Smieja Daniela, Czupalla Oliver, Günther Clemens, Bussi Simona, Coppo Alessandra, Jones Paul, Forni Matilde, Fretellier Nathalie, Bourrinet Philippe, Luetjens C Marc
Labcorp Early Development Services GmbH, Münster, Germany.
Bayer AG, Berlin, Germany.
Birth Defects Res. 2025 Apr;117(4):e2470. doi: 10.1002/bdr2.2470.
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.
美国食品药品监督管理局（FDA）要求四种钆基造影剂（GBCA）新药申请（NDA）持有人研究钆（Gd）潴留对小鼠和幼年非人灵长类动物（NHP）胎儿及新生儿发育的影响，以及重复使用GBCA对行为、神经和组织病理学终点的影响。
在食蟹猴的幼年毒性研究中，对两种线性（钆双胺和钆贝葡胺）和一种大环（钆布醇）GBCA进行了研究，旨在分别代表线性非离子型、线性离子型和大环型GBCA。评估了临床观察、体重、食物摄入量、临床化学、全组织病理学以及包括学习和记忆在内的行为/神经参数。此外，还对大脑和其他选定器官/组织中的Gd进行了定量分析。从出生后第28天开始，每4周对总共84只幼年动物（每组n = 12只）进行静脉给药，在29周内共给药8次。在给药结束时或恢复期后进行评估，以评估任何观察到的影响的可逆性。在给药阶段的第198天对每组4只动物进行尸检，在恢复期的第365天对其余每组8只动物进行尸检。
在给药期或恢复期结束时，未在幼年食蟹猴中观察到与GBCA相关的不良反应。钆布醇和钆双胺给药的未观察到效应水平（NOEL）为0.9 mmol/kg，钆贝葡胺为0.3 mmol/kg（由于高剂量组在恢复期学习方面存在非不良反应差异）。所有GBCA的未观察到不良反应水平（NOAEL）确定为至少0.9 mmol/kg。
在幼年食蟹猴接触所有测试GBCA等效临床剂量倍数后，其脑组织中观察到的Gd水平与任何不良形态或功能发现均无相关性。本研究表明，没有证据表明在发育过程中接触GBCA会对大脑产生行为、神经或组织病理学发现以及学习或记忆受损等长期影响构成潜在风险。
