pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2022-10-5-460-471pmedpharm-1196Research ArticleФАРМАКОЛОГИЯ И КЛИНИЧЕСКАЯ ФАРМАКОЛОГИЯPHARMACOLOGY AND CLINICAL PHARMACOLOGYОСОБЕННОСТИ ФАРМАКОКИНЕТИКИ ОЛОКИЗУМАБА У ПАЦИЕНТОВ C НОВОЙ КОРОНАВИРУСНОЙ ИНФЕКЦИЕЙ COVID-19CHARACTERISTICS OF OLOKIZUMAB PHARMACOKINETICS IN PATIENTS WITH NOVEL CORONAVIRUS INFECTION COVID-19https://orcid.org/0000-0002-6796-212XТавлуеваЕ. В.TavluevaE. V.

доктор медицинских наук, ведущий научный сотрудник отдела патогенетических аспектов старения ФГБУ «НМИЦ ТМП» Минздрава России; руководитель регионального сосудистого центра ГБУЗ «Городская клиническая больница им. Ф.И. Иноземцева ДЗМ».

105187, Россия, г. Москва, ул. Фортунатовская, д. 1

Doctor of Sciences (Medicine), Leading Researcher of the Department of Pathogenetic Aspects of Aging; Head of the Regional Vascular Center, Inozemtsev City Clinical Hospital

1, Fortunatovskaya St., Moscow, Russia, 105187

tavlev1@mail.ruhttps://orcid.org/0000-0003-4565-6743ЗерноваЕ. В.ZernovaE. V.

заместитель главного врача по терапевтической помощи

105187, Россия, г. Москва, ул. Фортунатовская, д. 1

Deputy Chief Physician for Therapeutic Care

1, Fortunatovskaya St., Moscow, Russia, 105187

evgenya.gor@mail.ruhttps://orcid.org/0000-0002-9283-9721КутеповаМ. П.KutepovaM. P.

врач-терапевт

105187, Россия, г. Москва, ул. Фортунатовская, д. 1

general practitioner

1, Fortunatovskaya St., Moscow, Russia, 105187

kutepovam@mail.ruhttps://orcid.org/0000-0002-5128-5005КостинаН. Э.KostinaN. E.

заведующая отделением пульмонологии

394066, Россия, г. Воронеж, пр-т Московский, д. 151

Head of the Department of Pulmonology

151, Moskovsky Ave., Voronezh, Russia, 394066

nata166k@yahoo.conhttps://orcid.org/0000-0001-8231-6591ЛесинаВ. С.LesinaV. S.

врач-пульмонолог

394066, Россия, г. Воронеж, пр-т Московский, д. 151

pulmonologist

151, Moskovsky Ave., Voronezh, Russia, 394066

vita252007@yandex.ruhttps://orcid.org/0000-0002-8908-0136МоулдД. Р.MouldD. R.

Ph.D., президент Projections Research, Inc.

19460, США, Пенсильвания, Фениксвилл, Springview Lane, 535

PhD, president Projections Research, Inc. 

535, Springview Lane, Phoenixville, PA, USA, 19460

drmould@pri-home.netИтоK.ItoK.

Ph.D.-MBA, научный консультант в Projections Research, Inc.

19460, США, Пенсильвания, Фениксвилл, Springview Lane, 535

PhD-MBA, scientific consultant Projections Research, Inc

535, Springview Lane, Phoenixville, PA, USA, 19460

kaori.ito@appliedpmx.comhttps://orcid.org/0000-0001-8148-5086ЗинченкоА. В.ZinchenkoA. V.

руководитель направления исследования биоаналогов

123154, Россия, г. Москва, ул. Берзарина, д. 19, кор. 1

Head of Biosimilars Research

Bld. 1, 19, Berzarin St., Moscow, Russia, 123154

a.zinchenko@rpharm.ruhttps://orcid.org/0000-0003-4189-7910ДолгоруковаА. Н.DolgorukovaA. N.

биостатистик

123154, Россия, г. Москва, ул. Берзарина, д. 19, кор. 1

biostatistician

Bld. 1, 19, Berzarin St., Moscow, Russia, 123154

an.dolgorukova@gmail.comhttps://orcid.org/0000-0001-6716-0357НикольскаяМ. В.NikolskayaM. V.

руководитель отдела медицинской документации

123154, Россия, г. Москва, ул. Берзарина, д. 19, кор. 1

Head of Medical Records Department

Bld. 1, 19, Berzarin St., Moscow, Russia, 123154

mv.nikolskaya@rpharm.ruhttps://orcid.org/0000-0003-4793-7477ЛемакМ. С.LemakM. S.

научный советник

123154, Россия, г. Москва, ул. Берзарина, д. 19, кор. 1

scientific adviser

Bld. 1, 19, Berzarin St., Moscow, Russia, 123154

lemak@rpharm.ruhttps://orcid.org/0000-0002-8735-7429ФилонО. В.FilonO. V.

директор департамента 

123154, Россия, г. Москва, ул. Берзарина, д. 19, кор. 1

Director of the Department

Bld. 1, 19, Berzarin St., Moscow, Russia, 123154

ov.filon@rpharm.ruhttps://orcid.org/0000-0003-2685-1623СамсоновМ. Ю.SamsonovM. Yu.

кандидат медицинских наук, доцент, медицинский директор

123154, Россия, г. Москва, ул. Берзарина, д. 19, кор. 1

Candidate of Sciences (Medicine), Associate Professor, Medical Director

Bld. 1, 19, Berzarin St., Moscow, Russia, 123154

samsonov@rpharm.ruГосударственное бюджетное учреждение здравоохранения города Москвы «Городская клиническая больница им. Ф.И. Иноземцева Департамента здравоохранения города Москвы»РоссияInozemtsev Municipal Clinical HospitalRussian FederationБюджетное учреждение здравоохранения Воронежской области «Воронежская областная клиническая больница № 1»РоссияVoronezh Regional Clinical Hospital No. 1Russian FederationБюджетное учреждение здравоохранения Воронежской области «Воронежская областная клиническая больница №1»РоссияVoronezh Regional Clinical Hospital No. 1Russian FederationProjections Research, IncСоединённые Штаты АмерикиProjections Research, IncUnited StatesАкционерное общество «Р-Фарм»РоссияJoint Stock Company “R-Pharm”Russian Federation202215122022105460471Copyright © Тавлуева Е.В., Зернова Е.В., Кутепова М.П., Костина Н.Э., Лесина В.С., Моулд Д.Р., Ито K., Зинченко А.В., Долгорукова А.Н., Никольская М.В., Лемак М.С., Филон О.В., Самсонов М.Ю., 20222022Тавлуева Е.В., Зернова Е.В., Кутепова М.П., Костина Н.Э., Лесина В.С., Моулд Д.Р., Ито K., Зинченко А.В., Долгорукова А.Н., Никольская М.В., Лемак М.С., Филон О.В., Самсонов М.Ю.Tavlueva E.V., Zernova E.V., Kutepova M.P., Kostina N.E., Lesina V.S., Mould D.R., Ito K., Zinchenko A.V., Dolgorukova A.N., Nikolskaya M.V., Lemak M.S., Filon O.V., Samsonov M.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/1196Цель

Цель. Изучение особенностей фармакокинетики олокизумаба при внутривенном введении у пациентов с COVID-19 среднетяжелого течения для купирования синдрома гипервоспаления.

Материалы и методы

Материалы и методы. Изучение фармакокинетики проводилось в рамках клинического исследования III фазы (исследование RESET, NCT05187793) эффективности и безопасности нового режима применения олокизумаба (внутривенно, в дозах 128 мг или 256 мг) у пациентов с COVID-19. Определение концентрации олокизумаба в плазме крови проводили методом иммуноферментного анализа. Популяционный анализ выполнен с помощью ранее разработанной фармакокинетической модели на основе линейной двухкамерной модели.

Результаты

Результаты. В анализ фармакокинетики были включены данные 8 пациентов с COVID-19 среднетяжелого течения, получавшие олокизумаб в дозе 128 мг внутривенно. Согласно результатам анализа в данной популяции наблюдалось увеличение клиренса препарата, по сравнению с данными, полученными у здоровых добровольцев и пациентов с ревматоидным артритом: 0,435, 0,178 и 0,147 л/сут, соответственно. Анализ параметров в рамках популяционной фармакокинетической модели показал, что основными факторами повышенного клиренса олокизумаба являются высокий индекс массы тела. Кроме того, независимым фактором повышения клиренса препарата является само наличие COVID-19.

Заключение

Заключение. У пациентов со среднетяжелым течением COVID-19 после внутривенного введения олокизумаба наблюдается увеличение клиренса препарата на фоне течения заболевания. Основной вклад в повышенный клиренс вносят особенности популяции пациентов с COVID-19, связанные с риском тяжелого течения заболевания и выраженным воспалением. При внутривенном введении в дозе 128 мг терапевтически значимый уровень олокизумаба сохранялся в течение всей острой фазы заболевания на протяжении 28 дней.

The aim of the article is to study pharmacokinetic characteristics of intravenous olokizumab in patients with moderate COVID-19 to relieve a hyperinflammation syndrome.

Materials and methods

Materials and methods. The pharmacokinetic study was conducted as a part of a phase III clinical study (RESET, NCT05187793) on the efficacy and safety of a new olokizumab regimen (intravenous, at the doses of 128 mg or 256 mg) in COVID-19 patients. Plasma concentrations of olokizumab were determined by the enzyme immunoassay. The population analysis was performed using a previously developed pharmacokinetic model based on a linear two compartment.

Results

Results. The pharmacokinetic analysis included the data from 8 moderate COVID-19 patients who had been administrated with olokizumab intravenously at the dose of 128 mg. According to the analysis results in this population, there was an increase in the drug clearance, compared with the data obtained in healthy volunteers and the patients with rheumatoid arthritis: 0.435, 0.178 and 0.147 l/day, respectively. The parameters analysis within the framework of a population pharmacokinetic model showed that the main factors for the increased olokizumab clearance are a high body mass index. In addition, the presence of COVID-19 itself is an independent factor in increasing the drug clearance.

Conclusion

Conclusion. After the intravenous olokizumab administration, an increase in the drug clearance is observed in moderate COVID-19 patients against the background of the disease course. The main contribution to the increased clearance is made by the characteristics of the population of COVID-19 patients associated with the risk of a severe disease and inflammation. When administered intravenously at the dose of 128 mg, a therapeutically significant olokizumab level was maintained throughout the acute disease phase for 28 days.

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The authors declare that there are no conflicts of interest present.