An Evaluation of the Long-term Impact of Gadolinium-based Contrast Agents on Sensory Nerves in Cynomolgus Monkeys.

OBJECTIVES

Previous studies in rodents have investigated the potential effects of gadolinium-based contrast agents (GBCAs) on the peripheral nervous system; this study aimed to assess the potential effects of 2 GBCAs on the peripheral nervous system of non-human primates (NHPs) and to evaluate their toxicokinetic profile.

MATERIALS AND

METHODS

Eighteen cynomolgus monkeys ( Macaca fascicularis ; 2 to 4 years old, Mauritian origin) of both sexes (3 animals/group/sex) were intravenously administered once with either gadobenate dimeglumine or gadoteridol at 0.3 mmol/kg, or with saline (0.6 mL/kg). This was followed by a 52-week recovery phase. Safety assessments were based on clinical observations, body weights, neurobehavioral observations, electrophysiologic nerve conduction tests, nerve assessment in skin biopsies (pre-dose and at weeks 2, 17, and 51), and clinical pathology evaluation. Blood for toxicokinetic evaluations was collected at pre-dose and at 5 minutes and at 1, 4, 7, and 24 hours post-dose.

RESULTS

No GBCA-related changes were noted from clinical and neurobehavioral observation. All sensory and motor nerve conduction metrics remained within a normal, physiologically functional range at all time points for all animals. Hematoxylin and eosin-stained sections revealed no induced changes in epidermal and subepidermal tissues. Image analysis did not reveal histomorphometrical differences between control and GBCA-treated animals. Systemic exposure to gadolinium (Gd) was comparable between sexes and was consistent after the administration of the 2 GBCAs; mean Gd half-life values, based on data from 5 minutes to 24 hours post-dose, were about 3.5 hours for gadobenate dimeglumine and about 3 hours for gadoteridol. For both GBCAs, systemic clearance was rapid at ∼0.16 L/h/kg, with a distribution volume ranging from 0.13 to 0.17 L/kg, indicating extracellular space distribution.

CONCLUSION

A single intravenous administration of 0.3 mmol/kg gadobenate dimeglumine or gadoteridol in NHPs was well tolerated and did not induce effects on the peripheral nervous system.