Abstract
OBJECTIVES: Gadoquatrane is a tetrameric extracellular gadolinium-based contrast agent (GBCA) with a T1 relaxivity of 11.8 L/(mmol Gd*s) at 1.41 T in human plasma, which is currently in Phase 3 clinical development. In the current study, the stability of gadoquatrane was assessed in comparison with approved macrocyclic GBCAs in several in vitro and in vivo assays. MATERIALS AND METHODS: Kinetic inertness, a key determinant of complex stability, was assessed for gadoquatrane, gadoteridol, gadobutrol, gadoterate, and gadopiclenol at equimolar Gd concentrations by measuring the time course of dissociation at pH 1.2 and 37°C using a complexometric assay. Kinetic inertness was also determined in human plasma at pH 7.4 and 37°C using ion exchange chromatography coupled to inductively coupled plasma mass spectrometry (ICP-MS). The binding of gadoquatrane, gadobutrol, and gadopiclenol to synthetic hydroxyapatite, the inorganic component of bone, was investigated in vitro and the Gd content in histological bone slices 1 week after a single injection of these 3 selected GBCAs in rats (0.6 mmol Gd/kg, equivalent to a human dose of 0.1 mmol Gd/kg) was analyzed using laser ablation coupled to ICP-MS. RESULTS: The dissociation half-lives at pH 1.2 (mean, 95% confidence interval in parenthesis) were 28.6 (28.1, 29.1) days for gadoquatrane, 14.2 (13.8, 14.6) days for gadopiclenol, 2.7 (2.6, 2.8) days for gadoterate, 14.1 (13.1, 15.1) hours for gadobutrol, and 2.2 (2.0, 2.4) hours for gadoteridol. After 15 days of incubation in human plasma at pH 7.4, no released Gd 3+ ions above the lower limit of quantification (LLOQ, 0.01% of total Gd) were observed for gadoquatrane and gadoterate, while for gadobutrol, gadopiclenol and gadoteridol the concentrations of released Gd 3+ ions reached 0.12 (0.11, 0.13)%, 0.20 (0.19, 0.21)%, and 0.20 (0.20, 0.21)%, respectively. The rates of dissociation for gadopiclenol and gadoteridol were similar. For gadoquatrane, gadobutrol, and gadopiclenol, the binding to hydroxyapatite was examined. It was very low (< 0.02% of total Gd) for all 3 GBCAs. The Gd concentration 1 week after the injection of 0.6 mmol Gd/kg of the 3 GBCAs in bone marrow were in a comparable range of 2.3-3.0 nmol Gd/g tissue. In the epiphysis the Gd concentrations for gadoquatrane (1.2 (1.0, 1.4)) and gadobutrol (1.2 (1.0, 1.4)) were lower compared to gadopiclenol (2.2 (1.9, 2.6)). In the diaphysis the respective values were 0.5 (0.4, 0.7) nmol Gd/g, 1.0 (0.8, 1.3) nmol Gd/g, and 2.7 (2.1, 3.5) nmol Gd/g. Elemental imaging of the femur obtained in this in vivo study revealed no Gd containing structures in the mineralized bone for gadoquatrane (< 1 nmol Gd/g). For gadopiclenol, a visible thin layer of Gd concentration (interquartile range [IQR]: 17-38 nmol Gd/g, maximum value ~80 nmol Gd/g) in the subcortical layer of the bone was observed. The same layer contained a lower Gd concentration for gadobutrol (IQR: 1.2-3.5 nmol Gd/g, maximum value ~12 nmol Gd/g). CONCLUSIONS: The investigations demonstrated that gadoquatrane has the highest kinetic inertness towards release of Gd 3+ ions in strong acidic environment compared to all approved macrocyclic GBCAs. In human plasma at pH 7.4 no release of Gd 3+ ions was observed from gadoquatrane, similar to gadoterate and kinetic inertness was higher than for gadoteridol, gadobutrol and gadopiclenol. The high stability of gadoquatrane was supported by very low Gd concentrations in mineralized bone in an in vivo study in rats.