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

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Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2023-07-27 , DOI: 10.1007/s11095-023-03559-0
Anne Weiss _{1,

2} , Robert J Bischof _{3,

4,

5} , Cornelia B Landersdorfer ₅ , Tri-Hung Nguyen ₅ , Andrew Davies ₆ , Jibriil Ibrahim _{4,

5} , Paul Wynne ₅ , Phillip Wright ₅ , Günter Ditzinger ₇ , A Bruce Montgomery ₈ , Els Meeusen _{3,

4} , Michelle P McIntosh ₅ , Morten Oa Sommer _{2,

7}

Affiliation

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.

中文翻译：

氯硝柳胺乙醇胺雾化剂在绵羊体内的单剂量药动学和肺功能

目的

氯硝柳胺被批准作为口服驱虫药，但其低口服生物利用度阻碍了其在胃肠道外需要高药物暴露的医疗用途。已开发出一种使用乙醇胺盐雾化和鼻内给药的氯硝柳胺优化解决方案，并在第一阶段试验中进行了测试。在本研究中，我们调查了通过静脉注射、口服或雾化给药后氯硝柳胺的肺部暴露量。

方法

我们对绵羊体内三种递增剂量的雾化氯硝柳胺的血浆和肺部药代动力学进行了表征，将其与静脉注射氯硝柳胺进行区室 PK 模型比较，并与人体等效批准的 2 g 口服剂量进行比较，以研究不同氯硝柳胺给药途径的肺部暴露。对五只羊进行单剂量给药后，测定了血浆和上皮衬里液（ELF）中的氯硝柳胺浓度。非房室和房室模型用于表征药代动力学特征。所有剂量组均进行肺功能测试。