RESUMEN
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.
RESUMEN
Favipiravir has demonstrated efficacy against the SARS-CoV-2 virus in several preliminary studies. This study aimed to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate COVID-19 in outpatients and hospitalized patients. We conducted an open-label, randomized, active-controlled trial of a generic form of favipiravir in patients with COVID-19 confirmed by PCR-test. Eligible patients (18-60 years) after stratification were randomly assigned (in a 2:1 ratio) to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for up to 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine) for up to 10 days. The co-primary outcomes were the time to clinical improvement and the time to viral clearance. Among 190 patients assessed for eligibility 168 were randomized to favipiravir (n=112) or to SOC (n=56) group. The median time to clinical improvement was 6.0 days (IQR 4.0;9.3) in the favipiravir group and 10.0 (IQR 5.0;21.0) days in the SOC group;the median difference was 4 days (HR 1.63;95% CI 1.14-2.34;P=0.007). The statistically significant difference in the median time to viral clearance was observed only for hospitalized patients: 3.0 (IQR 3.0;3.0) days in the favipiravir group vs. 5.0 (IQR 4.5;5.5) days in the SOC group (HR 2.11;95% CI 1.04-4.31;P=0.038). The rate of viral elimination on Day 5 in the favipiravir group was significantly higher than in SOC group: 81.2% vs. 67.9% (RR 1.22;05% CI 1.00-1.48;P=0.022). The rate of clinical improvement on Day 7 in the favipiravir group was 1.5-fold higher than in SOC group: 52.7% vs. 35.8% (RR 1.50;95% CI 1.02-2.22;P=0.020). Favipiravir was well-tolerated and the most common adverse reactions were asymptomatic hyperuricemia, transient elevation of ALT & AST, and mild gastrointestinal disorders. Favipiravir was superior to the SOC in shortening the time to clinical improvement in patients with mild to moderate COVID-19.