Bioequivalence study of generic nirmatrelvir in healthy volunteers

Nirmatrelvir is an antiviral drug that, in combination with ritonavir, is an effective agent for the etiotropic therapy of patients with mild to moderate COVID-19. The aim of the study was to evaluate bioequivalence of the generic drug nirmatrelvir Arpaxel in combination with ritonavir and the original drug Paxlovid, which is a combination of nirmatrelvir/ritonavir, in a single dose administration to healthy volunteers.Materials and methods. This research was an open-label, randomized, two-period crossover bioequivalence study. It included 2 periods, in each of which the volunteers received either a test drug (nirmatrelvir at the dose of 300 mg) in combination with ritonavir (100 mg), or a reference drug (a combination of nirmatrelvir 300 mg and ritonavir 100 mg), given as a single dose. A wash-out period between each of the administrations was 7 days. The blood sampling to determine the concentration of nirmatrelvir was carried out in the range from 0 to 36 h in each of the study periods. A nirmatrelvir concentration was determined by a validated HPLC-MS/MS method with a lower quantitation limit of 10 ng/mL. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0-36) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00-125.00%.Results. In the study were included 68 healthy volunteers, 67 participants of which were included in the bioequivalence population. The pharmacokinetic parameters of the drugs were comparable to each other. The 90% confidence interval for the ratio of the geometric mean of the maximum drug concentration in the blood plasma and the area under the pharmacokinetic curve << concentration-time >> from zero to the last blood draw within 36 hours of nirmatrelvir was 87.26-100.83 and 93.27-103.74%, which meets the criteria for assessing bioequivalence. The test drugs were well tolerated by the volunteers. The incidence of adverse events was similar for the test and reference drugs. No serious adverse events were recorded during the entire study.Conclusion. As a result of this study, bioequivalence of the test and reference drugs has been established.

Olokizumab reduces the risks of death in hospitalized patients with moderate and severe COVID-19

Aim - to evaluate the efficacy and safety of olokizumab in hospitalized patients with moderate to severe coronavirus disease COVID-19. Material and methods. A multicenter non-interventional retrospective study of olokizumab treatment in hospitalized patients with COVID-19 was conducted. The initial population in this study included 2926 patients with COVID-19. Patients with moderate or severe disease who were taking corticosteroids as part of standard therapy were selected for this analysis. The final population was 1738 patients. A test group (standard therapy: corticosteroids, antiviral, pathogenetic or symptomatic therapy in combination with olokizumab) and a comparison group (standard therapy only) were formed. Each group included 869 patients. The primary end point was all-cause mortality from the start of anti-inflammatory therapy to the end of follow-up. We also analyzed the incidence of transfer and the length of stay of patients in the intensive care unit, the duration of hospitalization, as well as the change in C-reactive protein level. Results and discussion. It was found that olokizumab significantly reduces the all-cause mortality compared with standard therapy: 54 (6.21%) cases compared with 111 (12.77%) in the control arm, p<0.001, odds ratio (OR) 2.21 [1.57;3.1]. The results of factor analysis confirmed that olokizumab increases the odds of recovery, OR 2.41 (95% CI 1.64-3.54, p<0.001). In addition, patients in olokizumab group showed significantly lower plasma CRP levels compared with control group. Already on the 2nd day after the start of therapy the CRP level was almost 2 times lower in the olokizumab group than in the control group (the median was 13 [5.6;28.55] mg/l and 25 [15.3;79.25] mg/L in the olokizumab and comparison groups, respectively). Conclusion. The results of the study confirm the clinical data on the efficacy of olokizumab as therapy for COVID-19 patients.Copyright © 2022 Tomsk Polytechnic University, Publishing House. All rights reserved.

Characteristics of Olokizumab Pharmacokinetics in Patients with Novel Coronavirus Infection Covid-19

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. Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

Olokizumab reduces the risks of death in hospitalized patients with moderate and severe COVID-19

Aim – to evaluate the efficacy and safety of olokizumab in hospitalized patients with moderate to severe coronavirus disease COVID-19. Material and methods. A multicenter non-interventional retrospective study of olokizumab treatment in hospitalized patients with COVID-19 was conducted. The initial population in this study included 2926 patients with COVID-19. Patients with moderate or severe disease who were taking corticosteroids as part of standard therapy were selected for this analysis. The final population was 1738 patients. A test group (standard therapy: corticosteroids, antiviral, pathogenetic or symptomatic therapy in combination with olokizumab) and a comparison group (standard therapy only) were formed. Each group included 869 patients. The primary end point was all-cause mortality from the start of anti-inflammatory therapy to the end of follow-up. We also analyzed the incidence of transfer and the length of stay of patients in the intensive care unit, the duration of hospitalization, as well as the change in C-reactive protein level. Results and discussion. It was found that olokizumab significantly reduces the all-cause mortality compared with standard therapy: 54 (6.21%) cases compared with 111 (12.77%) in the control arm, p<0.001, odds ratio (OR) 2.21 [1.57;3.1]. The results of factor analysis confirmed that olokizumab increases the odds of recovery, OR 2.41 (95% CI 1.64–3.54, p<0.001). In addition, patients in olokizumab group showed significantly lower plasma CRP levels compared with control group. Already on the 2nd day after the start of therapy the CRP level was almost 2 times lower in the olokizumab group than in the control group (the median was 13 [5.6;28.55] mg/l and 25 [15.3;79.25] mg/L in the olokizumab and comparison groups, respectively). Conclusion. The results of the study confirm the clinical data on the efficacy of olokizumab as therapy for COVID-19 patients. © 2022 Tomsk Polytechnic University, Publishing House. All rights reserved.