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Имновид — Imnovid (Помалидомид)

Имновид

Имновид — Imnovid (Помалидомид)

Препарат Имновид, с действующим веществом Помалидомид — является представителем нового класса противоопухолевых иммуномодуляторов. Имновид одобрен в США (FDA) для терапии рецидивирующей и рефрактерной множественной миеломы в феврале 2013 года. В августе 2013 г. препарат получил одобрение в ЕС, в мае 2015 г. Имновид зарегистрировали в РФ. Имновид отличается прямой антимиеломной активностью, иммуномодулирующей способностью и подавляет стромальные клетки, поддерживающие рост опухолевых клеток миеломы.

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Описание

Препарат Имновид, с действующим веществом Помалидомид — является представителем нового класса противоопухолевых иммуномодуляторов. Имновид одобрен в США (FDA) для терапии рецидивирующей и рефрактерной множественной миеломы в феврале 2013 года. В августе 2013 г. препарат получил одобрение в ЕС, в мае 2015 г. Имновид зарегистрировали в РФ. Имновид отличается прямой антимиеломной активностью, иммуномодулирующей способностью и подавляет стромальные клетки, поддерживающие рост опухолевых клеток миеломы.

В ходе клинического исследования с участием 455 пациентов была доказана эффективность Имновида в лечении множественной миеломы. Считается, что Имновид в комбинации с дексаметазоном существенно повышает длительность ремиссии. Препарат Имновид одобрен для лечения взрослых пациентов с множественной миеломой. В данное время продолжаются исследования по изучению безопасности и эффективности комбинированных режимов лечения.

Показания к применению Имновид

Имновид применяется в сочетании с дексаметазоном для лечения взрослых пациентов с рецидивирующей и рефрактерной множественной миеломой.

Состав Имновид

1 капсула содержит:

  • активное вещество — помалидомид 1 мг;
  • вспомогательные вещества: маннитол, крахмал прежелатинизированный, натрия стеарил фумарат.
  • оболочка капсулы: крышечка — желатин, титана диоксид, индигокармин, белые чернила**;
  • корпус — желатин, титана диоксид, железа оксид желтый, черные чернила*.
  • *состав чернил для маркировки капсулы: белые чернила — шеллак, титана диоксид, симетикон, пропиленгликоль, аммония гидроксид, изопропанол, н-бутанол;
  • **черные чернила — шеллак, пропиленгликоль, аммония гидроксид, изопропанол, н-бутанол, железа оксид черный, этанол безводный, вода очищенная.

1 капсула содержит:

  • активное вещество: помалидомид 3 мг;
  • вспомогательные вещества: маннитол, крахмал прежелатинизированный, натрия стеарил фумарат;
  • оболочка капсулы: крышечка — желатин, титана диоксид, индигокармин, белые чернила*;
  • корпус — желатин, титана диоксид, железа оксид желтый, индигокармин, белые чернила*
  • *состав чернил для маркировки капсулы: белые чернила — шеллак, титана диоксид, симетикон, пропиленгликоль, аммония гидроксид, изопропанол, н-бутанол;

1 капсула содержит:

  • активное вещество: помалидомид 4 мг;
  • вспомогательные вещества: маннитол, крахмал прежелатинизированный, натрия стеарил фумарат;
  • оболочка капсулы: крышечка — желатин, титана диоксид, индигокармин, белые чернила*;
  • корпус — желатин, титана диоксид, бриллиантовый синий, белые чернила

Фармакодинамика

Имновид оказывает прямое противомиеломное действие, характеризуется иммуномодулирующим свойством и тормозит активность стромальных клеток.

Также способен избирательно угнетать пролиферацию и вызывать апоптоз гемопоэтических клеток опухоли. Помимо этого, помалидомид блокирует пролиферацию линий клеток множественной миеломы, устойчивых к леналидомиду. Помалидомид также угнетает ангиогенез, блокируя адгезию и миграцию клеток эндотелия.

Препарат избирательно подавляет размножение и вызывает апоптоз у гематопоэтических клеток опухоли. Также, помалидомид тормозит размножение клеток множественной миеломы (ММ), устойчивых к леналидомиду, и характеризуется синергизмом с дексаметазоном по способности вызывать апоптоз у опухолевых клеток. Имновид усиливает клеточный иммунитет с участием Т-клеток и блокирует образование противоспалительных цитокинов. Имновид также блокирует ангиогенез, угнетая адгезию и миграцию клеток эндотелия. В рандомизированном исследовании III фазы (MM) помалидомид (в сочетании с низкими дозами дексаметазона) соотносился со стандартной терапией высокодозным дексаметазоном у пациентов с ранним рецидивом ММ, которые получили терапию леналидомидом и бортезомибом. Было показано, что помалидомид снижает уровень прогрессии на 52 процента (PFS 4.0 vs 1.9 мес.) и увеличивает общую продолжительность жизни (12.7 vs 8.1 месяцев).

Фармакокинетика

Абсорбция

При однократном приеме количество абсорбции помалидомида составила не менее 73 процентов и его максимальная концентрация в плазме крови достигается за 2-3 часа. Воздействие помалидомида (по показателю площадь под кривой «концентрация-время» AUC) увеличивается почти линейно и пропорционально дозе. При многократном дозировании степень накопления помалидомида составляет 27-31% по AUC.

При одновременном приеме с высококалорийной жирной пищей скорость впитывания помалидомида замедляется, значение максимальной концентрации снижается примерно на 25процентов, но общее впитывание практически не меняется, величина AUC уменьшается всего на 8процентов. Следовательно помалидомид можно принимать вне зависимости от приема пищи.

Распределение

При равновесной концентрации средний кажущийся объем распределения (Vd/K) помалидомида находится в пределах 62-138 литров. После применения помалидомида в течение 4 дней по 2 мг в день он определяется в семенной жидкости здоровых добровольцев в концентрации примерно 67процентов от уровня в плазме крови, который достигается через 4 часа (примерное Тmax) после приема препарата. In vitro взаимодействие белков плазмы с энантиомерами помалидомида находится в пределах от 12процентов до 44процентов и не зависит от концентрации.

Биотрансформация

У здоровых добровольцев после однократного приема внутрь меченого помалидомида (2 мг) основным компонентом в крови был помалидомид (примерно 70% от уровня радиоактивности плазмы). Количество метаболитов не превышало 10% относительно исходного соединения или общего уровня радиоактивности плазмы.

Гидроксилирование с дальнейшей глюкуронизацией или гидролизом составляет основной метаболический путь. In vitro изоферменты системы цитохрома Р450, CYP3A4, CYP1A2 являются основными ферментами, принимающих участие в гидроксилировании помалидомида. Меньшее значение было у изоферментов CYP2D6 и CYP2C19. Помалидомид является также субстратом Р-гликопротеина in vitro. Комбинированное использование помалидомида с активным ингибитором CYP3A4/5 и P-gp кетоконазолом или с мощным индуктором CYP3A4/5 карбамазепином не показывало клинически значимого влияния на экспозицию помалидомида. Совместное использование активного ингибитора CYP1A2 флувоксамина и присутствии кетоконазола повышало воздействие помалидомида на 104процента при 90процентах доверительном интервале в сравнении с комбинацией помалидомид-кетоконазол. При одновременном с помалидомидом использовании активного ингибитора CYP1A2 (напр., эноксацин, флувоксамин и ципрофлоксацин), пациентов следует тщательно обследовать для своевременного выявления нежелательных лекарственных реакций.

in vitro на основании данных помалидомид не индуцирует и не подавляет изоферменты системы цитохрома Р450. не тормозит другие изученные транспортеры лекарственных веществ. При сочетании помалидомида с субстратами таких путей клинически значимые лекарственные взаимодействия слабовероятны.

Выведение

Средний период полувыведения помалидомида из плазмы крови составляет 9.5 часов у здоровых добровольцев и 7.5 часов у лиц с множественной миеломой. Средний общий клиренс (CL/F) препарата Имновид составляет приблизительно 7-10 л/часов. У здоровых добровольцев после однократного приема внутрь меченого помалидомида (2 мг) примерно 73процента и 15процентов радиоактивной дозы выводилось через почки и кишечник. При этом около 2процентов и 8процентов дозы помалидомида с углеродной меткой выводилось через почки и кишечник в неизмененном виде.
В значительной степени Помалидоми дподвергается биотрансформации, и формирующиеся метаболиты, преимущественно, выводятся через почки. Образовавшиеся в результате гидролиза или гидроксилирования с последующей глюкуронизацией, три основных метаболита, составляют, соответственно, 23процента, 17процентов и 12процентов от общего содержания метаболитов в моче.
Количество метаболитов, образовавшихся с участием цитохрома Р450, составило примерно 43процента от уровня общей радиоактивности, a нe-CYP зависимых гидролитических метаболитов — 25процентов. В неизмененном виде выводится 10% помалидомида (2% — через почки и 8% — через кишечник).

Особенности применении у отдельных групп пациентов

Дети и подростки

В связи с отсутствием данных по безопасности и эффективности препарата у детей и подростков в возрасте до 18 лет, он не рекомендуется для применения у данной категории пациентов.

Пожилые пациенты

У пожилых пациентов данных о фармакокинетике помалидомида нет. У пациентов старше 65 лет, получавших помалидомид, в клинических исследованиях не требовалось изменения дозы.

Нарушения функций почек

Исследования помалидомида у пациентов с почечной недостаточностью не проводились. Не включали в клинические исследования, пациентов с умеренной или тяжелой почечной недостаточностью (КК 45 мл/мин). Следует тщательно наблюдать за пациентами с почечной недостаточностью для своевременного выявления нежелательных реакций.

Нарушения функции печени

У пациентов с печеночной недостаточностью исследования помалидомида не проводились, т.к. пациентов, у которых значения общего сывороточного билирубина превышали 2.0 мг%, не включали в клинические исследования. Необходимо тщательно наблюдать за пациентами с нарушением функций печени для своевременного выявления нежелательных реакций.

Фармацевтические характеристики

Помалидомид выпускается в капсулах для перорального применения по 1, 2, 3, 4 мг. Содержимое капсул — порошок желтого цвета

Капсулы желатиновые:

  • №3 с корпусом и крышкой желтого цвета.
  • №4, с темно-синей непрозрачной крышечкой с нанесенной на ней маркировкой белыми чернилами «POML» и желтым непрозрачным корпусом с нанесенной на нем маркировкой черными чернилами «1 mg».
  • №2, с темно-синей непрозрачной крышечкой с нанесенной на ней маркировкой белыми чернилами «POML» и зеленым непрозрачным корпусом с нанесенной на нем маркировкой белыми чернилами «3 mg».
  • №2, с темно-синей непрозрачной крышечкой с нанесенной на ней маркировкой белыми чернилами «POML» и синим непрозрачным корпусом с нанесенной на нем маркировкой белыми чернилами «4 mg».

Упаковка, срок годности, условия хранения

По 7 капсул в блистере. Блистер из ПВХ/ПТФХЭ и алюминиевой фольги. По 3 блистера вместе с инструкцией в пачке картонной. 21 шт. — банки полимерные (3) с контролем первого вскрытия — пачки картонные.

Хранить при температуре не выше 25 °С.
Хранить в недоступном для детей месте.

Срок годности 3 года.

 

 

 

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

 

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