Objective: To obtain initial data on the safety and efficacy of a novel polymeric, synthetic blood pool contrast agent [O-monomethoxypoly(ethylene glycol)-O'succinyl]poly(N-epsilon-L-lysyl [99mTc]diethylenetriamine pentaacetate monoamide, we performed a preclinical evaluation and phase 1 clinical trial under an investigator-sponsored investigational new drug application.
Materials and methods: Methoxypoly(ethylene glycol)ethylenetriaminopentaacetic acid was formulated into a kit containing the polymer, stannous chloride, and a buffer. Kits were stored in frozen form for subsequent labeling with technetium-99m. Acute and subacute toxicity studies were carried out in rats and rabbits. Healthy human volunteers (n = 6) were then enrolled in a prospective, open-label phase 1 clinical study.
Results: Animal studies showed no signs of acute or subacute toxicity at doses 280 times the proposed dose for humans. In the clinical trial with humans, no significant abnormalities of laboratory values, ECG findings, or hemodynamic parameters were seen. One volunteer experienced facial flushing and palpitations. Four volunteers showed typical blood pool biodistribution, with a blood half-life of 20.6 +/- 2.3 hr. At 24 hr after administration, 22.1% +/- 2.5% of the injected dose had been excreted through the kidneys. Two other volunteers showed a different biodistribution (primarily to liver and spleen), presumably associated with labeling instability.
Conclusion: Synthetic methoxypoly(ethylene glycol)-grafted polymers can have long circulation times in humans. Pharmaceuticals based on such polymers are expected to have clinical applications in cardiovascular imaging, gastrointestinal bleeding studies, and capillary leak imaging.