Описание
Сертикан – это лекарственный препарат, относящийся к группе ингибиторов mTOR, ингибиторов пролиферативного сигнала. Препарат используется для профилактики отторжения после трансплантации сердца и почки, печени, а также для лечения некоторых онкологических заболеваний (рак почки). Основное действующее вещество — Эверолимус. Вещество Эверолимус является сильным ингибитором роста и пролиферации опухолевых клеток, фибробластов, эндотелиальных клеток, гладкомышечных клеток кровеносных сосудов. В будущем вероятно расширение показаний для использования данного препарата при появлении новых проверенных данных о его эффективности.
Состав препарата Сертикан
Одна таблетка диспергируемая содержит:
- активное вещество — эверолимус 0,1 мг; 0,25 мг; 0,5 мг; 0,75 мг или 1 мг;
- дополнительные вещества: бутилгидрокситолуол, моногидрат лактозы,лактоза безводная, гипромеллоза, кремния диоксид коллоидный безводный, стеарат магния, кросповидон.
Показания
- Профилактика отторжения трансплантата у взрослых реципиентов/ пациентов с низким и умеренным иммунологическим риском после аллогенной трансплантации почки или сердца. Имеется ограниченная информация о применении Сертикана в педиатрии при трансплантации почки.
- Профилактика отторжения трансплантата у пациентов после трансплантации печени.
- Распространенный (метастатический) рак почечно-клеточный (при неэффективности антиангиогенном лечении).
- Рак молочной железы, клубневый склероз, нейроэндокринные опухоли поджелудочного происхождения.
Фармакодинамика
Сертикан — это иммунодепрессант, подавляющий активацию Т-клеточного звена. На поверхности Т-лимфоцитов находятся специфические рецепторы к факторам роста – интерлейкинам. Связывание интерлейкинов со такими рецепторами, связанное с присутствием в крови чужеродного антигена, запускает внутри Т-клеток цепь внутриклеточных сигнальных путей, который в норме приводит к размножению Т-лимфоцитов. Эверолимус ингибирует один из циклов внутриклеточной передачи сигнала путем взаимодействия с молекулой mTOR, что приводит к торможению деления клеток.
Эффект эверолимуса не ограничивается влиянием на Т-клетки. Он подавляет стимулируемое факторами роста размножение как гемопоэтических, так и негемопоэтических клеток (например гладкомышечных). Стимулируемое фактором роста деление гладкомышечных клеток сосудов, которое запускается при повреждении эндотелиальных клеток и влечет к формированию неоинтимы. Таким образом Эверолимус играет большую роль в патогенезе хронического отторжения. В исследованиях показано подавление формирования неоинтимы у крыс с аллотрансплантатом аорты.
У больных с метастатическим или распространенным почечным раком, усиливавшегося после предшествующего лечения ингибиторами тирозиновых киназ или цитокинами, эверолимус достоверно снижал риск усисливания заболевания и смерти пациентов на 67%. В течение 6 месяцев у 36% больных, получавших эверолимус, не отмечалось прогрессирования заболевания. Считается, что использование эверолимуса значительно улучшает качество жизни больных, по оценке влияний симптомов заболеваний на различные сферы жизни пациента.
Фармакокинетика
Всасывание
Максимальных концентраций эверолимус достигал через 1-2 часа после приема. В диапазоне доз 0,25 мг-15 мг концентрации эверолимуса в крови пациентов после трансплантации дозопропорциональны. Относительная биодоступность диспергируемой таблетки, на основании показателя AUC, по сравнению с обычной таблеткой составляет 0,90 (90%, CI 0,76-1,07).
Влияние пищи. При приеме препарата с очень жирной пищей максимальная концентрация и AUC эверолимуса уменьшались на 60% и на 16% соответственно. Чтобы привести вариабельность к минимуму, эверолимус следует принимать одновременно с пищей, или без нее.
Распределение
У здоровых добровольцев и лиц с умеренными нарушениями функции печени взаимодействие с белками плазмы составляет около 74%. Объем распределения в конечной фазе у пациентов после трансплантации почки, находящихся на поддерживающей терапии, составляет 342±107 л. Связывание с белками плазмы крови составляет приблизительно 74% у здоровых добровольцев и у пациентов с умеренной печеночной недостаточностью. В конечной фазе объем распределения у пациентов, перенесших трансплантацию почки и находящихся на поддерживающей терапии, составляет 342 ± 107 л.
Метаболизм
Эверолимус является основой для синтеза CYP3A4 и Р-гликопротеина. Основные пути метаболизма вещества — это О-деалкилирование и моногидроксилирование. Два основных метаболита образуются путем гидролиза циклического лактона. Ни один из них не имеет существенной иммуносупрессивной активности. В системном кровотоке находится в основном эверолимус.
После приема внутрь Сертикана, вещество эверолимус является центральным компонентом, находящимся крови больного. Шесть основных метаболитов эверолимуса найдены в крови у человека, в том числе три метаболита, образованные путем моногидроксилирования, два метаболита с гидролитически открытыми кольцами, а также конъюгат эверолимуса с фосфатидилхолином. Эти метаболиты в исследованиях токсичности показали примерно в 100 раз меньшую активность, чем сам эверолимус, таким образом, активное вещество считается важнейшим за основную часть общей фармакологической активности эверолимуса.
Выведение.
После введения меченого радиоактивной меткой однократной дозы эверолимуса пациентам после трансплантации, большая часть (80%) радиоактивности определялась в кале, небольшое количество (5%) выделялось с мочой. В неизменном виде вещество не определялось ни в кале, ни в моче.
Фармакокинетика у отдельных групп больных.
Нарушения функции почек
В период лечения рекомендуется регулярный контроль функции почек. При повышении содержания сывороточного креатинина следует рассмотреть вопрос о коррекции режима иммуносупрессивного лечения. применять одновременно другие лекарственные средства, которые могут нарушать функцию почек, следует с осторожностью.
Нарушения функции печени.
У 8 больных с умеренными нарушениями функции печени (класс В Чайлд-Пью) AUC эверолимуса возрастала приблизительно в 2 раза по сравнению с 8 здоровыми лицами. Показатель AUC положительно коррелировал с увеличением протромбинового времени и концентрацией сывороточного билирубина, но отрицательно коррелировал с концентрацией сывороточного альбумина. В случае, если концентрация билирубина была > 34 мкмоль/л, протромбиновое время составляло > 1,3 INR (пролонгация > 4 секунд) и/или концентрация альбумина была < 35 г/л, то наблюдалась тенденция к повышению показателя AUC у лиц с умеренно выраженной печеночной недостаточностью. Влияние тяжелой печеночной недостаточности (класс С Чайлд-Пью) на AUC достоверно не изучено, однако, возможно, оно такое же или более выраженное, чем воздействие умеренной печеночной недостаточности.
Пожилые пациенты
У взрослых пациентов в возрасте от 16 до 70 лет наблюдалось снижение клиренса, эверолимуса на 0,33 % в год. Корректировки дозы не требуется.
Этническая принадлежность
Согласно проведенному популяционному анализу фармакокинетических параметров, клиренс Сертикана после перорального применения (CL/F) был, в среднем, на 20% выше у негроидной расы, перенесших трансплантацию.
Фармацевтические характеристики
Таблетки от белого до желтоватого цвета, круглые, со скошенными краями. На одной стороне нанесена гравировка «CU» (у дозировки 0,25 мг гравировка «С», у дозировки 0,75 мг: тиснение «СL»).
Упаковка, срок годности, условия хранения
Таблетки диспергируемые, в блистере по 0,1 мг; 0,25 мг; 0,5 мг; 0,75 мг или 1 мг. По 10 таблеток в блистере из ПА/Алюм./ПВХ. В картонной упаковке по 5, 6, 10 и 25 блистеров упаковано вместе с инструкцией.
Препарат следует хранить в недоступном для детей месте, при температуре не выше 25 °С, в защищенном от света месте.
Срок хранения 3 года.
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