Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации, Петровский б-р, д. 8, стр. 2, Москва, 127051, Российская Федерация Резюме. Рассмотрены особенности действия инсулина на организм пациента, виды препаратов инсулина и его аналогов, применяемых для лечения сахарного диабета, и предъявляемые к ним требования. Показано, что определение биологической активности является одним из главных показателей качества данной группы препаратов. Приведено краткое описание методов анализа инсулина и его аналогов, основанных как на действии гормона на организм в целом (in vivo: двойной перекрест, эугликемический клэмп), так и на отдельных этапах его взаимодействия с системами организма (in vitro: рецепторно-связывающий анализ, фосфорилирование, метаболические методы). В связи с появлением на фармацевтическом рынке биоаналогов инсулина в статье поднимается вопрос о необходимости сохранения в нормативных документах показателя «Биологическая активность», определяемого на животных. Проведенный анализ методов определения биологической активности in vivo и in vitro убедительно показывает невозможность замены моделей с использованием животных на существующие в настоящее время методы анализа, выполняемые на клеточных культурах. Следовательно, модели на животных по-прежнему необходимы, так как только они позволяют дать адекватную оценку качества инсулинов по показателю «Биологическая активность». Принимая во внимание мировые тенденции к сокращению использования животных в испытаниях, авторы указывают на необходимость разработки методов, результаты которых будут сопоставимы с результатами определения биологической активности in vivo. Ключевые слова: инсулин; аналоги инсулина; биоподобные препараты; биоаналоги; биологическая активность; методы in vivo и in vitro; ИР-1 и ИР-2; рецепторно-связывающий анализ; фосфорилирование; метаболическая активность Для цитирования: Батуашвили ТА, Симутенко ЛВ, Шадрин ПВ, Неугодова НП. Современные подходы к определению биологической активности инсулина и его аналогов. Ведомости Научного центра экспертизы средств медицинского применения. 2019;9(2):85-92. https://doi.Abstract. The paper considers insulin's specific action on the patient's body, types of insulin preparations and insulin analogues which are used for the treatment of diabetes, as well as applicable requirements for these products. It was demonstrated that determination of biological activity is one of the key quality parameters of this type of medicines. The paper summarises the methods used for evaluation of insulin and its analogues, which are based both on the hormone's general action on the body (in vivo: double crossing, euglycemic clamp, etc.), and on certain aspects of the hormone's interaction with the body systems (in vitro: receptor-binding assay, phosphorylation, metabolic methods). Due to the appearance of insulin biosimilars on the pharmaceutical market, the article raises the issue that the «Biological potency» parameter test...
In recent years, there has been a tendency to equate the results of insulin testing by physicochemical methods with its biological activity. However, it should be emphasised that the effectiveness of insulin preparations can be judged only by the reaction of the whole organism, i.e. by the hypoglycaemic action, which is a composite indicator. The determination of the biological activity of insulin has become especially relevant with the pharmaceutical market entry of insulin biosimilars, which are practically not analogous to the original medicinal products. The effectiveness of insulin products cannot be adequately evaluated using only physicochemical testing. At present, the biological activity of insulin is tested in rabbits. Additionally, the State Pharmacopoeia of the Russian Federation includes an alternative method to determine this parameter using mice. Owing to the physiological characteristics of mice, an adequate test would require special attention to the selection of test concentrations of insulin. The aim of the study was to offer recommendations for choosing the range of insulin concentrations for determining its biological activity in mice with due consideration of changes in their sensitivity depending on the season. Materials and methods: the authors analysed the results of testing the biological activity of insulin in female mice, bearing in mind the analytical range of the method specified in the State Pharmacopoeia of the Russian Federation. Test concentrations of insulin were selected taking into account seasonal shifts in insulin sensitivity of the animals. Results: the study demonstrated significant dose dependence and linearity of the responses of female mice to insulin in the concentration range of 0.03–0.3 IU/mL. Therefore, this range can be recommended as a guideline for determining the biological activity of insulin in female mice. The selection of test concentrations is illustrated with specific examples. Conclusions: the authors offer a methodological approach to the selection of insulin concentrations and the assessment of the validity of test results during biological activity determination using twin-crossover tests in female mice.
In recent years, there has been a tendency to equate the results of insulin testing by physicochemical methods with its biological activity. However, it should be emphasised that the effectiveness of insulin preparations can be judged only by the reaction of the whole organism, i.e. by the hypoglycaemic action, which is a composite indicator. The determination of the biological activity of insulin has become especially relevant with the pharmaceutical market entry of insulin biosimilars, which are practically not analogous to the original medicinal products. The effectiveness of insulin products cannot be adequately evaluated using only physicochemical testing. At present, the biological activity of insulin is tested in rabbits. Additionally, the State Pharmacopoeia of the Russian Federation includes an alternative method to determine this parameter using mice. Owing to the physiological characteristics of mice, an adequate test would require special attention to the selection of test concentrations of insulin. The aim of the study was to offer recommendations for choosing the range of insulin concentrations for determining its biological activity in mice with due consideration of changes in their sensitivity depending on the season. Materials and methods: the authors analysed the results of testing the biological activity of insulin in female mice, bearing in mind the analytical range of the method specified in the State Pharmacopoeia of the Russian Federation. Test concentrations of insulin were selected taking into account seasonal shifts in insulin sensitivity of the animals. Results: the study demonstrated significant dose dependence and linearity of the responses of female mice to insulin in the concentration range of 0.03–0.3 IU/mL. Therefore, this range can be recommended as a guideline for determining the biological activity of insulin in female mice. The selection of test concentrations is illustrated with specific examples. Conclusions: the authors offer a methodological approach to the selection of insulin concentrations and the assessment of the validity of test results during biological activity determination using twin-crossover tests in female mice.
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