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
Niklas Walther, Robert Schultz-Heienbrok, Heino Staß, Victor M Corman, Nils C Gassen, Marcel A Müller, Christian Drosten, Martin Witzenrath, Hweeling Lee, Maximilian G Posch
doi:10.1101/2024.05.06.24306928
Aim Niclosamide is an established anthelmintic substance and a promising candidate for treating cancer, viral infections, and other diseases. However, its solubility in aqueous media is low, and the systemic bioavailability of the commercially available chewing tablet is poor, limiting the use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene glycol 400 was developed and investigated in healthy volunteers to assess safety, tolerability, and pharmacokinetics in comparison to the marketed tablet. (ClinicalTrials.gov: NCT04644705)
Methods The study consisted of three parts: Part A was a double-blind placebo-controlled single ascending dose trial in three dose groups (200, 600, and 1600 mg) with four participants receiving either the investigational niclosamide formulation or placebo (3:1) under fasted and/or fed conditions. Part B was a crossover study comparing 1600 mg investigational niclosamide solution with the marketed 2000 mg chewing tablet in four healthy volunteers. Part C was a double-blind placebo-controlled multiple-dose trial comparing 1200 mg and 1600 mg (verum: placebo 4:2) in two dose groups with six subjects each, who received daily doses for seven days.
Results . .
Supporting information
S1
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Aim</jats:title><jats:p>Niclosamide is '
'an established anthelmintic substance and a promising candidate for treating cancer, viral '
'infections, and other diseases. However, its solubility in aqueous media is low, and the '
'systemic bioavailability of the commercially available chewing tablet is poor, limiting the '
'use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene '
'glycol 400 was developed and investigated in healthy volunteers to assess safety, '
'tolerability, and pharmacokinetics in comparison to the marketed tablet. '
'(ClinicalTrials.gov:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" '
'ext-link-type="clintrialgov" '
'xlink:href="NCT04644705">NCT04644705</jats:ext-link>)</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The '
'study consisted of three parts: Part A was a double-blind placebo-controlled single ascending '
'dose trial in three dose groups (200, 600, and 1600 mg) with four participants receiving '
'either the investigational niclosamide formulation or placebo (3:1) under fasted and/or fed '
'conditions. Part B was a crossover study comparing 1600 mg investigational niclosamide '
'solution with the marketed 2000 mg chewing tablet in four healthy volunteers. Part C was a '
'double-blind placebo-controlled multiple-dose trial comparing 1200 mg and 1600 mg (verum: '
'placebo 4:2) in two dose groups with six subjects each, who received daily doses for seven '
'days.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>No serious or '
'severe adverse events occurred. The most frequent adverse events were mild to moderate '
'gastrointestinal reactions. There was also no apparent dependence between drug exposure '
'levels (AUC, Cmax) and the severity and incidence of adverse events detectable. A relevant '
'food effect was observed with a mean AUC<jats:sub>last</jats:sub>about 2-fold higher in fed '
'condition compared to fasted condition. In Part B, dose-normalized '
'C<jats:sub>max</jats:sub>and AUC<jats:sub>last</jats:sub>were similar for niclosamide '
'solution and tablet. Absorption of niclosamide solution was highly variable. Some individuals '
'showed high absorption (C<jats:sub>max</jats:sub>>2µg/ml) whereas others did absorb only '
'marginally. Importantly, there was no dose linearity in the range of 200 mg – 1600 mg. No '
'signs of relevant systemic drug accumulation after multiple administrations were '
'observed.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Overall '
'safety and tolerability observed in healthy subjects were benign. This is also true for '
'individual “high absorbers” (C<jats:sub>max</jats:sub>>2µg/ml), encouraging further '
'research into niclosamide as a potential therapeutic agent. Galenic optimization, however, '
'will remain challenging as evident from the observed exposure variability and non-linear PK. '
'Non-linearity, if confirmed by additional data, might make niclosamide more suitable for '
'multi-dose rather than high single dose regimens. The observed food effect should also be '
'considered when further investigating systemic niclosamide exposures.</jats:p></jats:sec>',
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