Overall Gadolinium Exposure Within the First 5 Months After Injection of Human Equivalent Doses of Gadopiclenol, Gadoterate, or Gadobutrol in Healthy Rats.

Introduction: Gadopiclenol is a high relaxivity macrocyclic and nonionic Gadolinium-Based Contrast Agent (GBCA) for central nervous system (CNS) and Body MRI, approved in September 2022 by the Food and Drug Administration and in December 2023 by the European Medicine Agency and others European health authorities. Gadopiclenol is currently indicated at half gadolinium-dose (0.05 mmol/kg body weight) compared to the other nonspecific marketed GBCAs. This study aims to evaluate the impact of this gadolinium (Gd) dose reduction in terms of overall Gd body exposure. Requiring tissue samples at different times, this information is only accessible through animal experiment. In this study, the Gd exposure over a 5-month period was evaluated in healthy rats after a single injection of gadopiclenol in comparison with 2 other macrocyclic GBCAs approved for human use, gadobutrol and gadoterate, all administered at their respective human equivalent dose (HED).

Material and methods: Healthy 9-week-old female Sprague-Dawley rats were randomly allocated to 4 groups, receiving 1 single intravenous injection of gadoterate (Dotarem, 0.6 mmol/kg), gadobutrol (Gadovist, 0.6 mmol/kg), gadopiclenol (Elucirem, 0.3 mmol/kg), or saline (control group). Animals were euthanized 1 day (D1), 1 week (W1), 1 month (M1), or 5 months (M5) after the injection (n = 10/group and time-point). Selected tissues (including central [CNS] and peripheric nervous system [PNS] organs, excretion organs, bone) were collected for subsequent total Gd determination with inductively coupled plasma mass spectrometry. Based on Gd concentration measurements at these different time points, the 5 months overall exposure to Gd in each organ was estimated by calculating the area under the curve (AUC), between the first and the last time point. The whole study was performed in a blinded manner.

Results: Following gadopiclenol administration to rats at the HED, overall Gd exposure over 5 months was found to be 25% to 40% lower compared to gadoterate and gadobutrol, respectively. Organ by organ, Gd exposure reduction is observed over the studied period in the plasma, CNS (cerebellum, cortical brain, subcortical brain, brain stem, spinal cord), PNS (spinal nodes, sciatic nerve, footpads), the spleen, the skin, the liver, and the kidney. In the femur, the Gd exposure after gadopiclenol administration was higher or equivalent compared to gadobutrol and gadoterate in the mineral parts of the bone (diaphysis and epiphysis), but lower in the bone marrow. Residual Gd found in each tissue studied is extremely low relative to the injected dose), with values ranging from 10 -6 (CNS) to 10 -3 (kidney, mineral bone) % injected dose/g of organ.

Conclusions: Under our experimental conditions, the overall measured Gd exposure over 5 months following gadopiclenol injection in rats at the HED is 25-40% lower than that after gadoterate and gadobutrol injections, respectively.