- Title
- Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep
- Creator
- Weiss, Anne; Bischof, Robert; Landersdorfer, Cornelia; Nguyen, Tri-Hung; Davies, Andrew; Ibrahim, Jibrill; Wynne, Paul; Wright, Phillip; Ditzinger, Gunter; Montgomery, Alan; Meeusen, Els; McIntosh, Michelle; Sommer, Morten
- Date
- 2023
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/197219
- Identifier
- vital:18834
- Identifier
-
https://doi.org/10.1007/s11095-023-03559-0
- Identifier
- ISSN:0724-8741 (ISSN)
- Abstract
- Purpose: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization. Methods: We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups. Results: Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide. Conclusions: Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose. © 2023, The Author(s).
- Publisher
- Springer
- Relation
- Pharmaceutical Research Vol. 40, no. 8 (2023), p. 1915-1925
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- http://creativecommons.org/licenses/by/4.0/
- Rights
- Copyright © 2023, The Author(s)
- Rights
- Open Access
- Subject
- 3214 Pharmacology and pharmaceutical sciences; Nebulization; Niclosamide; Pulmonary pharmacokinetics
- Full Text
- Reviewed
- Funder
- Open access funding provided by Technical University of Denmark. This study was funded by UNION therapeutics A/S and Innovationsfonden Denmark (grant number: 0208-00081). Anne Weiss acknowledges support from Innovationsfonden Denmark (grant 0153-00209). Morten OA Sommer acknowledges funding from The Novo Nordisk Foundation under NNF grant number: NNF20CC0035580.
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