Characteristics of olokizumab pharmacokinetics in patients with novel coronavirus infection COVID-19

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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. 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. 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. 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.

作者简介

Evgenia Tavlueva

Inozemtsev Municipal Clinical Hospital

编辑信件的主要联系方式.
Email: tavlev1@mail.ru
ORCID iD: 0000-0002-6796-212X

Doctor of Sciences (Medicine), Leading Researcher of the Department of Pathogenetic Aspects of Aging, Head of the Regional Vascular Center

俄罗斯联邦, 1, Fortunatovskaya St., Moscow, 105187

Evgenia Zernova

Inozemtsev Municipal Clinical Hospital

Email: evgenya.gor@mail.ru
ORCID iD: 0000-0003-4565-6743

Deputy Chief Physician for Therapeutic Care

俄罗斯联邦, 1, Fortunatovskaya St., Moscow, 105187

Marina Kutepova

Inozemtsev Municipal Clinical Hospital

Email: kutepovam@mail.ru
ORCID iD: 0000-0002-9283-9721

general practitioner

俄罗斯联邦, 1, Fortunatovskaya St., Moscow, 105187

Natalya Kostina

Voronezh Regional Clinical Hospital No. 1

Email: nata166k@yahoo.com
ORCID iD: 0000-0002-5128-5005

Head of the Department of Pulmonology

俄罗斯联邦, 151, Moskovsky Ave., Voronezh, 394066

Victoria Lesina

Voronezh Regional Clinical Hospital No. 1

Email: vita252007@yandex.ru
ORCID iD: 0000-0001-8231-6591

pulmonologist

俄罗斯联邦, 151, Moskovsky Ave., Voronezh, 394066

Diane Mould

Projections Research, Inc

Email: drmould@pri-home.net
ORCID iD: 0000-0002-8908-0136

PhD, president

美国, 535, Springview Lane, Phoenixville, PA, 19460

Kaori Ito

Projections Research, Inc

Email: kaori.ito@appliedpmx.com

PhD-MBA, scientific consultant

美国, 535, Springview Lane, Phoenixville, PA, 19460

Arkady Zinchenko

Joint Stock Company “R-Pharm”

Email: a.zinchenko@rpharm.ru
ORCID iD: 0000-0001-8148-5086

Head of Biosimilars Research

俄罗斯联邦, Bld. 1, 19, Berzarin St., Moscow, 123154

Antonina Dolgorukova

Joint Stock Company “R-Pharm”

Email: an.dolgorukova@gmail.com
ORCID iD: 0000-0003-4189-7910

biostatistician

俄罗斯联邦, Bld. 1, 19, Berzarin St., Moscow, 123154

Maria Nikolskaya

Joint Stock Company “R-Pharm”

Email: mv.nikolskaya@rpharm.ru
ORCID iD: 0000-0001-6716-0357

Head of Medical Records Department

俄罗斯联邦, Bld. 1, 19, Berzarin St., Moscow, 123154

Maria Lemak

Joint Stock Company “R-Pharm”

Email: lemak@rpharm.ru
ORCID iD: 0000-0003-4793-7477

scientific adviser

俄罗斯联邦, Bld. 1, 19, Berzarin St., Moscow, 123154

Olga Filon

Joint Stock Company “R-Pharm”

Email: ov.filon@rpharm.ru
ORCID iD: 0000-0002-8735-7429

Director of the Department

俄罗斯联邦, Bld. 1, 19, Berzarin St., Moscow, 123154

Mikhail Samsonov

Joint Stock Company “R-Pharm”

Email: samsonov@rpharm.ru
ORCID iD: 0000-0003-2685-1623

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

俄罗斯联邦, Bld. 1, 19, Berzarin St., Moscow, 123154

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2. Figure 2 – Goodness of fit plots for the final model. Note: DV – dependent variable; PRED – predicted values; IPRED – individual predicted values; TAD – time after the last dose; CWRES – conditional weighted residuals calculated using the FOCI algorithm.

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3. Figure 1 – Diagram of linear two compartment model to describe olokizumab pharmacokinetics. Note: Q/Vc, Q/Vp – speed constants of exchange between cameras; Kel – elimination rate constant.

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4. Figure 3 – Assessments of the normality assumption of interindividual variability. Note: ETA = η; IIV – interindividual variability; CL - clearance; Vc – volume of the central chamber; Vp – volume of the peripheral chamber; Normal QQ Plot – quantile-quantile plot for assessing normality of the distribution.

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5. Figure 4 – Graphical representation of observed and predicted pharmacokinetic olokizumab profiles for COVID-19 patients, healthy volunteers, and RA patients. Note: The area marked in pink is the boundaries of the 95% confidence interval for estimating the median; the areas marked in gray are the boundaries of the 95% confidence interval for estimating the 5th and 95th percentiles.

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版权所有 © Tavlueva E., Zernova E., Kutepova M., Kostina N., Lesina V., Mould D., Ito K., Zinchenko A., Dolgorukova A., Nikolskaya M., Lemak M., Filon O., Samsonov M., 2023

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