Toxicological Safety Evaluation of Gadobutrol

Abstract

Gadobutrol (Gadovist/Gadavist, Bayer Pharma AG, Berlin, Germany) is a nonionic, macrocyclic, gadolinium-based contrast agent for magnetic resonance imaging of the central nervous system as well as liver and kidneys and for contrast enhancement in magnetic resonance angiography. For risk assessment of the single diagnostic use in humans, the toxicity of this compound was evaluated with a series of preclinical studies. Preclinical studies into acute, repeated-dose, reproductive, and developmental toxicity as well as genotoxicity, local tolerance, contact-sensitizing potential, and antigenicity were performed. In rodents, lethality was observed after a single intravenous administration of 20 mmol/kg, representing doses at least 2 orders of magnitude higher than the standard single diagnostic dose in humans (0.1 mmol/kg). The no observed adverse effect levels after repeated (daily) administrations over the course of 4 weeks exceeded the single diagnostic dose in humans by a factor of 12 in rats and 10 in dogs (calculated on the basis of body weight), and no unexpected organ toxicity was observed. The most salient finding of repeated dosing in both rats and dogs was vacuolization of renal tubular epithelium without concomitant effect on kidney function, which represents a well-known finding for this class of compounds. Gadobutrol was not teratogenic in rats, rabbits, and monkeys even when given repeatedly during organogenesis at maximum dose levels tested, being 25 to 100 times (based on body weight) above the diagnostic dose in humans. No indications of potential genotoxic, contact allergenic, or immunotoxic effects were observed. In local tolerance testing, gadobutrol was well tolerated after intravenous administration. Gadobutrol was well tolerated with high safety margins between the single diagnostic dose of 0.1 mmol/kg in humans and the doses showing effects in animal studies.