Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector62110.25692/ACEN.2019.4.9ReviewsОбзорыUnknownTherapeutic drug monitoring of levetiracetam in newbornsОсобенности терапевтического лекарственного мониторинга леветирацетама у новорожденныхBondarevaIrina B.БондареваИрина Борисовна
Russian Federation
i_bomdareva@yahoo.comIvzhitsMarina A.ИвжицМарина Александровна
Russian Federation
i_bomdareva@yahoo.comZyryanovSergey K.ЗыряновСергей Кенсаринович
Russian Federation
i_bomdareva@yahoo.comChenkurovMikhail S.ЧеркуновМихаил Станиславович
Russian Federation
i_bomdareva@yahoo.comPeoples' Friendship University of RussiaФГАОУ ВО «Российский университет дружбы народов»City Clinical Hospital No.24ГБУЗ "Городская клиническая больница № 24 Департамента здравоохранения г. Москвы"26122019134657626122019Copyright ©; 2019, Bondareva I.B., Ivzhits M.A., Zyryanov S.K., Chenkurov M.S.Copyright ©; 2019, Bondareva I.B., Ivzhits M.A., Zyryanov S.K., Chenkurov M.S.2019Bondareva I.B., Ivzhits M.A., Zyryanov S.K., Chenkurov M.S.Bondareva I.B., Ivzhits M.A., Zyryanov S.K., Chenkurov M.S.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/621

Neonatal seizures in full-term and preterm infants represent a common neurological syndrome. Levetiracetam (LEV) is one of the new and widely prescribed second- or third-line antiepileptic drug for the treatment of seizures. Routine therapeutic drug monitoring of LEV was not recommended due to its almost ideal pharmacokinetic profile: linear pharmacokinetics, predictable dose-concentration relationship, wide therapeutic index, favourable safety profile, and unlikely clinically significant drug-drug pharmacokinetic interactions.

In newborns, drug pharmacokinetics may be under the influence of maturation process. LEV pharmacokinetics in newborns appears to be age (gestational, postnatal) dependent and highly variable within the age ranges. These aspects make therapeutic drug monitoring a useful procedure for therapy optimization in this specific patient population.

In population modeling based on therapeutic drug monitoring and nonlinear mixed effects models, covariates were found that should significantly affect the LEV clearance and volume of distribution in newborns — creatinine clearance and total body weight. Using of these regression equations can help to adjust the LEV doses without the patient's measured concentration data. But the significant magnitudes of the interindividual variability remaining in these final regression models justify the need for therapeutic drug monitoring and Bayesian adaptive control for personalization of LEV dosage regimens in neonates.

Неонатальные судороги у доношенных и недоношенных новорожденных (НР) являются часто встречающимся неврологическим синдромом. Одним из новых и широко назначаемых противоэпилептических препаратов 2–3-й линии для терапии судорог у НР является леветирацетам (LEV). Рутинное применение терапевтического лекарственного мониторинга LEV не было рекомендовано, поскольку препарат имеет практически идеальный фармакокинетический профиль: линейная фармакокинетика, предсказуемое соотношение доза–концентрация, высокий терапевтический индекс, благоприятный профиль безопасности, маловероятное клинически значимое фармакокинетическое взаимовлияние с другими препаратами.

У НР практически все основные процессы, определяющие фармакокинетику препарата, могут находиться под влиянием еще незаконченного процесса созревания. Фармакокинетика LEV у НР зависит от возраста (гестационного, постнатального), но внутри возрастных диапазонов наблюдается значительная межиндивидуальная вариабельность. Все это свидетельствует о необходимости терапевтического лекарственного мониторинга для оптимизации терапии LEV в этой специфической популяции пациентов.

При популяционном моделировании с использованием данных терапевтического лекарственного мониторинга и нелинейных моделей смешанных эффектов были выявлены ковариаты, значимо влияющие на клиренс и объем распределения LEV у НР, — клиренс креатинина и масса тела. Использование таких регрессионных соотношений может помочь в корректировке доз LEV без измерения концентраций у пациента. Однако значительная доля межиндивидуальной вариабельности, которую не удается объяснить с помощью регрессионной модели, свидетельствует в пользу терапевтического лекарственного мониторинга и Байесовского адаптивного подхода для персонализации режимов дозирования LEV у НР.

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