Описание
Препарата Котеллик в 2014 году получил статус орфанного (редкого) препарата для лечения злокачественной меланомы с мутацией BRAF V600, с основным действующим веществом кобиметинибом.
По данным клинических испытаний III фазы было показано, что комбинированная терапия кобиметинибом и зелборафом приводит к значительному увеличению выживаемости без прогрессирования, общей выживаемости и объективного ответа у пациентов с метастической или местно-распространенной меланомой с наличием мутации BRAF V600.
Состав Котеллик
- активное вещество: кобиметиниба гемифумарат — 22.20 мг, что соответствует 20 мг кобиметиниба;
- вспомогательные вещества: лактозы моногидрат, целлюлоза микрокристаллическая, кроскармеллоза натрия, магния стеарат;
- состав пленочной оболочки: поливиниловый спирт, титана диоксид, макрогол/ПЭГ 3350, тальк
Показания к применению Котеллик
- метастатическая или неоперабельная меланома с мутацией BRAF V600 у взрослых пациентов в комбинации с вемурафенибом.
Фармакологическое действие
Механизм действия
Основным путем передачи сигнала, который регулирует выживаемость клеток, пролиферацию клеток, ангиогенез, клеточный цикл и миграцию клеток является путь митоген-активируемой протеинкиназы МАРК (Mitogen-Activated Protein Kinase) / внеклеточный сигнал-регулируемой киназы ERK (Extracellular signal Regulated Kinase).
Препарат Котеллик — высокоизибирательный аллостерический ингибитор киназ МЕК1/2 (MAPK/ERK Kinase) принимаемый во внутрь. В цитологических и биохимических исследованиях препарат Котеллик показал высокую подавляющую способность, а также in vivo на моделях ксенотрансплантата опухолей, включая опухоли, несущие мутации BRAF и KRAS показал активность в отношении широкого спектра опухолей. было показано в биохимических и структурных исследованиях взаимодействие препарат Котеллика с МЕК киназой, с незначительной чувствительностью к динамическим конформационным изменениям, наблюдаемым при переходе МЕК в фосфорилированную форму. Следовательно, кобиметиниб сохраняет ингибирующую активность и связывающую способность при фосфорилировании МЕК. В отношении линий опухолевых клеток и опухолей с высокими уровнями фосфорилирования МЕК кобиметиниб показал наиболее высокую активность, что часто определяется в опухолях с мутациями BRAF. Обработка кобиметинибом в доклинических исследованиях МАРК-дисрегулированных опухолевых клеток и опухолей ведет к фосфорилированию киназ ERK1/2, единственных известных субстратов МЕК1/2.
От активности киназ ERK1/2 зависит передача сигнала по МАРК-пути, которые фосфорилируют белковые мишени в цитоплазме и ядре, и вызывающие прогрессирование клеточного цикла, выживаемость, миграцию клеток, пролиферацию клеток. кобиметиниб, таким образом, противодействует онкогенной и промитогенной активности, за счет ингибирования МЕК1/2, индуцируемой через МАРК-путь.
Комбинация препарата Котеллик и вемурафениба подавляет реактивацию МАРК-пути через МЕК1/2 за счет одновременного воздействия на BRAF и МЕК. Это тем самым приводит к более выраженному ингибированию передачи сигналов и к апоптозу большего числа опухолевых клеток по сравнению с монотерапией вемурафенибом в доклинических исследованиях.
Фармакокинетика
Всасывание
При приеме препарата Котеллик в дозировке 60 мг у пациентов с онкологическими заболеваниями отмечается средняя скорость всасывания с медианой времени до достижения максимальной концентрации в плазме крови 2.4 часа. Средние показатели максимальной концентрации в равновесном состоянии и AUC0-24 составляют 273 нг/мл и 4340 нг×ч/мл. В равновесном состоянии среднее значение коэффициента накопления составляет приблизительно 2.4 часа. Препарат Котеллик обладает линейной фармакокинетикой в диапазоне дозировок от приблизительно 3.5 мг до 100 мг.
Абсолютная биодоступность кобиметиниба у здоровых лиц составляет 45.9процентов. У здоровых лиц было показано, что препарат Котеллик через кишечник интенсивно метаболизируется и выводится. Степень всасывания составляет приблизительно 88процентов, что указывает на высокий уровень всасывания и пресистемный метаболизм.
Не изменяется фармакокинетика кобиметиниба при приеме препарата с пищей (в т.ч. с высоким содержанием жиров) в сравнении с приемом препарата натощак у здоровых лиц. Препарат можно принимать независимо от приема пищи, поскольку пища не влияет на фармакокинетику кобиметиниба.
Распределение
Связывание кобиметиниба с белками плазмы in vitro составляет 94.8%. Преимущественного связывания с эритроцитами человека при этом не наблюдается (соотношение кровь-плазма 0.93).
Объем распределения у здоровых лиц, получивших кобиметиниб в дозировке 2 мг (в/в), составляет 1050 литров. По данным популяционного фармакокинетического анализа кажущийся объем распределения у онкологических больных составляет 806 литров.
Метаболизм
В ходе исследования массового баланса у здоровых лиц было изучено соотношение кобиметиниба и его метаболитов.
В среднем, 94% дозы восстанавливается в течение 17 дней. Препарат Коттелик через кишечник интенсивно метаболизируется и выводится; при этом преобладания ни одного из метаболитов не отмечается.
Основные пути метаболизма кобиметиниба — глюкуронирование с помощью изофермента UGT2B7 и окисление с помощью изофермента CYP3А. Кобиметиниб является основным веществом, выявляемым в плазме крови. В плазме крови доля окисленных метаболитов составляет не более 10% от общего числа циркулирующей радиоактивности, при этом не выявлено специфических для человека метаболитов.
Доля неизмененного препарата в кале и моче составляет 6.6% и 1.6% от введенной дозы соответственно, что указывает на то, что препарат подвергается метаболизму преимущественно и выводится почками в незначительном количестве. In vitro было показано, что Коттелик не является ингибитором ОСТ2, ОАТ1 или ОАТЗ.
Выведение Котеллик
Средний клиренс составляет 10.7 л/ч после внутривеного введения кобиметиниба в дозировке 2 мг. У онкологических больных средний кажущийся клиренс после приема кобиметиниба в дозировке 60 мг составляет 13.8 л/часа
Средний период полураспада кобиметиниба составляет 43.6 часов (диапазон от 23.1 до 69.6 часов).
Фармакокинетика у особых групп пациентов
Раса, пол, этническая принадлежность, исходная оценка по ECOG, а также легкое и умеренное нарушение функции почек по данным популяционного фармакокинетического анализа не влияют на фармакокинетику кобиметиниба.
Статистически значимыми ковариантами для клиренса и объема распределения препарата Котеллика являются возраст и масса тела соответственно. Однако согласно результатам анализа чувствительности клинически значимого влияния на экспозицию в равновесном состоянии ни одна из этих ковариант не оказывает.
Кобиметиниб преимущественно подвергается метаболизму с минимальным выведением почками по данным доклинических исследований и исследований массового баланса. Специальные исследования фармакокинетики препарата Котеллика у пациентов с нарушением функции почек не проводились.
У больных с легким и умеренным нарушением функции почек, а также у больных с нормальной функцией почек (КК ≥90 мл/мин) согласно результатам популяционного фармакокинетического анализа данных КК не оказывает значимого влияния на экспозицию Котеллика.
Для определения необходимости в коррекции дозы у пациентов с тяжелым нарушением функции почек данных недостаточно.
Фармакокинетику кобиметиниба оценивали у пациентов с умеренным нарушением функции печени (класс В по шкале Чайлд-Пью), больных с тяжелым нарушением функции печени (класс С по шкале Чайлд-Пью), пациентов с легким нарушением функции печени (класс А по шкале Чайлд-Пью) и у здоровых добровольцев. По сравнению со здоровыми лицами у пациентов с легким или умеренным нарушением функции печени системная экспозиция после применения кобиметиниба в однократной дозировке была сходной. Отмечались более низкие экспозиции кобиметиниба у пациентов с тяжелым нарушением функции печени (среднее геометрическое соотношение AUC0 составляет 0.69 по сравнению со здоровыми добровольцами). Данное явление не считается клинически значимым. Пациентам с нарушением функции печени, таким образом, при применении препарата Котеллик не рекомендуется коррекция дозы.
Доклинические данные по безопасности
Канцерогенность
Исследования канцерогенности кобиметиниба не проводились.
Мутагенность
Стандартные исследования генотоксичности дали отрицательные результаты.
Удлинение интервала QT
В in vitro условиях препарат Котеллик вызывает умеренно выраженное подавление ионного hERG-канала (концентрация, необходимая для подавления hERG-канала (IC50) = 0.5 мкМ [266 нг/мл]), что приблизительно в 18 раз больше, чем максимальная концентрация в плазме крови при применении в дозировке 60 мг (максимальная концентрация несвязанного препарата = 14 нг/мл [0.03 мкМ]).
При терапии пациентов препаратом Котеллик в комбинации с вемурафенибом дополнительного клинического влияния на удлинение интервала QT не отмечалось.
Оценка общей токсичности
У крыс и собак в исследованиях токсичности были определены в целом обратимые дегенеративные изменения в ЖКТ, костном мозге, тимусе, коже, надпочечниках, селезенке, печени, почках, лимфатических узлах, яичниках, влагалище, сердце при экспозиции в плазме ниже клинически эффективного уровня.
Не выявили специфических рисков для человека доклинические исследования (на основании результатов стандартных фармакологических исследований по генотоксичности и безопасности).
Фармацевтические характеристики
Круглые таблетки, покрытые пленочной оболочкой. Таблетки белого цвета; на одной стороне таблетки гравировка «СОВ».
Упаковка, срок годности, условия хранения Котеллик
Таблетки упакованы в блистер из двухслойной ПВХ/ПВДХ пленки и алюминиевой фольги, в количестве по 21 таблетке. Вместе с инструкцией по 3 блистера помещены в пачку картонную.
Срок годности 3 года.
Хранить при температуре не выше 30°С. Хранить в недоступном для детей месте.
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 Котеллик (кобиметиниб) по странам СНГ: Россия, Украина, Кыргызстан (Бишкек), Белоруссия, Узбекистан (Ташкент),
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