An Open Label, Cross-Over Phase 1 Study to Determine the Safety, Tolerability and Pharmacokinetics of Multiple Oral Doses of Niclosamide Under Fed and Fasted Conditions in Healthy Volunteers.

Background/

Objectives

Niclosamide is an U.S. Food and Drug Administration (FDA)-approved antihelminthic drug with a long-established safety profile and demonstrated in vitro antiviral activity against Zika virus. Its evaluation for systemic indications has been limited by its poor oral bioavailability. This Phase I study assessed whether oral administration of the approved niclosamide formulation could achieve plasma concentrations comparable to those with reported antiviral activity.

Methods

This single-center, open-label, randomized, two-period crossover Phase I study evaluated the safety, tolerability, and pharmacokinetics of oral niclosamide in healthy adult volunteers. Twelve participants received niclosamide 2 g once daily for three consecutive days under fed or fasted conditions, followed by crossover after a 14-day washout period. Plasma niclosamide concentrations were quantified using a validated Liquid Chromatography-Mass Spectrometry (LC-MS/MS) assay, and pharmacokinetic parameters were derived via non-compartmental analysis. Safety assessments included adverse event monitoring, clinical laboratory testing, vital signs, electrocardiograms, and physical examinations.

Results

Nine participants per protocol completed the study. Niclosamide was safe and well tolerated under both fed and fasted conditions, with only mild to moderate, transient adverse events and no serious or severe events. Systemic exposure was markedly higher following fed administration, with mean maximum observed plasma concentration (Cmax) and Area Under the Curve (AUC) values several-fold greater than those observed under fasted conditions. Under fed conditions, mean plasma niclosamide concentrations exceeded the reported in vitro Zika virus half-maximal inhibitory concentration (IC50) (0.22 µM) for approximately 9 h post-dose on both Day 1 and Day 3. Fasted administration did not consistently achieve this exposure threshold. No unexpected accumulation was observed with repeated once-daily dosing.

Conclusions

Oral niclosamide administered at the approved daily dose of 2 g is safe and well tolerated in healthy volunteers. Administration with food substantially enhances systemic exposure and transiently achieves plasma concentrations associated with in vitro antiviral activity against Zika virus. These findings support further development of optimized niclosamide formulations to achieve sustained systemic exposure for antiviral therapeutic applications.