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Зелбораф — Zelboraf (Вемурафениб)

Зелбораф

Зелбораф — Zelboraf (Вемурафениб)

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.

Категория:

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

Двояковыпуклые, овальной формы таблетки. Таблетка от розовато-белого до оранжево-белого цвета, покрытая пленочной оболочкой. Имеется гравировка «VЕМ» на одной стороне таблетки.

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.

 

 

 

 

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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Работаем и отправляем Зелбораф (Вемурафениб) по странам СНГ: Россия, Украина, Кыргызстан (Бишкек), Белоруссия, Узбекистан (Ташкент),
а также можем отправить Зелбораф (Вемурафениб) по регионам Казахстана: Нур-Султан (Астана), Шымкент, Талдыкорган, Актау и другие.

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    Whereas both workout routines involve lifting weights from
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    The deadlift is the king of workouts when it comes to constructing energy and muscle mass all
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    On the other hand, the Romanian Deadlift is a variation that locations a greater emphasis on the hamstrings and glutes.
    It is executed by hinging at the hips with a slight bend in the knees,
    lowering the barbell down the shins to simply beneath knee degree, and then driving via the heels to return to the beginning position.
    As a coach, I personally advocate them to my shoppers
    all the time because rowing is a superb type of low-impact cardio.
    Nevertheless, it’s important to discover ways to use a rowing
    machine appropriately as a end result of improper type can reduce your performance and even lead to accidents.
    The pull-up mimics the pulling movement; all you want is a pull-up bar.
    Instead of pulling the bar down, you’re pulling your physique
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    power. Due to its clear advantages to the entire posterior chain, the Romanian Deadlift was catapulted into recognition over the decades.

    The glute bridge and hip thrust are nice for isolating the glutes, however they don’t load the glutes as heavily
    in a stretched position, in order that they is probably not fairly perfect for stimulating muscle development.
    The good morning is great for working the glutes,
    too, and it does load the glutes and hamstrings in a stretched place,
    however our strength can be restricted by our lower again muscular tissues.
    Of all the lifts out there, the Romanian deadlift is likely considered
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    For powerlifters, that’s important because it helps to improve
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    Of course, we love the barbell; however, typically, you could find yourself in a state of affairs the place you have no entry.
    Unlike the standard deadlift, the Romanian deadlift makes use
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    And when in comparison with different lifts, the eccentric portion can be carried out slower.
    Nonetheless, deadlifts are the commonest explanation for harm in the
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    This makes it a kind of high-hipped standard deadlift, the place
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    The Romanian/stiff-leg deadlift starts from a standing position, the hips are driven back till
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    At the identical time you might be constructing the muscle memory to perform a correct
    hip hinge. Squats, deadlifts, leg presses and the like are all quad dominant workouts.

    Whereas you do get some activation of the hip extensor  muscle groups (hamstrings and glutes) the
    quads are taking nearly all of the load. To cut back the
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    Not only does it goal the posterior chain muscle tissue, however
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    Moreover, this train stimulates the release of progress hormone and testosterone,
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    Since deadlifts recruit multiple muscle teams, joints, and stabilizing muscle tissue,
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    With the proper kind, the deadlift can add a
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    The deadlift targets multiple muscle groups, improves general power and energy,
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    When it involves deadlift form, two issues differentiate the Romanian deadlift.
    Romanian Deadlift (RDL) There are some good debates as as to
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    some think about it a multijoint transfer since its dependent upon both
    the knee and hip joints for fulfillment.Romanian Deadlift vs Deadlift.
    The Romanian Deadlift is considered one of the mostly used among the varied deadlift techniques.
    In reality lots of people that think they’re performing a deadlift are typically actually doing a Romanian Deadlift.

    The American Council on Train famous that posterior-chain coaching is crucial to enhance all-round energy, energy, posture and suppleness.
    (The squat is another posterior-chain train.) When performing a
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    Even should you’ve never stepped foot into a fitness center
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    method fits you best. Bear In Mind to prioritize proper form, listen to your body, and seek the guidance of with professionals when essential.
    Train smart and benefit from the journey to extra
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    Subsequently, extra consideration have to be paid and if any shoulder ache is felt at any stage of the lift, movement must
    be ceased immediately. Some bodybuilders will lock out the
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    You do want to understand that Arnold presses contain a
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    to persist with different compound shoulder workout routines.

    This caters to the internal rotation perform of the anterior delt, increasing
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    No, the Arnold press isn’t one of many core lifts that individuals do.
    No, the Arnold press exercise is not commonly
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    Your abs and glutes will naturally become engaged in a kneeling or half-kneeling position.
    Although dumbbells aren’t ideal for heavy reps,
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    And the starting hand place (palms facing in) is easier
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    If you lack mobility on this area, you could be extra more
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    This is as a result of it includes a rotation via your shoulder joints in addition to an overhead press.
    This keeps your shoulder joints shifting with
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    Just like commonplace shoulder pressing variations, the Arnold press works on shoulder flexion.
    Combining this with the twist and inside rotation in the course of
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    Your back presses towards the backrest and your toes are firmly on the ground, so you’ve a secure sitting position. You should kind a slight hole again to alleviate
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    and can save the lifter both time and any threat of creating an unbalanced deltoid muscle group.
    Every of those muscle tissue performs a dynamic role throughout a sure portion of the exercise’s vary of movement, permitting
    them to develop in terms of strength and mass.
    If the Arnold press isn’t as efficient or isolated as you would like, try the
    following alternative workout routines out. Frequent signs that this error is being made are a sensation of tightness in the trapezius, the shoulders rotating inwards or poor upper back curvature as nicely.
    In a similar case to improper upper back curvature, jutting the neck forwards or tucking the chin excessively can each compromise the integrity of the lifter’s stance.
    In order to get the most out of the Arnold press and forestall any injuries, keep away from the next frequent mistakes.

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