Evaluation of Gadolinium-Based Contrast Agents in Juvenile Non-Human Primates Including Behavioral Evaluations Such...

The US Food and Drug Administration (FDA) requested the four Gadolinium-Based Contrast Agents (GBCA) New Drug Application (NDA) holders to investigate the effects of gadolinium (Gd) retention on fetal and neonatal development in mice and juvenile non-human primates (NHP) as well as the effects of repeated GBCA administrations on behavioral, neurological, and histopathological endpoints.

Two linear (gadodiamide and gadobenate dimeglumine) and one macrocyclic (gadobutrol) GBCA, intended to be representative of linear non-ionic, linear ionic, and macrocyclic GBCAs, were investigated in a juvenile toxicity study in the cynomolgus monkey. Clinical observations, body weight, food consumption, clinical chemistry, full histopathology, and behavioral/neurological parameters including learning and memory were assessed. Additionally, Gd was quantified in the brain and other selected organs/tissues. A total of 84 juvenile animals (n = 12/group) were intravenously dosed every 4 weeks from postnatal day 28 for a total of 8 administrations over 29 weeks. Evaluation at the end of dosing, or after a recovery phase, was conducted to assess the reversibility of any observed effects. Necropsy was performed on Day 198 of the dosing phase for four animals/group and Day 365 of the recovery phase for the remaining eight animals/group.

No GBCA-related adverse effects were observed in juvenile cynomolgus monkeys either at the end of the dosing or recovery periods. The no-observed-effect-levels (NOEL) for gadobutrol and gadodiamide administration were 0.9 mmol/kg and, for gadobenate dimeglumine, 0.3 mmol/kg (due to a non-adverse difference in learning during the recovery phase in the high dose group). The no-observed-adverse-effect-level (NOAEL) for all GBCAs was established as at least 0.9 mmol/kg.

Gd levels observed in brain tissue of cynomolgus monkey after juvenile exposure to multiples of equivalent clinical doses of all GBCAs tested did not correlate with any adverse morphological or functional findings. This study showed no evidence that exposure to GBCA during development presents a potential risk for long-term effects such as behavioral, neurological, or histopathological findings in the brain, and/or impaired learning or memory.