Phase I Pharmacokinetics Study of Drug for Infusion «Areplivir» (INN: Favipiravir) (LLC "PROMOMED RUS", Russia)

Abstract

Introduction. The novel coronavirus infection COVID-19 (Coronavirus Disease 2019) is caused by an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) virus SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2). Favipiravir is the antiviral drug recommended for etiotropic treatment of COVID-19. Parenteral therapy has advantages over the other routes of the drug administration: there are no interaction with food and digestive enzymes, may be used for patients with diseases of the digestive system and unconscious patients. For parenteral drug administration of favipiravir the drug "Areplivir" has been registered in Russia. Aim. The aim is pharmacokinetics study of drug "Areplivir", a lyophilisate for the preparation of a concentrate for the infusion solution (the manufacturer is JSC "Biokhimic", LLC "Promomed RUS" as registration certificate holder) by intravenous infusion in healthy volunteers in a phase I pharmacokinetics study. Materials and methods. The clinical and analytical phases of the pharmacokinetic study as well as pharmacokinetic analyses have been performed as part of a clinical trial of the drug "Areplivir" in different doses, a lyophilisate for the preparation of a concentrate for the infusion solution (LLC "Promomed RUS", Russia). Chromatographic separation and detection were carried out on a LC-2040C high-performance liquid chromatograph (Shimadzu Corporation, Japan) with a built-in UV detector, a low-pressure four-component gradient pump, a degasser, an autosampler, a column thermostat and a controller. The pharmacokinetic parameters were calculated with the Boomer pharmacokinetic analysis add-in for Microsoft Excel (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA). Descriptive pharmacokinetic statistics were calculated with Microsoft Excel (Microsoft Corporation, USA). Correlation and Regression Analysis were conducted with IBM SPSS Statistics (version 23.0), IBM, USA. Results and discussion. For single dose administration of 400, 800, 1600 and 1800 mg in 4 cohorts of 5 volunteers pharmacokinetic parameters were calculated. For C max and an administered dose the strong correlation coefficient on the Chaddock scale ( r = 0,98; p = 0,02; r – Pearson correlation coefficient; p – the reached significance value) and the determination coefficient ( R 2 = 0,96; F = 45,97; p = 0,02; R 2 – determination coefficient; F – the actual value of the Fisher's criterion) were statistically significant. For AUC 0- t and an administered dose the strong correlation coefficient on the Chaddock scale ( r = 0,97; p = 0,03) and the determination coefficient ( R 2 = 0,94; F = 33,54; p = 0,03) were statistically significant. The obtained results show the linearity of C max and an administered dose and the linearity of AUC 0- t and an administered dose (400–1800 mg). Conclusion. According to the concentrations of favipiravir from the analytical phase of the pharmacokinetic study the pharmacokinetic parameters were calculated, averaged pharmacokinetic profiles in linear and log-linear scales were plotted after single dose administrations of the drug "Areplivir" in different doses, a lyophilisate for the preparation of a concentrate for the infusion solution (LLC "Promomed RUS", Russia). The linearity of C max and a single administered dose and the linearity of AUC 0- t and a single administered dose of the drug "Areplivir" have been demonstrated for doses of 400 to 1800 mg. The results justified the study of multiple dose administration of "AREPLIVIR" and the subsequent phases of clinical trials.