Описание
Торизел — противоопухолевый препарат с действующим веществом Темсиролимус. Темсиролимус является селективным ингибитором фермента mTOR-киназы (mammalian Target of Rapamycin — мишени для рапамицина у млекопитающих), в результате чего нарушаются процессы трансляции белков, прекращается рост опухолевых клеток в G1 фазе, в которые регулируют клеточный цикл. Что в итоговом результате ингибирует рост и деление опухолевых клеток. Одновременно блокада mTOR-киназы ведет к нарушению продукции ангиогенного сосудистого эндотелиального фактора роста, вследствие чего происходит торможение развития кровеносных сосудов.
Состав
Один мл концентрата содержит:
- активное вещество: темсиролимус 25 мг;
- вспомогательные вещества: альфа-токоферол, этанол, лимонная кислота, пропиленгликоль;
- растворитель: полисорбат-80, макрогол 400, этанол.
Показания
- распространенный почечно-клеточный рак.
- рецидивирующая и/или рефрактерная лимфома из клеток мантийной зоны.
Фармакодинамика
Темсиролимус является избирательным ингибитором фермента mTOR-киназы. Темсиролимус взаимодействует с внутриклеточным белком (FKBP-12), с образованием комплекса белок-темсиролимус, который в дальнейшем связывается с mТОR-киназой и подавляет активность данного фермента, за счет чего опосредованно контролирует размножение клеток. Подавление активности фермента mTOR-киназы ведет к остановке роста опухолевых клеток в GI фазе, в результате чего происходит избирательное нарушение трансляции белков, регулирующих клеточный цикл, таких как циклины с-мик, D-типа и орнитин декарбоксилазa. Темсиролимус показывает свое действие в комплексе с белком FKBP-12 и mTOR-киназой. При связывании mTOR-киназы блокируется ее способность к фосфорилированию и контролю активности протеиновых факторов трансляции (4Е-ВР1 и S6K, оба «подчиняются» mTOR-киназе в Р13-киназном/АКТ пути), контролирующих деление клетки.
Кроме белков, регулирующих клеточный цикл, mTOR-киназа может регулировать трансляцию факторов, индуцируемых гипоксией (HIF): HIF-1 и HIF-2-альфа. Данные факторы транскрипции определяют способность опухолей приспосабливаться к гипоксическим микросредам и продуцировать ангиогенный фактор сосудистого эндотелиального фактора роста (VEGF). Таким образом, противоопухолевый эффект темсиролимуса, можно также объяснить его способностью снижать уровни HIF и VEGF в опухоли или опухолевой микросреде, что ведет к торможению развития кровеносных сосудов.
В ходе рандомизированных исследований у больных распространенной почечно-клеточной карциномой были получены данные об эффективности и безопасности препарата Торизел. Еженедельная монотерапия темсиролимусом в дозе 25 мг зачительно увеличивала показатель общей выживаемости у пациентов с распространенной почечно-клеточной карциномой в сравнении с монотерапией интерфероном альфа и комбинацией темсиролимуса с интерфероном альфа.
Фармакокинетика
Абсорбция.
При однократном введении темсиролимуса в/в в дозе 25 мг больным почечно-клеточной карциномой среднее значение максимальной коцетрации в цельной крови составляло 585 нг/мл, и среднее значение AUC в крови равнялось 1627 нг/мл·час.
Распределение.
Темсиролимус показывает полиэкспоненциальное распределение, которое можно объяснить предпочтительным связыванием с белком FKBP-12 в клетках крови. Среднее значение (стандартное отклонение, SD) константы диссоциации (Кd) связывания равнялось 5,1 (3,0) нг/мл, что отражает концентрацию, при которой происходит захват 50% участков связывания в клетках крови. Распределение темсиролимуса зависит от дозы, со средним максимальным специфическим связыванием в клетках крови 1,4 мг (от 0,47 до 2,5 мг) препарата. При однократном в/в введении 25 мг темсиролимуса среднее значение объема распределения в равновесном состоянии в цельной крови больных почечно-клеточной карциномой составило 172 л.
Метаболизм.
эффективный метаболит темсиролимуса — Сиролимус. Он является основным его метаболитом у людей после в/в инфузии. Исследования in vitro метаболизма темсиролимуса показали наличие и других его метаболитов — секо-темсиролимуса и секо-сиролимуса. Дополнительными путями метаболизма были гидроксилирование, восстановление и деметилирование. При однократном в/в введении 25 мг темсиролимуса больным с почечно-клеточной карциномой AUC сиролимуса была в 2,7 раза больше AUC темсиролимуса, главным образом за счет более длительного периода полувыведения сиролимуса.
Выведение.
После однократной в/в инфузии 25 мг темсиролимуса среднее значение системного клиренса темсиролимуса составило (11,4±2) л/час. Средние значения периода полувыведения темсиролимуса и сиролимуса были равны 17,7 и 73,3 ч соответственно. Выведение, в основном, происходило с фекалиями (78%). Выведение почками активного вещества и метаболитов составило 4,6% от введенной дозы. Сиролимус и темсиролимус in vitro являются субстратами Р-гликопротеина. Не исследовали влияние данного ингибирования на элиминацию темсиролимуса и сиролимуса in vivo.
На фармакокинетику темсиролимуса и сиролимуса раса, пол и масса тела больного существенно не влияют.
Возраст существенно не влияет на фармакокинетику темсиролимуса и сиролимуса (фармакокинетика темсиролимуса и сиролимуса изучалась у пациентов в возрасте до 79 лет). У пациентов пожилого возраста коррекция дозы не требуется.
Фармакокинетика темсиролимуса и сиролимуса у детей не исследовалась.
Коррекция дозы не требуется у пациентов с нарушением функции почек.
При необходимости использования препарата Торизел у пациентов с нарушением функции печени легкой степени (концентрация билирубина превышает верхнюю границу нормы не более чем в 1.5 раза, или активность аспартатаминотрансферазы (АСТ) выше верхней границы нормы, а концентрация билирубина не превышает верхнюю границу нормы) препарат Торизел следует применять с осторожностью. Противопоказано использование препарата Торизел у пациентов с концентрацией билирубина в плазме крови, превышающей верхнюю границу нормы в 1,5 раза и бoлее.
Фармацевтические характеристики
Торизел представляет собой концентрат в комплекте с растворителем для приготовления раствора для инфузии.
- Концентрат: прозрачный бесцветный или светло-желтый раствор.
- Растворитель: прозрачный или практически прозрачный раствор от светло-желтого до желтого цветa.
Каждый флакон с концентратом для приготовления раствора для инфузий содержит 30 мг темсиролимуса. Концентрация темсиролимуса составляет 25 мг/мл.
После разведения флакона с концентратом (1,2 мл) прилагаемым растворителем концентрация темсиролимуса в полученном растворе составит 10 мг/мл.
Упаковка, срок годности, условия хранения
Концентрат для приготовления раствора для инфузий 30 мг/1,2мл
По 1,2 мл концентрата во флаконах из прозрачного стекла (тип I), укупоренных резиновой бутилкаучуковой пробкой с покрытием из фторполимера и закатанных алюминиевым колпачком, снабженным пластиковым отрывным колпачком.
Растворитель
По 2,2 мл растворителя во флаконах из прозрачного стекла (тип I), укупоренных резиновой бутилкаучуковой пробкой с покрытием из фторполимера и закатанных алюминиевым колпачком, снабженным пластиковым отрывным колпачком.
По 1 флакону с концентратом в комплекте с растворителем (1 флакон) вместе с инструкцией по применению в картонной пачке.
Хранить препарат Торизел в защищенном от света месте, при температуре 2–8°C (не замораживать).
Хранить в недоступном для детей месте.
Срок годности
- препарата Торизел 3 года;
- растворителя — 3 года.
Наша компания работает как на территории Казахстана, так и осуществляет доставку в страны ближнего зарубежья. Обращайтесь к нам за консультациями по контактным телефонам.
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