Популяционное фармакокинетическое/фармакодинамическое моделирование и терапевтический лекарственный мониторинг ванкомицина у новорождённых и недоношенных новорождённых

Актуальность. Ванкомицин широко используется для лечения тяжёлых инфекций, вызванных грамположительными микроорганизмами, включая метициллино-резистентные штаммы Staphylococcus aureus. При проведении антибактериальной терапии важно не только добиться оптимальной эффективности, но и минимизировать риски развития потенциальных нежелательных реакций. Особенно это актуально для препаратов с узким терапевтическим диапазоном, к которым относится ванкомицин, а также для таких особых групп пациентов, как новорождённые и недоношенные новорождённые, для которых характерен высокий уровень межиндивидуальной фармакокинетической и фармакодинамической (ФК/ФД) вариабельности. Дозирование ванкомицина в этих группах пациентов рекомендуют проводить под контролем терапевтического лекарственного мониторинга (ТЛМ). Цель. Основной целью работы был описательный анализ особенностей популяционного ФК/ФД моделирования ванкомицина в популяции новорождённых и недоношенных новорождённых. Материал и методы. Поиск статей был инициирован в поисковой системе PubMed® (MEDLINE) за период с 1981 г. до августа 2024 г. Результаты. Описаны основные подходы к персонализации режимов дозирования ванкомицина, методы расчёта рекомендованного в настоящее время целевого ФК/ФД индекса по данным ТЛМ для оптимизации терапии в клинической практике, включая Байесовский подход на основе мониторирования показателя «площадь под фармакокинетической кривой» (AUC) с помощью специализированного программного обеспечения. Представлены результаты систематического литературного обзора популяционных ФК/ФД моделей ванкомицина, описаны структуры моделей и идентифицированные факторы, влияющие на ФК вариабельность в популяции недоношенных новорождённых. В большинстве исследований в популяции новорождённых фармакокинетика ванкомицина лучше всего описывалась однокамерной моделью. В отобранных исследованиях (n=31), включающих недоношенных новорождённых, значения клиренса и объёма распределения ванкомицина были оценены в широком диапазоне (0,01–0,22 л/ч/кг и 0,47–1,5 л/кг соответственно) с оценками выраженной межиндивидуальной вариабельности ФК параметров, достигающей в исследованиях 50%. В большинстве этих исследований масса тела, почечная функция и/или возраст были выявлены как значимые предикторы клиренса ванкомицина, а масса тела — важный предиктор объёма распределения ванкомицина. Выводы. В популяции новорождённых наблюдаемая значительная межиндивидуальная ФК/ФД вариабельность ванкомицина приводит к высокому риску недостаточного или избыточного его дозирования при использовании стандартизованных схем, что свидетельствует в пользу процедуры ТЛМ для оптимизации терапии. Идентификация факторов, вносящих вклад в ФК вариабельность ванкомицина, и использование рассчитанных популяционных ФК моделей может помочь в выборе начального режима дозирования ванкомицина. Тем не менее, доля остаточной необъяснённой вариабельности, обычно остающаяся в этих финальных регрессионных моделях, демонстрирует необходимость ТЛМ для персонализации режимов дозирования ванкомицина. Дозирование на основе мониторирования AUC, желательно с применением Байесовского подхода, можно рассматривать как наилучший вариант для достижения целевых концентраций ванкомицина, наиболее вероятно обеспечивающих успех проводимой терапии MRSA инфекций, и для профилактики развития микробной резистентности у новорождённых.

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