Описание
Препарат Алеценза — высокоселективный ингибитор тирозинкиназ ALK (anaplastic lymphoma kinase) и RET (REarranged during Transfection). По данным исследований подавление тирозинкиназы ALK приводило к блокаде нисходящих сигнальных путей и вызывало апоптоз у опухолевых клеток. Действующее вещество препарата алектиниб. Алектиниб в условиях in vitro и in vivo показывал активность в отношении мутантных форм фермента ALK, в т.ч. с мутациями, обусловливающими резистентность к кризотинибу. М4 — oсновной метаболит алектиниба, in vitro также показал результативность и активность, схожую с алектинибом.
По данным исследований алектиниб не является субстратом белка устойчивости рака молочной железы или Р-гликопротеина, выполняющих функцию белков-переносчиков в ГЭБ, и, таким образом, обладает способностью проникать в ЦНС и задерживаться в ней.
На моделях ксенотрансплантатов опухоли у мышей алектиниб индуцирует регрессию опухоли, и проявляет противоопухолевую активность в мозге и увеличивает выживаемость на моделях животных с внутричерепными опухолями.
Состав Алеценза
Капсула содержит:
- 150 мг алектиниба (в виде алектиниба гидрохлорида 161.33 мг);
- Вспомогательные вещества: натрий лаурилсульфат, лактоза моногидрат, гидроксипропилцеллюлоза, магния стеарат, карбоксиметилцеллюлоза кальция;
- Оболочка капсулы: гипромеллоза, каррагинан, калия хлорид, титана диоксид, кукурузный крахмал, карнаубский воск;
- Чернила для печати: железа оксид красный, железа оксид желтый, алюминиевый лак на основе индигокармина, карнаубский воск, белый шеллак, глицерил моноолеат.
Показания препарата Алеценза
- Как монотерапия при метастатическом или местно-распространенном немелкоклеточном раке легкого с опухолевой экспрессией киназы анапластической лимфомы (ALK-положительный).
Фармакодинамика
Препарат Алектиниб — высокоселективный ингибитор тирозинкиназ ALK (anaplastic lymphoma kinase) и RET (REarranged during Transfection). По данным исследований подавление тирозинкиназы ALK приводило к блокаде нисходящих сигнальных путей и вызывало апоптоз у опухолевых клеток. Действующее вещество препарата алектиниб. Алектиниб в условиях in vitro и in vivo показывал активность в отношении мутантных форм фермента ALK, в т.ч. с мутациями, обусловливающими резистентность к кризотинибу. М4 — oсновной метаболит алектиниба, in vitro также показал результативность и активность, схожую с алектинибом.
Алектиниб проявляет активность в условиях in vitro и in vivo в отношении мутантных форм фермента ALK, включая мутации, ответственные за резистентность к кризотинибу. Ведущий метаболит алектиниба (М4) продемонстрировал схожую активность в условиях in vitro.
По данным проведенных экспериментов показано,что алектиниб не является субстратом белка резистентности рака молочной железы (BCRP) или Р-гликопротеина, являющихся эффлюксными транспортерами через гематоэнцефалический барьер и, следовательно, способных поступать и распределяться в центральной нервной системе.
Фармакокинетика
Всасывание
После перорального приема после приема пищи алектиниба у пациентов с ALK-положительным НМРЛ в дозе 600 мг 2 раза/сут отмечалось быстрое всасывание препарата. Tmax — приблизительно от 4 до 6 часов.
При приеме алектиниба в дозе 600 мг 2 раза/сут равновесное состояние алектиниба достигается в течение 7 дней и остается неизменным. При этом согласно данным популяционного фармакокинетического анализа средний геометрический коэффициент накопления равен 5.6. Показана пропорциональность доз алектиниба в диапазоне от 300 мг до 900 мг после приема пищи в популяционном фармакокинетическом анализе.
У здоровых добровольцев абсолютная биодоступность при применении алектиниба после приема пищи составляла 36.9% (33.9-40.3%).
При однократном пероральном применении алектиниба в дозе 600 мг прием высококалорийной пищи с большим содержанием жиров увеличивал экспозицию препарата в 3 раза по сравнению с приемом натощак.
Распределение
В независимости от концентрации действующего вещества алектиниб и M4 имеют высокий уровень связывания с белкaми плазмы крови человека (>99%). В условиях in vitro среднее соотношение концентраций в крови и в плазме человека составляет 2.64 и 2.50 для алектиниба и М4 соответственно (при клинически значимых концентрациях).
Средний геометрический объем распределения алектиниба после внутривенного введения составлял 475 л, что свидетельствует о широком распределении алектиниба в тканях.
По данным in vitro, алектиниб не является субстратом Р-гликопротеина. Алектиниб и метаболит М4 не являются субстратами белка резистентности рака молочной железы (BCRP) и полипептида транспортера органических анионов (ОАТР) 1В1/ВЗ.
Метаболизм
Исследования метаболизма в условиях in vitro показали, что изофермент CYP3A4 является основным изоферментом CYP (цитохрома P450), который опосредует метаболизм алектиниба и М4, при этом определено, что данный изофермент осуществляет 40-50% метаболизма в гепатоцитах человека. Согласно результатам исследования массового баланса алектиниб и М4 являлись основными циркулирующими веществами в плазме крови, их общее содержание составляло 76% от общей радиоактивности в плазме крови. Среднее геометрическое соотношение метаболит/препарат в равновесном состоянии – 0.399.
Элиминация
По данным однократного приема внутрь меченого 14С алектиниба, у здоровых участников основная часть меченого 14С выводилась с калом (97,8%) и небольшая часть выводилась с мочой (0,46%). С калом 84% и 5,8% дозы выводилось соответственно в виде неизмененного алектиниба или метаболита М4.
По результатам популяционного фармакокинетического анализа, кажущийся клиренс алектиниба (CL/F) составил 81,9 л/ч. Среднее геометрическое отдельных значений полувыведения алектиниба составило 32,5 часа. Соответствующие значения для метаболита М4 составили соответственно 217 л/час и 30,7 ч.
Фармакокинетические характеристики у отдельных категорий пациентов
Влияние возраста, массы тела, расы и пола
Клинически значимого влияния возраст, масса тела, раса и пол не оказывали на системное воздействие алектиниба и метаболита М4. В клинические исследования были включены пациенты с массой тела в диапазоне от 36,9 до 123 кг. Отсутствуют данные о пациентах с крайне высокой массой тела (более 130 кг).
Пациенты с нарушением функции почек. Алектиниб и М4 выводятся почками в незначительных количествах в неизмененном виде (<0.2% дозы). Данные, полученные у пациентов с нарушением функции почек легкой и средней степени тяжести, показывают, что нарушение функции почек не оказывает значительного влияния на фармакокинетику алектиниба. По данным популяционной фармакокинетики для больных с нарушением функции почек тяжелой степени тяжести отсутствуют. Поскольку алектиниб выводится почками в незначительной степени, коррекции дозы у таких пациентов не требуется.
Пациенты с нарушением функции печени. Основным путем выведения алектиниба является печеночный метаболизм. У пациентов с нарушением функции печени возможно увеличение концентрации алектиниба ( М4.0 в плазме крови. Показано, что у больных с нарушением функции печени легкой степени тяжести (общий билирубин на исходном уровне ≤ВГН и активность АСТ >ВГН или общий билирубин на исходном уровне >1.0-1.5×ВГН и любая активность АСТ на исходном уровне) соответствовали таковым у пациентов с нормальной функцией печени (общий билирубин ≤ВГН и активность АСТ ≤ВГН).
После однократного перорального приема алектиниба в дозе 300 мг пациентами с нарушением функции печени тяжелой степени тяжести (класс С по шкале Чайлд-Пью) Сmax алектиниба была такой же как и у здоровых добровольцев; AUCinf у пациентов с нарушением функции печени тяжелой степени тяжести (класс С по шкале Чайлд-Пью) была в 2.2 раза выше, чем у здоровых добровольцев, а Сmax и AUCinf для М4 были на 39% и 34% ниже соответственно. Таким образом, общая комбинированная экспозиция для алектиниба и М4 (AUCinf) была в 1.8 раз выше у пациентов с нарушением функции печени тяжелой степени тяжести по сравнению со здоровыми добровольцами.
В ходе изучения применения препарата у пациентов с нарушением функции печени средней степени тяжести (класс B по шкале Чайлд-Пью) наблюдалась умеренно повышенная экспозиция алектиниба по сравнению со здоровыми добровольцами. Однако у пациентов с нарушением функции печени средней степени тяжести (класс B по шкале Чайлд-Пью), в целом, не отмечалось отклонений в показателях билирубина, альбумина или протромбинового времени, что указывает на их возможное неполное соответствие пациентам с нарушением функции печени умеренной степени тяжести со сниженной метаболической способностью.
Фармацевтические характеристики Алеценза
Твердые капсулы, размер 1, корпус и крышечка капсулы от белого до желтовато-белого цвета.
На корпусе капсулы нанесена надпись «150 mg» черного цвета. На крышечке капсулы нанесена надпись «ALE» черного цвета.
Содержимое капсулы: порошок или скомковавшийся порошок от белого до светло-желтого цвета.
Условия хранения и срок годности Алеценза
По 8 капсул в контурную ячейковую упаковку (блистер) из полиамид/алюминий/ поливинилхлорид и фольги алюминиевой композиционной (алюминий/сополимер винил-хлорида/ винилацетата полибутилметакрилат). Семь контурных ячейковых упаковок (блистеров) вместе с инструкцией по применению помещают в картонную пачку (промежуточная упаковка), на которую с целью контроля первого вскрытия наклеивают голограммы.
4 промежуточных упаковки помещают в картонную пачку (потребительская упаковка) с контролем первого вскрытия (в виде перфорации).
Срок годности 3 года.
Хранить при температуре не выше 30 °C в оригинальной упаковке для защиты от света и влаги. 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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