Pharmacokinetics and Tolerability of the Cancer-Targeting MRI Contrast Agent MT218 in Healthy Males

Abstract

Objective: The aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males.

Materials and methods: This was a double-blind, randomized, placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.01, 0.02, 0.04, and 0.08 mmol/kg), 4 subjects received MT218 and 2 subjects received placebo (saline) in bolus injections. The highest dose group (0.08 mmol/kg) was assessed in 2 cohorts, 1 fasted and 1 nonfasted. Clinical laboratory tests, vital signs, and electrocardiograms were investigated. Gadolinium concentrations were measured in plasma samples collected before administration and over a 24-hour period postinjection, and in urine specimens collected until 22 days. A noncompartmental model was used for pharmacokinetic analysis. A clinical and biological safety follow-up was carried out for up to 6 months.

Results: No clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, or vital signs were reported at any time point for any treatment group. No serious adverse events were observed in any dose group. Transient dizziness, hyperhidrosis, and injection site coldness were the main adverse events reported in both the MT218 and placebo groups. The mean total apparent clearance decreased slightly with increasing dose, and the median plasma t 1/2 ranged from 1.7 hours in the 0.01 mmol/kg group to 2.7 hours in the 0.08 mmol/kg nonfasted group. MT218 was rapidly excreted via renal filtration with 42.9% to 52.8% of the injected dose measured in urine within the first hour after administration, and 92.5% to 117.3% in urine within 24 hours. No Gd was detected by inductively coupled plasma mass spectrometry in urine after 21 days.

Conclusion: Single intravenous administration of MT218 was safely tolerated in the healthy males. Its pharmacokinetic parameters and safety profile are well aligned with those of other gadolinium-based contrast agents.

Figure 1.

Chemical Structure of ZD2-N3-Gd(HP-DO3A) (MT218).

Figure 2.

Gadolinium plasma concentration – time curve of the 0.01, 0.02, 0.04, and 0.08 (combined) mmol/kg groups. (Error bars are standard deviations)

Figure 3.

Percentage of injected gadolinium urine excretion over 24 h for the dose groups of 0.01, 0.02, 0.04, and 0.08 (combined) mmol/kg.