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

RATIONALE AND OBJECTIVES. A series of preclinical tests were undertaken dur ing the developmental process to determine the safety profile of gadoverset amide injection (OptiMARK (R)). METHODS. Acute intravenous, acute intracisternal, and repeated-dose toxicit ies; cardiovascular effects; and genetic and reproductive toxicology charac teristics 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 sho wed a no observable effect level at 3 mmol/kg, Dosed daily for 4 weeks, gad oversetamide injection (0.1 mmol kg(-1) d(-1)) caused no serious irreversib le changes in any organs in rats and dogs, At a dose of 0.1 mmol/kg, gadove rsetamide injection caused no significant (P < 0.05) changes in cardiovascu lar function in anesthetized dogs. Gadoversetamide injection showed no muta genic activity. Fertility, reproductive performance, and postnatal fetal de velopment 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 th e 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 exceedi ng the intended human clinical dose.