Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers

Therapeutically, new oral anticoagulants (NOACs) are considered to be non-inferior or superior to vitamin K antagonists (warfarin). NOACs are included in current guidelines for the treatment of various cardiovascular diseases. Rivaroxaban medicinal products have been shown to effectively fight thrombotic complications of the new coronavirus infection, COVID-19. The wide clinical use of rivaroxaban products motivates the development of generics.The aim of the study was to compare the pharmacokinetics and safety of rivaroxaban medicinal products in a single-dose bioequivalence study in healthy volunteers under fasting conditions.Materials and methods: the bioequivalence study compared single-dose oral administration of Rivaroxaban, 10 mg film-coated tablets (NovaMedica Innotech LLC, Russia), and the reference product Xarelto®, 10 mg filmcoated tablets (Bayer AG, Germany), in healthy volunteers under fasting conditions. The open, randomised, crossover trial included 46 healthy volunteers. Each of the medicinal products (the test product and the reference product) was administered once; blood samples were collected during the 48 h after the administration. The washout between the study periods lasted 7 days. Rivaroxaban was quantified in plasma samples of the volunteers by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).Results: no adverse events or serious adverse events were reported for the test and reference products during the study. The following pharmacokinetic parameters were obtained for Rivaroxaban and Xarelto®, respectively: Cmax of 134.6 ± 58.0 ng/mL and 139.9 ± 49.3 ng/mL, AUC0–48 of 949.7 ± 354.5 ng×h/mL and 967.6 ± 319.9 ng×h/mL, AUC 0–∞ of 986.9 ± 379.7 ng×h/mL and 1003.6 ± 320.4 ng×h/mL, T1/2 of 8.2 ± 3.2 h and 7.8 ± 3.3 h. The 90% confidence intervals for the ratios of Cmax, AUC0–48, and AUC0–∞ geometric means were 88.04–108.67%, 89.42–104.92% and 89.44–104.81%, respectively.Conclusions: the test product Rivaroxaban and the reference product Xarelto® were found to have similar rivaroxaban pharmacokinetics and safety profiles. The study demonstrated bioequivalence of the medicinal products

Применение проточной цитометрии для оценки качества биомедицинских клеточных продуктов

Flow cytometry is the most common method of identification and quantitation of cell surface markers. Flow cytometry can be used for  cell counting and characterization of cell types and subtypes by  labeling cells with fluorochrome-conjugated monoclonal antibodies.  Manufacturers of human cell-based medicinal products have accumulated significant experience in flow cytometry and  developed a large number of procedures that can be validated and  included into cell products specifications. The present review  summarises the experience gained with the use of flow cytometry for characterization of human cell lines used to develop cell therapy  products. Since all biomedical cell products (BMCPs) have a cellular  component, it will be necessary to use the flow cytometry method for identification testing of BMCPs during evaluation of their quality.Метод проточной цитометрии — наиболее информативный метод идентификации и количественного определения поверхностных маркеров клеток. Проточная цитометрия дает  возможность проводить подсчет клеток, а также характеризацию их типов и подтипов путем  мечения клеток моноклональными антителами, конъюгированными с флуорохромом. В  настоящее время производителями продуктов на основе клеток человека накоплен  значительный опыт применения проточной цитометрии, разработано большое количество  методик, подлежащих валидации и включению в спецификацию на клеточный продукт. В  обзоре авторами рассмотрен опыт применения метода проточной цитометрии для оценки  качества клеточных линий человека, используемых, в частности, для создания препаратов с целью применения в клеточной терапии. Учитывая обязательное наличие клеточного  компонента в составе биомедицинских клеточных продуктов (БМКП), метод проточной  цитометрии будет являться обязательным при подтверждении подлинности в ходе экспертизы качества БМКП в Российской Федерации

Международный опыт нормативно-правового регулирования препаратов, содержащих жизнеспособные клетки человека

The intensive development of cellular technologies stipulates the introduction at the global level of medicinal products based on viable human cells, which in most countries are referred to as biomedical cell products. The authors conducted a comparative analysis of the regulatory framework in different countries and determined special aspects of regulation of cell therapy products (analogues of biomedical cell products). Some countries have mechanisms for priority review of cell therapy products for marketing authorization, such as accelerated assessment, accelerated approval, or conditional marketing authorisation. These mechanisms are currently absent in Russia, because of the novelty of the regulatory framework, and the biological properties of innovative cell products. Biomedical cell products are regarded as a separate class of medicinal products in Russia, they are not treated as biologicals and are regulated by the Federal Law No. 180-FZ «On Biomedical Cell Products» of June 23, 2016. The main difference in regulation of cell-based products in the Russian Federation is the principle of unified requirements for marketing authorisation of autologous, allogeneic, and combined biomedical cellular products, and the absence of the «hospital exemptions» mechanism that exists in many countries. This mechanism allows prescription and use of personalised autologous medicines produced in the laboratory of a medical institution for a particular patient.Интенсивное развитие клеточных технологий обусловливает внедрение в мировую медицинскую практику препаратов на основе жизнеспособных клеток человека, которые в большинстве стран определяются как биологические лекарственные препараты. Авторами проведен сравнительный анализ нормативно-правовой базы разных стран мира и определены особенности регулирования препаратов для клеточной терапии (аналогов биомедицинских клеточных продуктов). В некоторых странах существуют механизмы приоритетного рассмотрения препаратов для клеточной терапии для вывода на рынок, например процедуры ускоренного рассмотрения, ускоренного утверждения, условной регистрации. Учитывая новизну нормативной базы и биологические особенности инновационных препаратов — биомедицинских клеточных продуктов, в Российской Федерации подобные механизмы в настоящее время отсутствуют. Биомедицинские клеточные продукты в России являются отдельным классом медицинских средств, отличным от биологических лекарственных препаратов, и регулируются Федеральным законом № 180-ФЗ «О биомедицинских клеточных продуктах» от 23 июня 2016 г. Основным отличием регулирования клеточных препаратов в России является принцип единых требований вывода на рынок аутологичных, аллогенных и комбинированных биомедицинских клеточных продуктов и отсутствие механизма «исключения для больничного производства» (hospital exemptions), действующего во многих странах и заключающегося в допущении применения персонифицированного аутологичного препарата, произведенного в конкретной лаборатории при медицинской организации для определенного пациента по назначению конкретного врача

Use of Flow Cytometry for Quality Evaluation of Biomedical Cell Products

Flow cytometry is the most common method of identification and quantitation of cell surface markers. Flow cytometry can be used for  cell counting and characterization of cell types and subtypes by  labeling cells with fluorochrome-conjugated monoclonal antibodies.  Manufacturers of human cell-based medicinal products have accumulated significant experience in flow cytometry and  developed a large number of procedures that can be validated and  included into cell products specifications. The present review  summarises the experience gained with the use of flow cytometry for characterization of human cell lines used to develop cell therapy  products. Since all biomedical cell products (BMCPs) have a cellular  component, it will be necessary to use the flow cytometry method for identification testing of BMCPs during evaluation of their quality

International Approaches to Regulation of Medicinal Products Containing Viable Human Cells

The intensive development of cellular technologies stipulates the introduction at the global level of medicinal products based on viable human cells, which in most countries are referred to as biomedical cell products. The authors conducted a comparative analysis of the regulatory framework in different countries and determined special aspects of regulation of cell therapy products (analogues of biomedical cell products). Some countries have mechanisms for priority review of cell therapy products for marketing authorization, such as accelerated assessment, accelerated approval, or conditional marketing authorisation. These mechanisms are currently absent in Russia, because of the novelty of the regulatory framework, and the biological properties of innovative cell products. Biomedical cell products are regarded as a separate class of medicinal products in Russia, they are not treated as biologicals and are regulated by the Federal Law No. 180-FZ «On Biomedical Cell Products» of June 23, 2016. The main difference in regulation of cell-based products in the Russian Federation is the principle of unified requirements for marketing authorisation of autologous, allogeneic, and combined biomedical cellular products, and the absence of the «hospital exemptions» mechanism that exists in many countries. This mechanism allows prescription and use of personalised autologous medicines produced in the laboratory of a medical institution for a particular patient