Preclinical safety evaluation of Gd-EOB-DTPA (Primovist).

OBJECTIVES: Gadoxetic acid [gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA); Primovist] is a liver specific contrast agent for magnetic resonance imaging. For risk assessment of the single diagnostic use the toxicity of this compound was assessed. MATERIALS AND METHODS: Studies into acute, repeated-dose, reproductive and developmental toxicity, and local tolerance, contact sensitizing, and genotoxic potential were performed. RESULTS: Lethality was observed after a single intravenous administration at doses 2 orders of magnitude higher than the clinical dose. The no observed adverse effect levels after repeated administration markedly exceeds the single diagnostic dose in humans and no unexpected organ toxicity was observed. No indications of reproductive and developmental toxicity, potential contact allergenic, and genotoxic effects were observed. Gd-EOB-DTPA was well tolerated after intravenous administration. CONCLUSIONS: Gd-EOB-DTPA was well tolerated with high safety margins between the single diagnostic dose and the doses showing adverse effects in animal studies.

Preclinical safety assessment of Vasovist (Gadofosveset trisodium), a new magnetic resonance imaging contrast agent for angiography.

OBJECTIVES: Vasovist (EPIX Pharmaceuticals and Schering AG) is a newly developed blood pool contrast agent for magnetic resonance imaging with a high affinity for human albumin, making it an ideal tool for the detection of structural abnormalities such as stenosis and aneurysm. For the risk assessment of the single diagnostic use in patients, the toxicity of this compound was investigated. MATERIALS AND METHODS: Studies of acute, repeated-dose, reproductive, and developmental toxicity as well as local tolerance, immunotoxicity, and mutagenic potential were performed. RESULTS: Lethality was observed in rodents after single intravenous administration at doses of at least 2 orders of magnitude higher than the anticipated human dose of 0.03 mmol/kg. The no observed adverse effect level after repeated daily administration over the course of 4 weeks to monkeys exceeded the single diagnostic dose by a factor of 3.3. The main effect of repeated dosing in both rats and monkeys was vacuolation in kidney proximal tubules without concomitant effect on kidney function. Studies into reproduction toxicity have shown no evidence of effects on fertility or perinatal and postnatal development. Signs of embryo-fetal toxicity were observed in rabbits after repeated administration of high doses. No indications of immunotoxic and mutagenic effects were observed. In local tolerance testing, Vasovist was well tolerated after intravenous administration. CONCLUSIONS: Vasovist was well tolerated with reasonable safety margins between the single diagnostic dose of 0.03 mmol/kg in humans and the doses resulting in adverse effects in animal studies.