Описание
Кадсила с действующим веществом Трастузумаб эмтанзин является современным противоопухолевым и наиболее эффективным аналогом в современной линейке препаратов. Трастузумаб эмтанзин является конъюгатом моноклонального гуманизированного антитела (IgG1) селективно действуещего с рецептором человеческого эпидермального фактора роста 2 типа (HER2) и ингибитора полимеризации тубулина DM1 (производное мейтанзина), соединенных друг с другом посредством стабильного тиоэфирного линкера MCC (4-(N-малиенимидометил) циклогексан-1-карбоксилат). Эмтанзин представляет собой комплекс DM1-MCC.
Лекарство назначается пациенткам с метастатическим HER2-положительным раком молочной железы.
Состав
В одном флаконе содержится:
- активное вещество: трастузумаб эмтанзин 100 мг/160 мг;
- вспомогательные вещества: сахароза, янтарная кислота, натрия гидроксид, полисорбат.
Показания
• лечение больных с метастатическим HER2-положительным раком молочной железы, ранее получавших терапию таксаном и трастузумабом, или у которых произошел рост болезни во время или в течение 6 месяцев после завершения адъювантной терапии;
• адъювантная терапия больных с ранним HER2-положительным раком молочной железы и инвазивной остаточного образования после неоадъювантной терапии таксаном и трастузумабом.
Фармакодинамика
Механизм действия
Трастузумаб эмтанзин является конъюгатом моноклонального гуманизированного антитела (IgG1) селективно действуещего с рецептором человеческого эпидермального фактора роста 2 типа (HER2) и ингибитора полимеризации тубулина DM1 (производное мейтанзина), объединенных друг с другом посредством стабильного тиоэфирного линкера MCC (4-(N-малиенимидометил) циклогексан-1-карбоксилат). Эмтанзин представляет собой комплекс DM1-MCC.
Трастузумаб эмтанзин попадает в клетку путем связывания с HER2 и подвергается в лизосомах протеолитической деградации, что приводит к высвобождению DM1-содержащих цитотоксических катаболитов (главным образом, комплекса лизин-МСС-DM1). Как следствие, конъюгация DM1 с трастузумабом создает селективность цитотоксического действия вещества по отношению к опухолевым клеткам с гиперэкспрессией HER2 и упрощает доставку DM1 внутрь таких клеток.
Механизм воздействия трастузумаба эмтанзина является группой механизмов действия трастузумаба и DM1.
Трастузумаб эмтанзин, также как и трастузумаб, связывается с доменом IV внеклеточного домена HER2, а также с белком комплемента C1q и с рецепторами Fсγ, тем самым устраняет «слущивание» внеклеточного домена HER2 с поверхности клеток, ингибирует передачу внутриклеточного сигнала по пути фосфатидилинозитол-3-киназы (PI3-K), а также помогает активации антителозависимой клеточно-опосредованной цитотоксичности в клетке с гиперэкспрессией HER2.
DM1 — это цитотоксический элемент трастузумаба эмтанзина, который связывается и подавляет полимеризацию тубулина. За счет такого цитотоксического действия вещество трастузумаб эмтанзин, как и DM1, создает блокаду клеточного цикла в фазе G2/M, что в итоге приводит к программируемой гибели клеток. По результатам исследований цитотоксичности in vitro DM1 было доказано, что активность DM1 в 20-200 раз больше, чем активность алкалоидов барвинка и таксанов.
Структура линкера МСС лимитирует системное освобождение тубулина DM1 и помогает его направленной доставке в клетку, что подтверждается очень низким содержанием в плазме крови свободного DM1 .
Данные доклинического изучения безопасности
Генотоксичность.
По результатам исследований показано о наличии у трастузумаба эмтанзина кластогенной и/или анеугенной токсичности.
Репродуктивная токсичность.
Данные говорят, о наличии эмбриотоксического воздействия трастузумаба и о потенциальном эмбриотоксическом и тератогенном воздействии DM1.
Влияние на фертильность.
По результатам исследований высинилось о наличии риска нарушения фертильности при применении вещества трастузумаб эмтанзин.
Иммуногенность.
Возможно развитие иммунного ответа на препарат Кадсила.
Так как частота образования антител к препарату была низкой (в клинических исследованиях у примерно 5 процентов пациентов обнаруживали антитела к препарату Кадсила в одной и более временных точках после инфузии), нельзя сделать явный вывод об их влиянии на эффективность, фармакокинетику и безопасность терапии.
Фармакокинетика
Фармакокинетика трастузумаба эмтанзина при в/в введении каждые 3 нед в дозах 2,4–4,8 мг/кг носит линейный характер. У пациентов, получавших вещество в дозировках 1,2 мг/кг или менее, отмечен более высокий клиренс.
Средняя Cmax трастузумаба эмтанзина в сыворотке крови составляет 83,4 (±16,5) мкг/мл при в/в инфузии препарата в дозировке 3,6 мг/кг каждые 3 недели. После внутривенной инфузии Vd активного вещества в центральной камере составляет 3,13 литра и примерно равно объему плазмы.
Метаболизм.
Вещество трастузумаб эмтанзин предположительно подвержен катаболизму и деконъюгации за счет расщепления в клеточных лизосомах. In vitro исследования на микросомах печени человека показали, что низкомолекулярный компонент вещества трастузумаб эмтанзин (DM1) больше всего метаболизируется изоферментом CYP3A4 и в меньшем объеме изоферментом CYP3A5.
Катаболиты трастузумаба эмтанзина, MCC-DM1, Lys-MCC-DM1 и DM1 обнаруживаются в плазме человека в низких концентрациях.
Выведение.
После внутривенной инфузии трастузумаба эмтанзина у пациентов с метастатическим раком молочной железы с гиперэкспрессией HER2 клиренс вещества трастузумаба эмтанзина составил 0,68 л/день, период полувыведения— около 4-х дней. После многократных внутривенных инфузий каждые три недели аккумуляция трастузумаба эмтанзина не обнаруживалась.
Катаболиты трастузумаба эмтанзина больше выводятся с желчью и в меньших объемах с мочой.
Линейность/нелинейность
Трастузумаб эмтанзин при внутривенном введении каждые 3 недели продемонстрировал линейную фармакодинамику в интервале дозировок от 2.4 до 4.8 мг/кг; более высокий клиренс наблюдался у пациентов, получавших меньшую или равную 1.2 мг/кг дозировку.
На фармакокинетику трастузумаба эмтанзина раса, возраст, пол не влияют.
Нарушение функции почек.
По данным популяционного фармакокинетического исследования нарушения функции почек не влияют на фармакокинетику трастузумаба эмтанзина. Уровни фармакокинетических параметров препарата у пациентов с легкой и средней степенью нарушений функции почек схожи с таковыми у больных с нормальной функцией почек. Данные о фармакокинетике у больных с тяжелой и терминальной почечной недостаточностью накоплены в малых объемах.
Нарушения функции печени.
Печень является основным органом выведения DM1 и его катаболитов. По данным популяционного фармакокинетического исследования нарушения функции печени не влияет на фармакокинетику вещества трастузумаб эмтанзин. Уровни фармакокинетических параметров препарата у больных с легкой и умеренной тяжестью нарушения функций печени схожи с таковыми у больных с нормальной функцией печени.
Системные экспозиции (AUC) трастузумаба эмтанзина во время 1-го цикла у пациентов с легким и умеренным тяжестью нарушений функции печени были приблизительно на 38 и 67 процентов ниже экспозиций у пациентов с нормальной функцией печени соответственно. Во время 3-го цикла экспозиция трастузумаба эмтанзина (AUC) после повторного введения у больных с легким или умеренным тяжестью нарушения функции печени было в пределах уровней, наблюдаемых у больных с нормальной функцией печени. Исследования трастузумаба эмтанзина у пациентов с тяжелым нарушением функции печени не проводились не изучалась
Фармацевтические характеристики
Лиофилизат от белого до почти белого цвета, уплотненной в таблетку пористой массы.
Восстановленный раствор: раствор бесцветного или с коричневатого оттенка, прозрачный или слегка опалесцирующий.
Упаковка, срок годности, условия хранения
По 100 мг/160 мг трастузумаба эмтанзина во флаконах из бесцветного стекла 15 мл/20 мл соответственно. Каждый флакон с инструкцией размещен в картонную пачку.
Хранить при температуре 2-8 °C. Не замораживать, хранить в недоступном для детей месте,
Срок хранения 3 года.
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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