In Vitro and In Vivo Stability Assessment of the Investigational, Macrocyclic Gadolinium-Based Contrast Agent Gadoquatrane
Author Block: S. Gruendemann, T. Frenzel, J. Lohrke, J. Boyken, G. Jost, M. Berger, H-F. Ulbrich, H. Pietsch; Berlin/DE
Purpose: Gadoquatrane is a tetrameric extracellular macrocyclic gadolinium-based contrast agent (GBCA) with a T1 relaxivity of 11.8 L/(mmol Gd*s) at 1.41 T in human plasma, which has been submitted for regulatory approval in several countries. This study evaluated its stability in comparison with approved macrocyclic GBCAs in vitro and in vivo.
Methods or Background: All assays were conducted at equimolar Gd concentrations. Dissociation kinetics were measured for gadoquatrane, gadoteridol, gadobutrol, gadoterate, and gadopiclenol at pH 1.2 and 37°C using a complexometric assay. Stability in human plasma at pH 7.4 and 37°C was analyzed by ion exchange chromatography with ICP-MS. Rats received a single injection of gadoquatrane, gadobutrol, or gadopiclenol (0.6 mmol Gd/kg; human equivalent 0.1 mmol Gd/kg), and Gd distribution in bone was quantified by laser ablation ICP-MS one week later.
Results or Findings: At pH 1.2, dissociation half-lives were 28.6 days (gadoquatrane), 14.2 days (gadopiclenol), 2.7 days (gadoterate), 14.1 h (gadobutrol), and 2.2 h (gadoteridol). After 15 days in plasma (pH 7.4), no detectable Gd release was observed for gadoquatrane or gadoterate, while gadobutrol, gadoteridol, and gadopiclenol released 0.12%, 0.20%, and 0.20%, respectively. In rats, bone marrow Gd levels were similar across compounds (2.3-3.0 nmol/g). In epiphysis, concentrations were 1.2 nmol/g for gadoquatrane and gadobutrol, and 2.2 nmol/g for gadopiclenol. In diaphysis, levels were 0.5, 1.0, and 2.7 nmol/g, respectively. Elemental imaging showed lowest Gd in mineralized bone for gadoquatrane (<1 nmol/g) compared to gadobutrol and gadopiclenol.
Conclusion: Gadoquatrane demonstrated the highest kinetic inertness under acidic conditions and no measurable Gd release under physiological conditions in plasma. Its high stability was supported by very low Gd concentrations in mineralized bone in rats.
Limitations: These preclinical data do not allow direct conclusions regarding safety in humans.
Funding for this study: None
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