Aerosol Inhalation Delivery of Triazavirin in Mice: Outlooks for Advanced Therapy Against Novel Viral Infections

• Published in: Journal of pharmaceutical sciences Vol. 110; no. 3; pp. 1316 - 1322
• Main Authors: Valiulin, Sergey V., Onischuk, Andrey A., Dubtsov, Sergey N., Baklanov, Anatoly M., An'kov, Sergey V., Plokhotnichenko, Maria E., Tolstikova, Tatyana G., Dultseva, Galina G., Rusinov, Vladimir L., Charushin, Valery N., Fomin, Vasily M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2021; American Pharmacists Association®. Published by Elsevier Inc
• Subjects: Administration, Inhalation; Administration, Oral; Aerosols - administration & dosage; Aerosols - pharmacokinetics; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - blood; Antiviral Agents - pharmacokinetics; Antiviral drug; Azoles - administration & dosage; Azoles - blood; Azoles - pharmacokinetics; Bioavailability; Biological Availability; COVID-19 Drug Treatment; Drug aerosol; Drug Delivery Systems - instrumentation; Drug Elimination Routes; Elimination rate; Equipment Design; Humans; Male; Mice; Nebulizers and Vaporizers; Pharmacokinetics; Pulmonary drug delivery; Triazavirin; Triazines - administration & dosage; Triazines - blood; Triazines - pharmacokinetics; Triazoles; Triazavirin; Drug aerosol; Pulmonary drug delivery; Bioavailability; Pharmacokinetics; Elimination rate; Antiviral drug
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2020.11.016

Under pandemic-caused emergency, evaluation of the potential of existing antiviral drugs for the treatment of COVID-19 is relevant. Triazavirin, an antiviral drug developed in Russia for per-oral administration, is involved in clinical trials against SARS-CoV-2 coronavirus. This virus has affinity to epithelial cells in respiratory tract, so drug delivery directly in lungs may enhance therapeutic effect and reduce side effects for stomach, liver, kidneys. We elaborated ultrasonic method of triazavirin aerosol generation and investigated the inhalation delivery of this drug in mice. Mean particle size and number concentration of aerosol used in inhalation experiments are 560 nm and 4 × 105 cm−3, respectively. Aerosol mass concentration is 1.6 × 10−4 mg/cm3. Inhalation for 20 min in a nose-only chamber resulted in 2 mg/kg body delivered dose and 2.6 μg/mL triazavirin concentration in blood plasma. Elimination rate constant determined in aerosol administration experiments was ke = 0.077 min−1, which agrees with the value measured after intravenous delivery, but per-oral administration resulted in considerably lower apparent elimination rate constant of pseudo-first order, probably due to non-linear dependence of absorption rate on triazavirin concentration in gastrointestinal tract. The bioavailability of triazavirin aerosol is found to be 85%, which is about four times higher than for per-oral administration.