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

Autor: Devireddy VSR; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201002, India., Shafi H; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Verma S; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India.; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201002, India., Singh S; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Chakradhar JVUS; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Kothuri N; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Bansode H; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Raman SK; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Sharma D; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Azmi L; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India., Verma RK; Institute of Nano Science and Technology, Sector 81, Sahibzada Ajit Singh Nagar, 140306, India., Misra A; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector 10A, Janakipuram Extension, Sitapur Road, Lucknow, 226031, India. amit_misra@cdri.res.in.; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201002, India. amit_misra@cdri.res.in.
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2024 Nov; Vol. 41 (11), pp. 2189-2198. Date of Electronic Publication: 2024 Oct 17.
DOI: 10.1007/s11095-024-03782-3
Abstrakt: 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.
Competing Interests: Declarations. Conflict of Interest: None to declare. Generative AI declaration: No generative AI was used for any purpose.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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