Описание
Компания Medical&Pharma предлагает современное лекарство Велкейд (Бортезомиб PS-341). С действующим веществом Бортезомиб. Активное вещество препарата Велкейд ингибирует химотипсиноподобное действие протеасомы (крупного белкового комплекса, который присутствующей в цитозоле, ядре всех эукариотических клеток и катализирующей расщепление основных белков, участвующих в жизненном цикле клеток), вызывает торможение протеолиза и приводит к апоптозу. Препарат Велкейд вызывает замедление роста многих экспериментальных моделей человеческих опухолей, включая множественную миелому.
Состав
- активное вещество – бортезомиб 1.0 мг,
- вспомогательные вещества: маннитол, азот, вода для инъекций (удаляется в процессе производства), трет-бутанол (удаляется в процессе производства).
Показания
- для лечения взрослых пациентов с прогрессирующей множественной миеломой,(терапия 2-й линии), в качестве монотерапии или в комбинированной терапии с доксорубицином или дексаметазоном
- для лечения взрослых пациентов с множественной миеломой, в комбинированной терапии с сочетанием с мелфаланом и преднизоном.
- для индукционной терапии взрослых пациентов с множественной миеломой, в комбинированной терапии с дексаметазоном.
- для лечения взрослых пациентов с мантийноклеточной лимфомой, в комбинированной терапии с ритуксимабом, циклофосфамидом, доксорубицином и преднизолоном.
Фармакокинетика
Абсорбция
При внутривенном струйном введении бортезомиба в дозах 1.0 мг/м2 и 1.3 мг/м2, с клиренсом креатинина более 50 мл/мин, 11 больным множественной миеломой, средние концентрации препарата в плазме крови, после введения начальной дозы составляли соответственно 57 и 112 нг/мл. При следующих введениях бортезомиба значение средней максимальной концентрации в плазме крови находились в пределах 89-120 для дозы 1.3 мг/м2 и 67-106 нг/мл для дозы 1.0 мг/м2.
Распределение
Средний объем распределения бортезомиба у пациентов с множественной миеломой, после однократного или многократного внутривенного введения в дозах 1.0 мг/м2 и 1.3 мг/м2, составляет 1659 — 3294 л (489-1884 л/м2). По этим данным предполагают, что в периферических тканях, бортезомиб интенсивно распределяется. Связывание препарата с белками плазмы крови in vitro, при концентрациях бортезомиба 100-1000 нг/мл, составляет в среднем 83%. Фракции бортезомиба, связанные с белками плазмы не были зависимы от концентрации.
Биотрансформация
В условиях in vitro, преимущественно осуществляется изоферментами цитохрома P450 – CYP3A4, CYP1A2 и CYP2C19. Участие в метаболизме изоферментов CYP2C9 и CYP2D6 незначительно. Основным механизмом метаболизма бортезомиба является отщепление атомов бора с образованием двух метаболитов, которые путем гидроксилирования образуют нескольких других метаболитов. Метаболиты бортезомиба не ингибируют протеасому 26S.
Выведение
Средний период полувыведения препарата (Т1/2) при многократном введении составляет 40-193 часа. После первой дозы Бортезомиб быстрее выводится по сравнению с последующими дозами.
Пациенты с нарушением функции печени
В исследовании 1 фазы в течении первого цикла лечения проводились исследования фармакокинетики бортезомиба у у 61 онкологических больных с различной степенью тяжести нарушений функции печени с применением доз бортезомиба 0.5-1.3 мг/м2. Легкие нарушения функции печени не влияют на фармакокинетику бортезомиба. По сравнению с пациентами с нормальной функцией печени, наблюдается увеличение AUC (площадь под кривой «концентрация-время») препарата до 60% у больных со средней и тяжелой степени степенью тяжести нарушения функций печени. Рекомендуется уменьшение начальной дозы бортезомиба, для пациентов с нарушениями функции печени средней и тяжелой степени. Требуется тщательное наблюдение за такими пациентами.
Пациенты с нарушением функции почек
Фармакокинетика препарата при внутривенном применении в дозах 0.7-1.3 мг/м2 дважды в неделю у пациентов с различной степенью тяжести нарушений функции почек, также у пациентов на диализе, сопоставима с фармакокинетикой бортезомиба пациентов с нормальной функцией почек.
При внутривенном болюсном введении дозировки 1.3 мг/м2 дважды в неделю, фармакокинетика бортезомиба определялась у 104 педиатрических пациентов (2- 16 лет) с острым миелоидным лейкозом (ОМЛ)с или острым лимфобластным лейкозом (ОЛЛ). Клиренс бортезомиба повышается с увеличением площади поверхности тела (ППТ), исходя из популяционного фармакокинетического анализа. Средний геометрический (% CV) клиренс составлял 7.79 (25%) л/ч/м2, объем распределения в равновесном состоянии составлял 834 (39%) л/м2 и период полувыведения составлял 100 (44%) часов. Другие демографические показатели, после корректировки с учетом эффекта ППТ: такие как возраст, пол, масса тела не оказывали на клиренс бортезомиба клинически значимого воздействия. Клиренс бортезомиба у детей, нормализованный по ППТ, был аналогичен наблюдавшемуся у взрослых.
Фармакодинамика
Бортезомиб представляет собой модифицированную борную кислоту, обратимый высокоселективный ингибитор, подавляющий химотрипсиноподобное действие 26S-протеасомы эукариотических клеток. Протеасома — это крупный белковый комплекс, который присутствует в ядре и цитозоле всех эукариотических клеток и катализирует расщепление белков, конъюгированных с убиквитином. Убиквитин представляет собой протеасомный путь, который поддерживает внутриклеточный гомеостаз, играя основную роль в регуляции внутриклеточной концентрации многих белков. Подавление активности протеасомы ингибирует каскады реакций передачи сигнала в клетке, тем самым предотвращая этот селективный протеолиз. Нарушение механизма поддержания гомеостаза может приводить к гибели опухолевой клетки. In vivo препарат усиливал дифференцировку и активность остеобластов и ингибировал функцию остеокластов, вызывал замедление роста опухоли во многих экспериментальных моделях, включая множественную миелому.
In vitro миеломные клетки в 1000 раз более восприимчивы к апоптозу, вызванному препаратом, по сравнению с нормальными клетками.
Механизм разрушения миеломных клеток заключается в подавлении активности NF-kB (существует как димер р50-р65 в нормальных клетках), который связан с ингибирующим белком LkB, удерживающим его в цитозоли в неактивной форме. Некоторые опухоли содержат активированные формы NF-kB. 26S-протеасома активирует протеолитическую генерацию белков NF-kB (из неактивного предшественника р150 в р50) и вызывает разрушение ингибирующего белка LkB. Активированные белки NF-kB, проникая в ядро, влияют на пролиферацию клетки и на ее выживаемость. Данные процессы ведут к уменьшению количества воспалительных молекул, молекул клеточной адгезии (позволяют соединительным клеткам прикрепляться к клеткам костного мозга), цитокинов (стимулируют рост клеток миеломы) и антиапоптозных факторов.
Препарат вызывал замедление роста многих моделей человеческих опухолей in vivo, включая множественную миелому.
Фармацевтические характеристики
Белая или почти белая лиофилизированная масса или порошок, для приготовления раствора для внутривенного введения, 1.0 мг
Упаковка, срок годности,
условия хранения
Препарат помещают во флакон боросиликатного стекла типа I вместимостью 5 мл, закрытый серой пробкой из эластомера, обкатанный крышкой алюминиевой и закрытый сверху колпачком зеленым пластиковым. Один флакон помещают в контурную ячейковую упаковку из поливинилхлорида. Одна контурная упаковка вместе с инструкцией по медицинскому применению на государственном и русском языках помещается в пачку из картона.
Хранить в защищенном от света месте, в оригинальной упаковке, при температуре не выше 30 °С, в недоступном для детей месте. Приготовленный раствор хранят в оригинальном флаконе при температуре не выше 25 °С не более 8 часов.
Хранить 3 года с момента выпуска. Не применять по истечении срока годности.
Наша компания работает как на территории Кыргызстана, так и осуществляет доставку в страны ближнего зарубежья. Обращайтесь к нам за консультациями по контактным телефонам.
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