Journal Article

Comparative Preclinical Pharmacokinetics and Disposition of Favipiravir Following Pulmonary and Oral Administration as Potential Adjunct Therapy Against Airborne RNA Viruses

Singh, Sanjay, Azmi, Lubna, Misra, Amit, Chakradhar, J. V. U. S, Verma, Rahul Kumar, Bansode, Himanshu, Sharma, Deepak, Shafi, Hasham, Kothuri, Naresh, Verma, Sonia, Raman, Sunil Kumar, Devireddy, Venkata Siva Reddy

2024

Overview

BackgroundFavipiravir is administered orally, even against airborne RNA viruses, in a loading-dose/maintenance dose regimen. We investigated whether—(a) pulmonary delivery of favipiravir would generate high concentrations in the luminal side of the respiratory tract; and (b) avoiding first-pass metabolism by the liver by inhaled drug would generate comparable pharmacokinetics (PK) with doses significantly smaller than the oral maintenance dose.MethodsA dry powder inhalation (DPI) of favipiravir formulated by mixing with Inhalac 400® was prepared and characterized. Inhalations of ~ 120 µg dose strength, with or without a prior oral loading dose were administered to mice. Comparator mice received human-equivalent oral doses (3 mg). Three mice per sampling time point were sacrificed and favipiravir concentrations in the blood plasma, bronchio-alveolar lavage fluid (BALF) and lung tissue homogenate determined by HPLC.ResultsOne-compartment PK modeling of concentration–time data indicated that the area under the curve (AUC0-24 h) generated in the BALF recovered from mice receiving inhalations of ~ 1/25th of the oral dose subsequent to an oral loading dose was 86.72 ± 4.48 µg⋅mL−1⋅h. This was consistently higher than the AUC observed in the BALF of orally-dosed mice (56.71 ± 53.89 µg mL−1⋅h). In blood serum, the respective values of AUC were 321.55 ± 124.91 and 354.71 ± 99.60 µg⋅mL−1⋅h.ConclusionPulmonary delivery of significantly smaller doses of favipiravir generates meaningful drug disposition and pharmacokinetics at the site of respiratory viral infections. We provide the rationale for designing a self-administered, non-invasive, low-cost, targeted drug delivery system against airborne RNA virus infection.

• Publisher: Springer Nature B.V
• Subject: Alveoli / Drug delivery / Drug dosages / Drug metabolism / Drug therapy / Inhalation / Oral administration / Pharmacokinetics / Respiratory tract / RNA viruses