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

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.

Niclosamide, but not ivermectin, inhibits anoctamin 1 and 6 and attenuates inflammation of the respiratory tract

“…Delivery to airways of nebulized niclosamide is currently explored and was found to be well tolerated in clinical trials. Local delivery of niclosamide allows higher concentrations in the airway surface liquid, improves pharmacokinetic profiles and lowers systemic concentrations, thereby reducing toxicity [ 4 , 57 , 81 ]. The present data show positive effects of niclosamide and no toxicity even when applied at high concentrations to asthmatic mouse airways (Fig.…”

Clinical safety and pharmacokinetics of a novel oral niclosamide formulation compared with marketed niclosamide chewing tablets in healthy volunteers: a three-part randomized, double-blind, placebo-controlled trial

“…This variability further limits the value of Yomesan© for clinical use in other indications that require systemic exposure. Other formulations like niclosamide-loaded nanoparticles or inhalable/intranasal formulations are being developed and tested [10, 11, 12, 13, 14].…”

Predicting lung exposure of intramuscular niclosamide as an antiviral agent: Power‐law based pharmacokinetic modeling

“…22 To enable successful repurposing, efforts have focused on developing novel formulations such as inhalation powders or nanoparticles to enhance systemic exposure. [23][24][25][26][27][28] Notably, researchers such as Yang et al have explored modifying niclosamide into a prodrug to improve absorption and have developed a physiologically-based pharmacokinetic (PBPK) model proposing an effective oral administration regimen for achieving effective drug concentration in the lungs in COVID therapy. 29 While injections are a reliable method for improving bioavailability issues and are preferred for administering antibiotics, vaccines, and macromolecules, frequent dosing can be inconvenient due to their invasiveness.…”

“… 22 To enable successful repurposing, efforts have focused on developing novel formulations such as inhalation powders or nanoparticles to enhance systemic exposure. 23 , 24 , 25 , 26 , 27 , 28 Notably, researchers such as Yang et al. have explored modifying niclosamide into a prodrug to improve absorption and have developed a physiologically‐based pharmacokinetic (PBPK) model proposing an effective oral administration regimen for achieving effective drug concentration in the lungs in COVID therapy.…”

“…While suitable for local parasitic intestinal infections 21 its systemic efficacy for COVID‐19 therapy has been limited in recent studies 22 . To enable successful repurposing, efforts have focused on developing novel formulations such as inhalation powders or nanoparticles to enhance systemic exposure 23–28 . Notably, researchers such as Yang et al.…”