title: Non-clinical safety assessment of gadoterate meglumine (Dotarem(®)) in neonatal and juvenile rats.
abstract: The purpose of this study was to assess the safety of gadoterate meglumine, a gadolinium-based contrast agent used in magnetic resonance imaging, in neonatal and juvenile rats. Rats received a single intravenous administration on postnatal day (PND) 10 or 6 administrations (from PND 10 to 30), at doses of 0, 0.6, 1.25, and 2.5 mmol/kg/administration, i.e. equivalent to approximately 1, 2 and 4-times the usual human dose. The animals were sacrificed at the end of the treatment period or after a 60-day treatment-free period. No mortality and no significant treatment-related effect on clinical signs, macroscopic and histopathological findings, development, behavior, sexual maturation and hematology parameters were observed. Minor non-adverse changes were observed in clinical biochemistry and urinary parameters. Based on AUC0-t, gadoterate meglumine was more rapidly eliminated at PND 30 vs. PND 10, reflecting maturation of kidney function. At the end of the treatment period, Gd was measurable in all organs sampled after single or repeated dosing and levels were dose-dependent as expected, the highest ones being found in kidneys. The total Gd concentrations were similar in all the organs following a single or repeated dosing. At the end of the treatment-free period, only traces of gadolinium were quantifiable, almost exclusively in kidneys, reflecting the excretory function of this organ. In conclusion, single or repeated administration of gadoterate meglumine to juvenile rats was well tolerated.
authors.affiliation: WIL Research Europe, 329 Impasse du Domaine Rozier, Les Oncins, 69210 Saint-Germain-Nuelles, France. Electronic address: herve.giorgi@wilresearch.com.
authors.forename: Hervé
authors.initials: H
authors.lastname: Giorgi
authors.affiliation: MPI Research, 54943 N. Main Street, Mattawan, MI 49071, USA. Electronic address: Jennifer.Ammerman@mpiresearch.com.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ammerman
authors.affiliation: WIL Research Europe, 329 Impasse du Domaine Rozier, Les Oncins, 69210 Saint-Germain-Nuelles, France. Electronic address: jean-paul.briffaux@wilresearch.com.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Briffaux
authors.affiliation: Guerbet-Group, BP 57400, 95943 Roissy CDG Cedex, France. Electronic address: nathalie.fretellier@guerbet-group.com.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fretellier
authors.affiliation: Guerbet-Group, BP 57400, 95943 Roissy CDG Cedex, France. Electronic address: claire.corot@guerbet-group.com.
authors.forename: Claire
authors.initials: C
authors.lastname: Corot
authors.affiliation: Guerbet-Group, BP 57400, 95943 Roissy CDG Cedex, France. Electronic address: philippe.bourrinet@guerbet-group.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourrinet
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D008536:Meglumine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination; D018570:Risk Assessment; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; D008536:Meglumine; C072417:gadoterate meglumine
keywords: Contrast agents; Gadolinium; Gadolinium-based contrast agent; Juvenile toxicity; Safety