PHARMACOKINETICS, DOSE PROPORTIONALITY, AND TOLERABILITY OF GADOBUTROL AFTER SINGLE INTRAVENOUS-INJECTION IN HEALTHY-VOLUNTEERS

RATIONALE AND OBJECTIVES. Gadobutrol is a new gadolinium-based hydroph ilic and neutral macrocyclic contrast medium for magnetic resonance im aging. In this article, the authors report on the first application of gadobutrol in humans, up to a dose of 0.5 mmol/kg. METHODS. Gadobutro l was investigated after single intravenous administration in two phas e-1 studies testing low (0.5 mol/L) and high concentrations (1 mol/L) in healthy, male volunteers using a double-blind, randomized, placebo- controlled study with n = 55 for the low concentration (0.04, 0.1, 0.2 , 0.3, and 0.4 mmol/kg body weight), followed by n = 36 for the high c oncentration (0.3, 0.4, and 0.5 mmol/kg body weight). Vital signs and laboratory parameters were measured for all dose groups investigated, whereas for the calculation of the pharmacokinetic parameters, the dos e groups 0.04, 0.1, and 0.4 mmol/kg body weight were selected. RESULTS . Gadobutrol was well tolerated up to doses of 0.5 mmol/kg, and no rel evant changes in vital signs and laboratory parameters occurred. The t erminal disposition half-life of gadobutrol in plasma was approximatel y 1.5 hours. Total clearance approximated renal clearance and approxim ated the value of 120 mL/min, indicating glomerular filtration as the main pathway of elimination. The steady-state volume of distribution i ndicated predominantly extracellular distribution of gadobutrol. No me tabolites were detected. The renal excretion rate was linear over the large dose range tested, indicating dose-proportionate, first-order ki netics of gadobutrol. CONCLUSION. Single intravenous administration of gadobutrol was well tolerated up to the dose level of 0.5 mmol/kg bod y weight. These factors suggest that gadobutrol will be a safe magneti c resonance imaging contrast agent.