Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep

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...

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Bibliographic Details
Published in:Pharmaceutical research 2023-08, Vol.40 (8), p.1915-1925
Main Authors: Weiss, Anne, Bischof, Robert J, Landersdorfer, Cornelia B, Nguyen, Tri-Hung, Davies, Andrew, Ibrahim, Jibriil, Wynne, Paul, Wright, Phillip, Ditzinger, Günter, Montgomery, A Bruce, Meeusen, Els, McIntosh, Michelle P, Sommer, Morten OA
Format: Article
Language:English
Subjects:
Analysis
Bioavailability
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Dosage and administration
Ethanolamine
Ethanolamines
Gastrointestinal system
Gastrointestinal tract
Health aspects
Intranasal administration
Intravenous administration
Medical Law
Niclosamide
Oral administration
Original
Original Research Article
Pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Pulmonary function tests
Respiratory function
Sheep
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Summary: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.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-023-03559-0