Background

Fluorescent-guided surgery can be used for the identification of anatomical structures and tumors during surgery. Nizaracianine formerly known as ZW800-1, is a fluorophore which is cleared exclusively by the kidneys. Therefore, administration of nizaracianine makes real-time intraoperative imaging of the ureters possible, which can prevent potential risk to the ureters during surgery.  A single dose of nizaracianine has already proven to be safe and useful, however abdominopelvic surgery have long operating time and therefore there can be a need for repeated dose of nizaracianine.

Materials and methods

This phase 1 clinical trial is performed on healthy volunteers to assess the safety, fluorescent properties and pharmacokinetics of nizaracianine in three repeated doses. Four ascending dose levels of nizaracianine were investigated in four cohorts. Tested doses were 3 x 0.5 mg, 3 x 1.0 mg, 3 x 2.5 mg, and 3 x 5.0 mg nizaracianine. A total of 21 subjects were included.

Results

Safety

A total of 40 AEs occurred. Most of these were due to the placement of the Foley catheter. Five potentially related to nizaracianine AEs were observed, which included headache and fatigue.

Fluorescence

In all four dosing cohorts, clear fluorescent signals were visible in the Foley catheter tubing from 5 minutes after dosing and up to 8 hours after the first dose administration (Figure 1). There was no statistically significant difference in the mean of fluorescent intensity (MFI) in arbitrary units (AU) at almost all time points within the different dosing cohorts. Only 15, 150, and 180 minutes after the first dosing the MFI in the Foley catheter tubing was significantly lower in the lowest dosing cohort (p-value: 0.042, 0.040, and 0.039 respectively, Figure 2).

Pharmacokinetics

Plasma and urine concentration levels increased over time and the highest concentration level (C_max) was obtained after the final dose in each cohort. When comparing cohorts, the highest plasma concentration was obtained in the highest dose cohort (3 x 5.0 mg, Table 1). Plasma concentration spikes were clearly detectable directly after each dose, as were decreases in plasma concentration between doses. Nizaracianine was detectable in plasma 6 hours from the last dose.

Conclusion

The administration of nizaracianine in repeated doses appears to be safe. The optimal dosing of repeated doses of nizaracianine should be investigated in clinical trials, in which the fluorescent background signals in the abdominal cavity can be explored.

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