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Сиртуро — Sirturo (бедаквилин)

Сиртуро

Сиртуро — Sirturo (бедаквилин)

Открытый недавно препарат Сиртуро является противомикробным агентом группы диарилхинолинов с инновационным механизмом действия против туберкулеза. Механизм действия препарата Сиртуро основан на способности игнибировать фермент АТФ-синтазу. Этот фермент необходим клеткам Mycobacterium tuberculosis для производства энергии. Благодаря своему механизму действия Сиртуро является препаратом противотуберкулезных соединений нового класса.

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Описание

Открытый недавно препарат Сиртуро является противомикробным агентом группы диарилхинолинов с инновационным механизмом действия против туберкулеза. Механизм действия препарата Сиртуро основан на способности игнибировать фермент АТФ-синтазу. Этот фермент необходим клеткам Mycobacterium tuberculosis для производства энергии. Благодаря своему механизму действия Сиртуро является препаратом противотуберкулезных соединений нового класса.

15 июня 2018 был зарегистрирован оральный препарата Сиртуро, с основным действующим веществом — бедаквилин. Он применяется как часть комбинированной схемы лечения для лечения туберкулеза легких с множественной лекарственной резистентностью в тех случаях, когда эффективный режим лечения не может быть подобран по причинам переносимости или устойчивости. Препарат дает пациентам дополнительные возможности в борьбе с этим смертельным сложным заболеванием. Препарат Сиртуро получил одобрение для лечения туберкулеза легких с множественной лекарственной устойчивостью

Состав Сиртуро

1 таблетка содержит:

  • действующее вещество: бедаквилина фумарат 120.89 мг, что соответствует содержанию бедаквилина — 100 мг;
  • вспомогательные вещества: лактозы моногидрат, крахмал кукурузный, гипромеллоза, полисорбат, целлюлоза микрокристаллическая, магния стеарат, кроскармеллоза натрия, кремния диоксид коллоидный.

Показания к применению Сиртуро

применяется у взрослых (>18 лет) в комбинированной терапии туберкулеза легких, вызванного штаммами Mycobacterium tuberculosis с множественной лекарственной резистентностью. Препарат используют в случае, когда не возможно назначить другой режим лечения при устойчивости возбудителя или непереносимости препаратов.

Фармакодинамика

Бедаквилин относится к группе диарилхинолинов — новому классу противотуберкулезных соединений. Противомикобактериальное воздействие вещества связано со специфическим механизмом ингибирования протонной помпы микобактерий фермента Mycobacterium tuberculosis — аденозин 5’трифосфат-синтазы (АТФ-синтазу). Ингибирование синтеза АТФ ведет к нарушению выработки энергии и, как следствие, к гибели микробной клетки.

In vitro Бедаквилин активен в отношении лекарственно-чувствительных и лекарственно-устойчивых штаммов Mycobacterium tuberculosis с минимальной ингибирующей концентрацией.

Учитывая низкий средний уровень экспозиции у человека (от 23 — до 31 процентов) и низкую противомикобактериальную активность (ниже в 3-6 раз ) по сравнению с исходным веществом.

Внутриклеточная бактерицидная активность бедаквилина в первичных перитонеальных макрофагах была выше, чем внеклеточная активность.

Бедаквилин также оказывает бактерицидное воздействие на дремлющие туберкулезные микобактерии. На мышиной модели бедаквилин продемонстрировал бактерицидную и стерилизующую активность.

Препарат Сиртуро характериэуется противомикобактериальной активностью в отношении многих нетуберкулезных микобактерий. Mycobacterium xenopi, Mycobacterium shimoidei, Mycobacterium novocastrense. Немикобактериальные видык действию бедаквилина считаются устойчивыми.

Механизмы развития резистентности

Процессы, характеризующие устойчивость Mycobacterium tuberculosis к бедаквилину, включают в себя шесть вариантов мутаций в гене-мишени atpE, кодирующего АТФ-синтазу-мишень. Вторым способом приобретенной устойчивости, влияющим на минимальную ингибирующую концентрацию бедаквилина, считаются мутации в гене Rv0678 (отвечающие за экспрессию MmpS5-MmpL5 эффлюксной помпы). Целевые мутации, созданные в ходе доклинических исследований, привели к от 8 до 133-кратному увеличению минимальной ингибирующей концентрации бедаквилина, в следствии чего диапазон минимальной ингибирующей концентрации составил 0,25 — 4,0 мг/л. Основанные на активации эффлюксной помпы, мутации наблюдались у штаммов, изученных в рамках доклинических и клинических исследований. Это привело к 2-8-кратному увеличению минимальной ингибирующей концентрации бедаквилина, в результате чего диапазон минимальной ингибирующей концентрации составил 0,25 — 0,50 мг/л. Штаммы с эффлюксным механизмом устойчивости также менее чувствительны к клофазимину.

Однако четкая взаимосвязь между повышением минимальной ингибирующей концентрации бедаквилина относительно первоначального уровня и микробиологическими данными клинических исследований, в ходе которых пациенты получали бедаквилин длительностью 24 недели с дальнейшей фоновой терапией, не была выявлена.

Фармакокинетика Сиртуро

Анализ фармакокинетических свойств бедаквилина выполнялся на взрослых здоровых добровольцах и взрослых пациентах, инфицированных туберкулезом с множественной лекарственной резистентностью. у пациентов, инфицированных туберкулезом с множественной лекарственной устойчивостью, экспозиция бедаквилина была ниже, чем у здоровых.

Всасывание

При пероральном приеме отмечена высокая абсорбция бедаквилина. В плазме максимальная концентрация достигается приблизительно через 5 часов после приема. Максимальная концентрация и площадь под кривой «концентрация-время» увеличиваются пропорционально возрастанию дозировки вплоть до самых высоких исследованных доз (700 мг в сутки однократно или 400 мг в несколько приемов) без изменения времени достижения максимальной концентрации и периода полувыведения. Наибольшая биодоступность достигается при приеме с пищей (до 95%), которая примерно в 2 раза превышает биодоступность при приеме натощак. Таким образом, для увеличения биодоступности бедаквилина лекарство следует принимать во время еды.

Распределение

Бедаквилин и его активный метаболит N-монодезметил обладают большим объемом распределения (около 164 литров). Соотношение концентрации в тканях к концентрации в плазме = 30. Связывание с белками плазмы составляет > 99,9 процентов. Максимальные концентрации создаются в легочной ткани,селезенке, лимфатических узлах, печени и почках. Проникновение через гематоэнцефалический барьер незначительно.

Метаболизм

В первую очередь Бедаквилин подвергается метаболизму путем окисления, приводящего к образованию N-монодезметил. in vitro CYP3A4 является основным изоферментом семейства Р450, участвующим в метаболизме бедаквилина и образовании N-монодезметила.

В in vitro исследованиях бедаквилин не оказывает значимого воздействия на активность известных изоферментов семейства цитохрома Р450 (не ингибирует CYP2A6, CYP1A2, CYP2C8/9/10, CYP2D6, CYP2C19, CYP2E1, CYP4A, CYP3A4, CYP3A4/5 и не индуцирует активность CYP2C9, CYP1А2, CYP3A4 и CYP2C19).

Метаболит N-монодезметил существенного клинического эффекта с учетом его более слабой антибактериальной активности (в 4-6 раз ниже) не оказывает, по сравнению с первоначальным соединением.

Выведение Сиртуро

Бедаквилин выводится из организма главным образом кишечником. В клинических исследованиях выведение неизмененного бедаквилина почками составило ≤0,001 процента от введенной дозы, что свидетельствует о незначительном почечном клиренсе неизмененного препарата. При достижения максимальной концентрация бедаквилин в плазме снижается три-экспоненциальным путем. Терминальный период полувыведения бедаквилина и N-монодезметила составляет около 5,5 месяцев, что, возможно, отражает медленное высвобождение бедаквилина и N-монодезметила из периферических тканей.

Фармакокинетика в различных группах

Этническая принадлежность

По результатам популяционного фармакокинетического анализа была установлена более низкая экспозиция бедаквилина у больных негроидной расы, в сравнении с больными других рас. Частота положительных ответов у пациентов разных рас была сопоставимой.

Возраст, пол и этническая принадлежность

По данным популяционного фармакокинетического анализа лиц, с диагнозом туберкулез легких, не установлено половых, этнических и возрастных клинически значимых отличий в фармакокинетике бедаквилина.

Педиатрические пациенты (<18 лет)

Фармакокинетика препарата Сиртуро в педиатрической практике не оценивалась.

Пожилые пациенты (> 65 лет)

Данные о фармакокинетике препарата Сиртуро у людей в возрасте 65 лет и старше, с диагнозом туберкулез легких, ограничены.

Пациенты с недостаточностью функции почек

Главным образом препарат Сиртуро исследовали среди пациентов с нормальной функцией почек. Выведение неизмененного бедаквилина через почки незначительно (<0,001 процента). Почечная недостаточность легкой или умеренной степени предполагается, что не будет иметь клинически значимое влияние на фармакокниетику бедаквилина. У лиц с тяжелой почечной недостаточностью (клиренс креатинина < 30 мл/мин) или терминальной стадией почечной недостаточности с необходимостью использования гемодиализа или перитонеального диализа концентрация бедаквилина может повышаться за счет изменения всасывания, метаболизма и распределения препарата на фоне нарушения функции почек. Вввиду того, что бедаквилин в значительной степени связывается с белками плазмы, эффективность гемодиализа для удаления препарата из плазмы будет мало эффективной.

Пациенты с недостаточностью функции печени

После однократного приема препарата Сиртуро (400 мг) у 8 пациентов с умеренным нарушением функции печени (класс В по шкале Чайлд-Пью), AUC672 ч для бедаквилина и N-монодезметила была примерно на 20 процентов ниже по сравнению со здоровыми добровольцами. Не изучалась фармакокинетика бедаквилина у лиц с тяжелой печеночной недостаточностью.

ВИЧ-инфицированные пациенты

Ограничены данные о фармакокинетике препарата Сиртуро у ВИЧ-инфицированных пациентов.

Применение при беременности и кормлении грудью

  • Беременность

Не установлена безопасность препарата Сиртуро при беременности. Поэтому препарат противопоказан к использованию у беременных женщин.

  • Период лактации

Отсутствуют данные об использовании бедаквилина у женщин в период лактации. Поэтому использование препарата в период грудного вскармливания противопоказано.

Фармацевтические характеристики

Таблетки белого или почти белого цвета, круглые, двояковыпуклые, с выдавленной надписью «T» над «207» на одной стороне и «100» на другой.

Упаковка, срок годности, условия хранения Сиртуро

Во флаконах из полиэтилена высокой плотности по 188 таблеток, упакованных вместе с инструкцией в картонные пачки.

Хранить при температуре не выше 25°С. Хранить в оригинальной упаковке в защищенном от света месте. Хранить в недоступном для детей месте.

Срок годности 2 года.

 

 

 

 

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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а также можем отправить Сиртуро (бедаквилин) по регионам Казахстана: Нур-Султан (Астана), Шымкент, Талдыкорган, Актау и другие.

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