ABSTRACT
Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease. The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers. Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0-16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 - 125.00%. Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0-16) and Cmax were 96.31% - 113.64% and 91.37% - 114.8%, respectively. These intervals fit within the established limits of 80.00-125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs. Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.
ABSTRACT
Finding effective and safe medicines to fight SARS-CoV-2 infection is an urgent task. RPH-137 is an original trap fusion protein against SARS-CoV-2 virus. It comprises the angiotensin-converting enzyme type 2 extracellular domain and the human IgG1 Fc fragment. The aim of the study was to carry out a preclinical evaluation of the efficacy of RPH-137 and molnupiravir against SARS-CoV-2 infection. Material(s) and Method(s): the authors analysed RPH-137 expressed in a stable CHO cell line and molnupiravir used as an active pharmaceutical ingredient. Drug-mediated inhibition of virus-induced cytotoxicity was assessed in Vero cell culture. In vivo efficacy assessments were performed in Syrian hamsters. The animals were infected intranasally with SARS-CoV-2 (PIK35 clinical isolate) in the dose of 5 log TCID50. The authors evaluated body weight measurements, lung-body weight ratios, and lung histopathology findings and determined viral RNA levels in oropharyngeal swabs by RT-PCR using the amplification cycle threshold (Ct). The statistical analyses involved one- and two-way ANOVA, Student's t-test, and Mann-Whitney test. Result(s): RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells;the EC50 values of RPH-137 amounted to 4.69 mug/mL (21.3 nM) and 16.24 mug/mL (73.8 nM) for 50 TCID50 and 200 TCID50, respectively, whereas the EC50 values of molnupiravir were 0.63 mug/mL (1900 nM) for both doses. Intramuscular RPH-137 (30 and 80 mg/kg) had no effect on the infection process in Syrian hamsters. The comparison with the challenge control group showed that intraperitoneal RPH-137 (100 mg/kg) had statistically significant effects on a number of parameters, including a 27% reduction in inflammation and a 30% reduction in the total lesion area of the lungs by Day 7. Intragastric molnupiravir (300 mg/kg twice daily) significantly inhibited SARS-CoV-2 infection. Conclusion(s): both RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells. In Syrian hamsters, molnupiravir demonstrated a more pronounced inhibition of SARS-CoV-2 than RPH-137. However, RPH-137 had statistically significant effects on a range of parameters. This offers additional perspectives for further research.Copyright © 2023 Safety and Risk of Pharmacotherapy. All rights reserved.
ABSTRACT
Finding effective and safe medicines to fight SARS-CoV-2 infection is an urgent task. RPH-137 is an original trap fusion protein against SARS-CoV-2 virus. It comprises the angiotensin-converting enzyme type 2 extracellular domain and the human IgG1 Fc fragment. The aim of the study was to carry out a preclinical evaluation of the efficacy of RPH-137 and molnupiravir against SARS-CoV-2 infection. Materials and methods: the authors analysed RPH-137 expressed in a stable CHO cell line and molnupiravir used as an active pharmaceutical ingredient. Drug-mediated inhibition of virus-induced cytotoxicity was assessed in Vero cell culture. In vivo efficacy assessments were performed in Syrian hamsters. The animals were infected intranasally with SARS-CoV-2 (PIK35 clinical isolate) in the dose of 5 log TCID50. The authors evaluated body weight measurements, lung-body weight ratios, and lung histopathology findings and determined viral RNA levels in oropharyngeal swabs by RT-PCR using the amplification cycle threshold (Ct). The statistical analyses involved one- and two-way ANOVA, Student's t-test, and Mann–Whitney test. Results: RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells;the EC50 values of RPH-137 amounted to 4.69 μg/mL (21.3 nM) and 16.24 μg/mL (73.8 nM) for 50 TCID50 and 200 TCID50, respectively, whereas the EC50 values of molnupiravir were 0.63 μg/mL (1900 nM) for both doses. Intramuscular RPH-137 (30 and 80 mg/kg) had no effect on the infection process in Syrian hamsters. The comparison with the challenge control group showed that intraperitoneal RPH-137 (100 mg/kg) had statistically significant effects on a number of parameters, including a 27% reduction in inflammation and a 30% reduction in the total lesion area of the lungs by Day 7. Intragastric molnupiravir (300 mg/kg twice daily) significantly inhibited SARS-CoV-2 infection. Conclusions: both RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells. In Syrian hamsters, molnupiravir demonstrated a more pronounced inhibition of SARS-CoV-2 than RPH-137. However, RPH-137 had statistically significant effects on a range of parameters. This offers additional perspectives for further research.
ABSTRACT
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.
ABSTRACT
The pandemic of coronavirus disease 2019, etiologically associated with the SARS-CoV-2 virus, has drawn the attention of the medical community to new clinical and fundamental problems in the immunopathology of human diseases. During a detailed analysis of the clinical manifestations and immunopathological disorders in COVID-19, it became apparent that SARS-CoV-2 infection is accompanied by the development of a wide range of extrapulmonary clinical and laboratory disorders, some of which are characteristic of immunoinflammatory rheumatic diseases and other human autoimmune and autoinflammatory diseases. All this taken together served as a theoretical justification for the repositioning of anti-inflammatory drugs in COVID-19, previously specifically designed for the treatment of immunoinflammatory rheumatic diseases. The prospects for studying the autoimmune mechanisms of COVID-19 and the possibility of anti-inflammatory therapy are discussed.