – Dordrecht – London: Springer; 2014.P. 217–41.Shreya AB, Raut SY, Managuli RS, Udupa N, Mutalik S. Active targeting of drugs and bioactive molecules via oral administration by ligand-conjugated lipidic nanocarriers: recent advances. AAPS Pharm SciTech. 2018;20(1):15. https://doi.org/10.1208/s12249-018-1262-2Shreya AB, Raut SY, Managuli RS, Udupa N, Mutalik S. Active targeting of drugs and bioactive molecules via oral administration by ligand-conjugated lipidic nanocarriers: recent advances. AAPS Pharm SciTech. 2018;20(1):15. https://doi.org/10.1208/s12249-018-1262-2Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019;11(3):129. https://doi.org/10.3390/pharmaceutics11030129Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019;11(3):129. https://doi.org/10.3390/pharmaceutics11030129Hua S. Advances in oral drug delivery for regional targeting in the gastrointestinal tract – influence of physiological, pathophysiological and pharmaceutical factors. Front Pharmacol. 2020;11:524. https://doi.org/10.3389/fphar.2020.00524Hua S. Advances in oral drug delivery for regional targeting in the gastrointestinal tract – influence of physiological, pathophysiological and pharmaceutical factors. Front Pharmacol. 2020;11:524. https://doi.org/10.3389/fphar.2020.00524Sferrazza G, Siviero PD, Nicotera G, Turella P, Serafino A, Blandizzi C, Pierimarchi P. Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations. Expert Rev Clin Pharmacol. 2017;10(9):1007–19. https://doi.org/10.1080/17512433.2017.1348227Sferrazza G, Siviero PD, Nicotera G, Turella P, Serafino A, Blandizzi C, Pierimarchi P. Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations. Expert Rev Clin Pharmacol. 2017;10(9):1007–19. https://doi.org/10.1080/17512433.2017.1348227Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J. 2008;10(1):103–9. https://doi.org/10.1208/s12248-008-9010-2Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J. 2008;10(1):103–9. https://doi.org/10.1208/s12248-008-9010-2Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med. 2000;108(4):269–75. https://doi.org/10.1016/s0002-9343(99)00435-0Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am J Med. 2000;108(4):269–75. https://doi.org/10.1016/s0002-9343(99)00435-0Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose–response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest. 2001; 119(5):1322–8. https://doi.org/10.1378/chest.119.5.1322Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel N. Dose–response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest. 2001; 119(5):1322–8. https://doi.org/10.1378/chest.119.5.1322Kharitonov SA, Barnes PJ. Effects of corticosteroids on noninvasive biomarkers of inflammation in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1(3):191–9. https://doi.org/10.1513/pats.200402-011msKharitonov SA, Barnes PJ. Effects of corticosteroids on noninvasive biomarkers of inflammation in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1(3):191–9. https://doi.org/10.1513/pats.200402-011msZietkowski Z, Kucharewicz I, Bodzenta-Lukaszyk A. The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease. Respir Med. 2005;99(7):816–24. https://doi.org/10.1016/j.rmed.2004.12.008Zietkowski Z, Kucharewicz I, Bodzenta-Lukaszyk A. The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease. Respir Med. 2005;99(7):816–24. https://doi.org/10.1016/j.rmed.2004.12.008Steinijans VW, Neuhäuser M, Bretz F. Equivalence concepts in clinical trials. Eur J Drug Metab Pharmacokinet. 2000;25(1):38–40. https://doi.org/10.1007/bf03190056Steinijans VW, Neuhäuser M, Bretz F. Equivalence concepts in clinical trials. Eur J Drug Metab Pharmacokinet. 2000;25(1):38–40. https://doi.org/10.1007/bf03190056Laster LL, Johnson MF. Non-inferiority trials: the ‘at least as good as’ criterion. Stat Med. 2003;22(2):187–200. https://doi.org/10.1002/sim.1137Laster LL, Johnson MF. Non-inferiority trials: the ‘at least as good as’ criterion. Stat Med. 2003;22(2):187–200. https://doi.org/10.1002/sim.1137Zhang Z. Non-inferiority testing with a variable margin. Biom J. 2006;48(6):948–65. https://doi.org/10.1002/bimj.200610271Zhang Z. Non-inferiority testing with a variable margin. Biom J. 2006;48(6):948–65. https://doi.org/10.1002/bimj.200610271Zhi J, Melia AT, Eggers H, Joly R, Patel IH. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol. 1995;35(11):1103–8. https://doi.org/10.1002/j.1552-4604.1995.tb04034.xZhi J, Melia AT, Eggers H, Joly R, Patel IH. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol. 1995;35(11):1103–8. https://doi.org/10.1002/j.1552-4604.1995.tb04034.xSchröder H, Campbell DE. Absorption, metabolism and excretion of salicylazosulfapyridine in man. Clin Pharmacol Ther. 1972;13(4):539–51. https://doi.org/10.1002/cpt1972134539Schröder H, Campbell DE. Absorption, metabolism and excretion of salicylazosulfapyridine in man. Clin Pharmacol Ther. 1972;13(4):539–51. https://doi.org/10.1002/cpt1972134539Qureshi AI, Cohen RD. Mesalamine delivery system: do they really make much difference? Adv Drug Deliv Rev. 2005; 57(2):281–302. https://doi.org/10.1016/j.addr.2004.08.008Qureshi AI, Cohen RD. Mesalamine delivery system: do they really make much difference? Adv Drug Deliv Rev. 2005; 57(2):281–302. https://doi.org/10.1016/j.addr.2004.08.008Myers B, Evans DN, Rhodes J, Evans BK, Hughes BR, Lee MG, et al. Metabolism and urinary excretion of 5-amino salicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in the gastrointestinal tract. Gut. 1987;28(2):196–200. https://doi.org/10.1136/gut.28.2.196Myers B, Evans DN, Rhodes J, Evans BK, Hughes BR, Lee MG, et al. Metabolism and urinary excretion of 5-amino salicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in the gastrointestinal tract. Gut. 1987;28(2):196–200. https://doi.org/10.1136/gut.28.2.196Rudolph MW, Klein S, Beckert TE, Petereit H, Dressman JB.A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis. Eur J Pharm Biopharm. 2001;51(3):183–90. https://doi.org/10.1016/s0939-6411(01)00134-5Rudolph MW, Klein S, Beckert TE, Petereit H, Dressman JB.A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis. Eur J Pharm Biopharm. 2001;51(3):183–90. https://doi.org/10.1016/s0939-6411(01)00134-5Sandborn WJ. Rational selection of oral 5-aminosalicylate formulations and prodrugs for the treatment of ulcerative colitis. Am J Gastroentero. 2002;97(12):2939–41. https://doi.org/10.1111/j.1572-0241.2002.07092.xSandborn WJ. Rational selection of oral 5-aminosalicylate formulations and prodrugs for the treatment of ulcerative colitis. Am J Gastroentero. 2002;97(12):2939–41. https://doi.org/10.1111/j.1572-0241.2002.07092.xAumais G, Lefebvre M, Tremblay C, Bitton A, Martin F, Giard A, et al. Rectal tissue, plasma and urine concentrations of mesalamine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients. Aliment Pharmacol Ther. 2003;17(1):93–7. https://doi.org/10.1046/j.1365-2036.2003.01409.xAumais G, Lefebvre M, Tremblay C, Bitton A, Martin F, Giard A, et al. Rectal tissue, plasma and urine concentrations of mesalamine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients. Aliment Pharmacol Ther. 2003;17(1):93–7. https://doi.org/10.1046/j.1365-2036.2003.01409.x

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