Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers.
OBJECTIVE
Gadobutrol is a new gadolinium-based hydrophilic and neutral macrocyclic contrast medium for magnetic resonance imaging. In this article, the authors report on the first application of gadobutrol in humans, up to a dose of 0.5 mmol/kg.


METHODS
Gadobutrol was investigated after single intravenous administration in two phase-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 concentration (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 dose 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 relevant changes in vital signs and laboratory parameters occurred. The terminal disposition half-life of gadobutrol in plasma was approximately 1.5 hours. Total clearance approximated renal clearance and approximated the value of 120 mL/min, indicating glomerular filtration as the main pathway of elimination. The steady-state volume of distribution indicated predominantly extracellular distribution of gadobutrol. No metabolites were detected. The renal excretion rate was linear over the large dose range tested, indicating dose-proportionate, first-order kinetics of gadobutrol.


CONCLUSIONS
Single intravenous administration of gadobutrol was well tolerated up to the dose level of 0.5 mmol/kg body weight. These factors suggest that gadobutrol will be a safe magnetic resonance imaging contrast agent.
Institute of Human Pharmacology, Schering AG, Berlin, Germany.
T
T
Staks
G
G
Schuhmann-Giampieri
T
T
Frenzel
H J
HJ
Weinmann
L
L
Lange
J
J
Platzek
D000328:Adult; D003287:Contrast Media / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D005243:Feces / Q000737:chemistry; D005682:Gadolinium / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D010919:Placebos; D012449:Safety
D003287:Contrast Media; D009942:Organometallic Compounds; D010919:Placebos; C090600:gadobutrol; D005682:Gadolinium