Описание
Препарат Зелбораф предназначен для ингибирования мутированных форм BRAF, которые вызывают увеличение патологического неконтролируемого потока сигналов внутри злокачественных клеток, что ведет к росту опухоли. BRAF – это белок в сигнальном пути клетки, который помогает контролировать выживание и рост клеток. Основное действующее вещество препарата Зелбораф — Вемурафениб.
Вемурафениб — ингибитор BRAF-киназ с активирующими мутациями в кодоне V600E, разработанный для лечения поздних стадий меланомы. Наименование вемурафениб производное от V600E mutated BRAF inhibition. Распространяется под торговой маркой Зелбораф. 17 августа 2011 года вемурафениб был допущен к использованию для лечения поздних стадий меланомы. Тем самым став первым препаратом, созданным на основе фрагментного подхода, получившим одобрение регулятора. Вемурафениб вызывает запрограммированную смерть клетки в клеточной линии меланомы.
Вемурафениб работает только в меланоме больных, у которых заболевание было вызвано мутацией V600E BRAF. То есть если на аминокислотной последовательности ДНК, кодирующей белок B-Raf, в позиции N600 нормальный валин заменён на глутаминовую кислоту. Около 60 процентов меланом вызваны этой мутацией. Препарат Зелбораф так же результативен против редкой мутации V600K в том же гене. Клетки меланомы без этих мутаций не подавляются вемурафенибом; препарат Зелбораф парадоксально активизирует нормальный B-Raf белок и в таком случае, может способствовать росту опухоли.
Состав Зелбораф
Одна таблетка, покрытая пленочной оболочкой, содержит:
- активное вещество: вемурафениб — 240.00 мг. Вемурафениб содержится в виде ко-преципитата вемурафениба — 240. 000 мг (30 процентов) и гипромеллозы ацетата сукцината — 560.000 мг (70 процентов);
- вспомогательные вещества: кремния диоксид коллоидный безводный, кроскармеллоза натрия, гидроксипропилцеллюлоза, магния стеарат;
- пленочная оболочка: поливиниловый спирт, титана диоксид, макрогол 3350, тальк, железа оксид красный.
- Допускается применение готовой коммерческой смеси, например Опадрай II Розовый 85FI44
Показания к применению Зелбораф
- Препарат Зелбораф показан для лечения неоперабельной или метастатической меланомы с мутацией BRAF V600.
Фармакодинамика
Вемурафениб является ингибитором серин-треонин киназы BRAF. Мутации в гене BRAF приводят к конститутивной активации белка BRAF, который, при отсутствии типичных факторов роста, может способствовать пролиферации клеток.
Полученные в биохимических исследованиях, доклинические данные, показали, что вемурафениб может сильно понижать активность BRAF киназ с активирующими мутациями в кодоне 600. Данный ингибирующий результат был подтвержден в ходе реакции фосфорилирования внеклеточной сигнал-регулирующей киназы и клеточной антипролиферации в доступных клеточных линиях меланомы, экспрессирующих ген BRAF с V600 мутациями. В тестах антипролиферации на клеточных линиях с V600 мутациями (линии V600E, V600D, V600R и V600K) концентрация полумаксимального ингибирования (IC50) варьировала от 0.016 до 1.131 мкмоль, в то время как IC50 в отношении клеточных линий с «диким» типом гена BRAF составляла соответственно 12.06 и 14.32 мкмоль.
Пациенты с метастазами в головной мозг
Суммарная эффективность терапии препаратом Зелбораф у пациентов с метастазами в головной мозг составила 17.8 процентов и 17.9 процентов у пациентов, ранее не получавших/принимавших терапию, соответственно (17.8 процентов от общей популяции).
Фармакокинетика
Фармакокинетические параметры препарата Зелбораф пропорциональны дозировке при приеме препарата в диапазоне от 240 до 960 мг два раза в день. Максимальная концентрация максимального времени (Тmах) достигается через 4 часа. При длительном дозировании препарата Зелбораф примерно через 14 дней достигается равновесное состояние. Фактор кумуляции составляет около 7.4.
Всасывание
Абсолютная биодоступность вемурафениба не изучалась. Питание богатое жирной пищей увеличивает относительную биодоступность однократного приема препарата Зелбораф в дозировке 960 мг. Средние геометрические коэффициенты между состоянием натощак и состоянием насыщения в отношении максимальная концентрация (Сmах) и AUC составляли от 4.6 до 5. и 12.5, соответственно. Медиана максимального времени Тmах возрастала с 4 до 7.5 часов при однократном приеме вемурафениба с пищей. Влияние пищи на биоэквивалентность препарата Зелбораф после многократного дозирования не изучалось.
Распределение
Кажущийся объем распределения вемурафениба у пациентов с метастатической меланомой составил 91 литр. Вемурафениб характеризуется высокой степенью связывания с белками плазмы крови человека (более 99 процентов). Препарат Зелбораф имеет сродство только к небольшому количеству эритроцитов и доклинические исследования указывают на то, что препарат Зелбораф не переносится ликвором.
Метаболизм
In vitro CYP3A4 является первичным ферментом, ответственным за метаболизм вемурафениба. Относительная концентрация вемурафениба и его метаболитов в плазме крови человека, определенная в ходе однократного перорального применения вемурафениба, меченного С14, составила соответственно 95 процентов и 5 процентов.
Одновременное назначение рифампицина, сильного индуктора CYP3A4, существенно, примерно на 40 процентов, снижало концентрацию вемурафениба в плазме (AUC) после приема одной дозировки вемурафениба, на основании чего можно предположить, что участие CYP3A4 является важным метаболическим путем для препарата Зелбораф.
Выведение Зелбораф
Выведение осуществляется в значительной степени с желчью. В фекалиях обнаруживается до 73 процентов исходного вемурафениба и до 13 процентов метаболитов. В моче находится менее 1 процента радиоактивной метки (исследование ADME). У больных с метастатической меланомой кажущийся клиренс вемурафениба составляет 29.3 л/день. Медиана индивидуальных значений периода полувыведения вемурафениба составляет 56,9 часа.
Фармакокинетика у особых групп пациентов
Пожилые пациенты
Согласно результатам популяционного фармакокинетического анализа, статистически значимого влияния на фармакокинетику вемурафениба возраст пациентов не оказывает.
Пол
Наблюдаемый клиренс препарата у мужчин на 17 процентов, а наблюдаемый объем распределения — на 48 процентов больше, чем у женщин. Однако различия в отношении концентрации препарата Зелбораф относительно невелики, что указывает на отсутствие необходимости корректировать дозировку препарата Зелбораф в зависимости от пола больного.
Дети
Ограниченные фармакокинетические данные, полученные в клиническом исследовании от шести подростков в возрасте от 15 до 17 лет с меланомой стадии III или IV, положительной по мутации BRAF , свидетельствуют о том, что фармакокинетические характеристики вемурафениба у подростков в целом аналогичны с таковыми, наблюдаемыми у взрослых больных. Однако, сделать вывод невозможно, в связи с ограниченным объемом данных.
Пациенты с почечной недостаточностью
У пациентов с ограниченной функцией почек исследований фармакокинетики вемурафениба не проводилось.
Пациенты с печеночной недостаточностью
У пациентов с ограниченной функцией печени исследований фармакокинетики вемурафениба не проводилось.
Данные доклинических исследований
Канцерогенность
Исследования канцерогенности не проводились.
Мутагенность
Результаты стандартных исследований генотоксичности свидетельствуют о том, что вемурафениб не оказывает мутагенного действия.
Нарушение фертильности
Доклинические исследования влияния препарата на фертильность не проводились. В ходе токсикологических исследований с многократным введением препарата Зелбораф патологических изменений в органах репродуктивной системы не было выявлено.
Тератогенность
При введении препарата Зелбораф беременным самкам крыс в дозах до 250 мг/кг/день (практически в 1.7 раза выше клинической дозировки для человека, исходя из AUC) и беременным самкам кроликов в дозировках до 450 мг/кг/день (практически в 0.8 раза выше клинической дозировки для человека, исходя из AUC) признаков тератогенного действия вемурафениба на эмбрион/плод не было выявлено.
Содержание препарата в крови плода составляло 2-6 процента от содержания препарата Зелбораф в крови матери, что свидетельствует о том, что во время внутриутробного развития вемурафениб способен проникать через плаценту в кровь плода .
Фармацевтические характеристики
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Упаковка, срок годности, условия хранения Зелбораф
По 8 таблеток расположены в блистере из ориентированного полиамида/алюминиевой фольги/ПВХ и алюминиевой фольги. По 7 блистеров вместе с инструкцией по применению помещены в пачку картонную.
Хранить препарат Зелбораф нужно при температуре не выше 30°С в оригинальной упаковке для защиты от влаги. Хранить в недоступном для детей месте.
Срок годности 3 года.
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