Toxicological assessment of gadoversetamide injection (OptiMARK®), a new contrast-enhancement agent for use in magnetic resonance imaging

RATIONALE AND OBJECTIVES. A series of preclinical tests were undertaken during the developmental process to determine the safety profile of gadoversetamide injection (OptiMARK (R)). METHODS. Acute intravenous, acute intracisternal, and repeated-dose toxicities; cardiovascular effects; and genetic and reproductive toxicology characteristics were assessed in several animal species. RESULTS. Gadoversetamide injection demonstrated an acute intravenous median lethal dose of 25 to 28 mmol/kg and a maximum nonlethal dose of 14 mmol/kg in mice. In the dog, acute administration of gadoversetamide injection showed a no observable effect level at 3 mmol/kg, Dosed daily for 4 weeks, gadoversetamide injection (0.1 mmol kg(-1) d(-1)) caused no serious irreversible changes in any organs in rats and dogs, At a dose of 0.1 mmol/kg, gadoversetamide injection caused no significant (P < 0.05) changes in cardiovascular function in anesthetized dogs. Gadoversetamide injection showed no mutagenic activity. Fertility, reproductive performance, and postnatal fetal development were not affected at doses up to 0.5 mmol.kg(-1).d(-1) in the rat. No teratogenicity was observed at doses up to 4.2 mmol kg(-1).d(-1) in the rat and up to 1.6 mmol.kg(-1).d(-1) in the rabbit. CONCLUSIONS. Data from our toxicological assessment demonstrate the safety of gadoversetamide injection in a number of animal species at doses exceeding the intended human clinical dose.