Walther Niklas, Schultz-Heienbrok Robert, Staß Heino, Corman Victor M, Gassen Nils C, Müller Marcel A, Drosten Christian, Witzenrath Martin, Lee Hweeling, Posch Maximilian G
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Charité Research Organisation GmbH, Berlin, Germany.
PLoS One. 2025 Feb 25;20(2):e0303924. doi: 10.1371/journal.pone.0303924. eCollection 2025.
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).
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.
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 AUClast about 2-fold higher in fed condition compared to fasted condition. In Part B, dose-normalized Cmax and AUClast were similar for niclosamide solution and tablet. Absorption of niclosamide solution was highly variable. Some individuals showed high absorption (Cmax > 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.
Overall safety and tolerability observed in healthy subjects were benign. This is also true for individuals with high absorption (Cmax > 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.
ClinicalTrials.gov NCT04644705.
氯硝柳胺是一种已确定的驱虫物质，也是治疗癌症、病毒感染和其他疾病的有前景的候选药物。然而，它在水性介质中的溶解度较低，市售咀嚼片的全身生物利用度较差，限制了氯硝柳胺在全身治疗中的应用。开发了一种使用聚乙二醇400的口服液体制剂，并在健康志愿者中进行研究，以评估其安全性、耐受性和药代动力学，并与市售片剂进行比较。（ClinicalTrials.gov：NCT04644705）。
该研究包括三个部分：A部分是一项双盲安慰剂对照的单剂量递增试验，分为三个剂量组（200、600和1600mg），四名参与者在禁食和/或进食条件下接受研究用氯硝柳胺制剂或安慰剂（3:l）。B部分是一项交叉研究，在四名健康志愿者中比较1600mg研究用氯硝柳胺溶液与市售2000mg咀嚼片。C部分是一项双盲安慰剂对照的多剂量试验，比较两个剂量组（1200mg和1600mg，试验组：安慰剂4:2），每组六名受试者，每日给药，持续七天。
未发生严重或重度不良事件。最常见的不良事件是轻度至中度胃肠道反应。药物暴露水平（AUC、Cmax）与可检测到的不良事件的严重程度和发生率之间也没有明显相关性。观察到了明显的食物效应，进食条件下的平均末次AUC比禁食条件下高约2倍。在B部分中，氯硝柳胺溶液和片剂的剂量标准化Cmax和末次AUC相似。氯硝柳胺溶液的吸收差异很大。一些个体显示出高吸收（Cmax>2μg/ml），而另一些个体仅少量吸收。重要的是，在200mg至1600mg范围内没有剂量线性关系。多次给药后未观察到相关的全身药物蓄积迹象。
在健康受试者中观察到的总体安全性和耐受性良好。对于高吸收个体（Cmax>2μg/ml）也是如此，这鼓励对氯硝柳胺作为潜在治疗药物进行进一步研究。然而，从观察到的暴露变异性和非线性药代动力学来看，剂型优化仍将具有挑战性。如果其他数据证实存在非线性，可能会使氯硝柳胺更适合多剂量而非高单剂量方案。在进一步研究氯硝柳胺全身暴露时，也应考虑观察到的食物效应。
ClinicalTrials.gov NCT04644705。
