Modern directed antiviral COVID-19 therapy: results of multicenter clinical effectiveness and safety study of fixed nirmatrelvir+ritonavir combination

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Abstract

The article presents the data from an open, two-stage, multicenter study on the efficacy and safety evaluation of a combined drug (a fixed combination of nirmatrelvir 300 mg, and ritonavir 100 mg) in the complex therapy in COVID-19 patients.

The aim of the study was to assess the safety, tolerability and pharmacokinetic parameters of the fixed combination of nirmatrelvir 300 mg and ritonavir 100 mg in healthy volunteers, the efficacy and safety assessment of the drug in the combination therapy compared with the standard therapy in COVID-19 patients.

Material and methods. An open two-stage multicenter clinical study to assess the main pharmacokinetic parameters, safety, and efficacy against COVID-19 of the drug nirmatrelvir 300 mg and ritonavir 100 mg combination (Skyvira® PROMOMED RUS LLC, Russia) in the adult population, included 2 stages. At stage 1, safety, tolerability and pharmacokinetic parameters were evaluated in healthy volunteers (over 18 years of age) in order to confirm their comparability with the literature data known for a set of active substances. Phase 2 assessed efficacy and safety in COVID-19 patients. As a part of the second stage, the study involved 264 patients (men and women aged 18 to 80 years), who had been divided into two groups. The first group patients (n=132) received the study drugs (nirmatrelvir 300 mg and ritonavir 100 mg) – 1 tablet twice a day with an interval of 12±2 hours for 5 days in combination with pathogenetic and symptomatic therapy. The second group patients (n=132) received standard therapy in accordance with the approved Temporary Guidelines for the Prevention and Treatment of Novel Coronavirus Infection (Version 15 dated February 22, 2022).

Results. During the study, none of the patients from the (nirmatrelvir + ritonavir) group experienced a transition of the COVID-19 course to a heavier severity level, in contrast to the patients in the standard therapy group. The study participants included patients with comorbidities (68% of the general population), with risk factors for COVID-19 progression to a heavier severity level and the risk of hospitalization (75% of the general population). There were no cases of COVID-19 progression to a heavier severity level in the study drug group. By the 6th day, in the nirmatrelvir + ritonavir group, the proportion of the patients who had achieved a complete recovery was twice more and amounted to 35.61% (p=0.0001), and the proportion of the patients with a negative RNA analysis to SARS-CoV-2 was 20% higher than in the comparison group, and amounted to 82.58% (p=0.0001). The fixed nirmatrelvir + ritonavir combination therapy has a favorable safety profile comparable to the standard therapy. The identified adverse reactions were transient in nature and did not require discontinuation of therapy or changes in the treatment regimen.

Conclusion. The fixed nirmatrelvir + ritonavir combination has a favorable safety profile in COVID-19 patients, comparable to the standard therapy. The data obtained demonstrate a clinical and pharmacoeconomic feasibility of including the fixed (nirmatrelvir + ritonavir) combination in the COVID-19 treatment regimen.

About the authors

Larisa A. Balykova

National Research Ogarev Mordovia State University

Email: larisabalykova@yandex.ru
ORCID iD: 0000-0002-2290-0013

Doctor of Sciences (Medicine), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Pediatrics, Director ofNational Research Ogarev Mordovia State University

Russian Federation, 68, Bol’shevistskaya Str., Saransk, Republic of Mordovia, 430005

Natalya M. Selezneva

National Research Ogarev Mordovia State University

Email: nata_rm@mail.ru
ORCID iD: 0000-0002-3004-2063

Doctor of Sciences (Medicine), Associate Professor of the Department of Hospital Therapy,National Research Ogarev Mordovia State University

Russian Federation, 68, Bol’shevistskaya Str., Saransk, Republic of Mordovia, 430005

Elena I. Gorshenina

National Research Ogarev Mordovia State University

Email: lena.medfak@yandex.ru
ORCID iD: 0000-0001-9342-0909

Doctor of Sciences (Medicine), Associate Professor, Department of Hospital Therapy, Medical Institute ofNational Research Ogarev Mordovia State University

Russian Federation, 68, Bol’shevistskaya Str., Saransk, Republic of Mordovia, 430005

Olga I. Shepeleva

National Research Ogarev Mordovia State University

Email: shepeleva-oi@rambler.ru
ORCID iD: 0000-0001-8307-2787

Doctor of Sciences (Medicine), Associate Professor, Department of Hospital Therapy, Medical Institute,National Research Ogarev Mordovia State University

Russian Federation, 68, Bol’shevistskaya Str., Saransk, Republic of Mordovia, 430005

Natalya V. Kirichenko

Ivanovo Clinical Hospital named after the Kuvaevs

Email: igb2@ivreg.ru
ORCID iD: 0000-0002-4272-9540

pulmonologist, Deputy Chief Physician for medical affairs, Ivanovo Clinical Hospital n. a. the Kuvaevs

Russian Federation, Bld. 2, 52, Ermak Str., Ivanovo, 153025

Elena N. Simakina

Smolensk clinical hospital No. 1

Email: e.simakina@mail.ru
ORCID iD: 0000-0002-5709-8913

infectious disease specialist, Head of the Infectious Diseases Department of Smolensk clinical hospital No. 1, Smolensk

Russian Federation, 40, Frunze Str., Smolensk, 214006

Konstantin B. Kolontarev

Evdokimov Moscow State Medical and Dental University; Spasokukotsky City Clinical Hospital

Email: kbk@mail.ru
ORCID iD: 0000-0003-4511-5998

Doctor of Sciences (Medicine), Professor of the Department of Urology, Evdokimov Moscow State Medical and Dental University; urologist, Spasokukotsky City Clinical Hospital, Department of Health of the city of Moscow

Russian Federation, Bld. 1, 20, Delegatskaya Str., Moscow, 127473; 21, Vuchetich Str., Moscow, 127206

Dmitry Y. Pushkar

Evdokimov Moscow State Medical and Dental University; Spasokukotsky City Clinical Hospital

Email: pushkardm@mail.ru
ORCID iD: 0000-0002-6096-5723

Doctor of Sciences (Medicine),Professor, Head of the Department of Urology, EvdokimovMoscow State Medical and Dental University; urologist, Spasokukotsky City Clinical Hospital, Department of Health of the city of Moscow; academician of the Russian Academy of Sciences

Russian Federation, Bld. 1, 20, Delegatskaya Str., Moscow, 127473; 21, Vuchetich Str., Moscow, 127206

Dmitry N. Zemskov

National Research Ogarev Mordovia State University

Email: dizem1978@gmail.com
ORCID iD: 0000-0002-0181-4327

assistant of the Department of Biological and Pharmaceutical Chemistry with a Course of Organization and Management of Pharmacy, Medical Institute ofNational Research Ogarev Mordovia State University

Russian Federation, 68, Bol’shevistskaya Str., Saransk, Republic of Mordovia, 430005

Kira Y. Zaslavskaya

National Research Ogarev Mordovia State University

Email: kiryonok@yandex.ru
ORCID iD: 0000-0002-7348-9412

assistant of the Department of Biological and Pharmaceutical Chemistry with a Course of Organization and Management of Pharmacy, Medical Institute ofNational Research Ogarev Mordovia State University

Russian Federation, 68, Bol’shevistskaya Str., Saransk, Republic of Mordovia, 430005

Sergey M. Noskov

Yaroslavl State Medical University; Clinical Hospital No. 3,
Yaroslavl

Email: Noskov03@gmail.com
ORCID iD: 0000-0003-3456-9409

Doctor of Sciences (Medicine), Head of the Department of Hospital Therapy, Yaroslavl State Medical University; general practitioner, Clinical Hospital No. 3, Yaroslavl

Russian Federation, 5, Revolutionary Str., Yaroslavl, 150000; 61, Mayakovsky Str., Yaroslavl, 150007

Aleksey V. Taganov

Peoples’ Friendship University of Russia

Email: matis87177@yandex.ru
ORCID iD: 0000-0001-5056-374X

Doctor of Sciences (Medicine), Professor of the Department of Dermatovenereology with a Course of Cosmetology of the Faculty of Continuous Medical Education, Peoples’ Friendship University of Russia

Russian Federation, 6, Miklukho-Maklay Str., Moscow, 117198

Petr A. Bely

Evdokimov Moscow State Medical and Dental University

Author for correspondence.
Email: pbely@ncpharm.ru
ORCID iD: 0000-0001-5998-4874

Candidate of Sciences (Medicine), SeniorLaboratory Assistant, Department of Propaedeutics of Internal Diseases and Gastroenterology, Evdokimov Moscow State Medical and Dental University

Russian Federation, Bld. 1, 20, Delegatskaya Str., Moscow, 127473

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Supplementary files

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2. Figure 1 – Pharmacokinetic profile of average concentration values of nirmatrelvir a) and ritonavir b) over time (in a linear transformation) after a single dose of the study drug

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3. Figure 2 – Pharmacokinetic profile of average concentration values of nirmatrelvir a) and ritonavir b) over time (in a linear transformation) after multiple doses of the study drug

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Copyright (c) 2023 Balykova L.A., Selezneva N.M., Gorshenina E.I., Shepeleva O.I., Kirichenko N.V., Simakina E.N., Kolontarev K.B., Pushkar D.Y., Zemskov D.N., Zaslavskaya K.Y., Noskov S.M., Taganov A.V., Bely P.A.

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