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

• Published in: Pharmaceutical research 2024-11, Vol.41 (11), p.2189-2198
• Main Authors: Devireddy, Venkata Siva Reddy, Shafi, Hasham, Verma, Sonia, Singh, Sanjay, Chakradhar, J. V. U. S., Kothuri, Naresh, Bansode, Himanshu, Raman, Sunil Kumar, Sharma, Deepak, Azmi, Lubna, Verma, Rahul Kumar, Misra, Amit
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Administration, Oral; Alveoli; Amides - administration & dosage; Amides - pharmacokinetics; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Area Under Curve; Biochemistry; Biological products; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Bronchoalveolar Lavage Fluid - chemistry; Comparative analysis; Drug delivery; Drug delivery systems; Drug dosages; Drug metabolism; Drug therapy; Drugs; Dry Powder Inhalers; Female; Health aspects; Humans; Inhalation; Lung - metabolism; Male; Medical Law; Mice; Oral administration; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Powders; Pyrazines - administration & dosage; Pyrazines - pharmacokinetics; Respiratory agents; Respiratory tract; RNA; RNA Virus Infections - drug therapy; RNA viruses; RNA Viruses - drug effects; Tissue Distribution; Vehicles; Virus diseases
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-024-03782-3

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 (AUC 0-24 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. Graphical Abstract