Background: Favipiravir 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.
Methods: A 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.
Results: One-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.
Conclusion: Pulmonary 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.
Keywords: Dry powder inhalation; Preclinical pharmacokinetics; Pulmonary drug delivery; antiviral; favipiravir.
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.