Pharmacokinetics, Excretion, and Organ Distribution of the Novel Gadolinium-Based MRI Contrast Agent Gadoquatrane in...

Gadoquatrane is a tetrameric, macrocyclic, extracellular gadolinium-based MRI contrast agent with high relaxivity and stability, which is currently in Phase 3 clinical development. The aim of the present study was to characterize the pharmacokinetic profile of gadoquatrane in an animal species closely related to humans and to compare this profile with the profiles of the 2 long-established gadolinium-based contrast agents gadobutrol and gadoterate (Gd-DOTA) or, more precisely, with analogs of these agents. Non-Gd-based lanthanide analogs were used instead of the Gd-based versions to make the 3 co-injected compounds analytically differentiable.

Eight female cynomolgus monkeys were included. Six animals received a single intravenous injection of a mixture containing gadoquatrane, Dy-butrol and Tb-DOTA at the same dose (0.1 mmol lanthanide/kg body weight). Two control animals received placebo. Procedures included collection of blood, excreta, and selected tissue samples up to 58 days post dose. Inductively coupled plasma mass spectrometry was used to measure the concentrations of the lanthanide complexes in all samples. Lanthanide plasma concentrations were fitted to a 3-compartment model to obtain pharmacokinetic parameters. High-performance liquid chromatography connected to inductively coupled plasma mass spectrometry or high-resolution mass spectroscopy was used for metabolite profiling of gadoquatrane.

After the injection, gadoquatrane plasma concentrations decreased in 3 phases: a distribution phase (α-phase; half-life: ~3 min), a major elimination phase (β-phase; half-life: ~60 min), and a slow terminal elimination phase (γ-phase; half-life: approximately 25 h). The effective half-life was ~1.0 hour, the total plasma clearance was 0.11 L/kg/h, and the volume of distribution was 0.17 L/kg. Gadoquatrane was rapidly and almost exclusively renally excreted. On average, 97% of the dose (SD: 5.3%) was recovered in urine within the first 24 hours after the injection. Urinary excretion was still ongoing at day 58, albeit in very small quantities (0.01% of dose/day). Only minimal amounts of Gd were detected in organ and tissue samples (<110 ppm dose/g tissue at day 5 and <10 ppm dose/g tissue at day 58). The highest concentration was found in the kidney cortex at day 5 (41 nmol Gd/g tissue). The Gd concentrations in skin and selected brain sections were lower by a factor of 100 or 1000, respectively, at day 5. Gd tissue concentrations declined substantially in all tested tissues between day 5 and day 58. Similar results were obtained for Dy-butrol and Tb-DOTA. Metabolic degradation of gadoquatrane was not observed.

Gadoquatrane showed a pharmacokinetic profile very similar to that of macrocyclic comparator products. There were no indications of an increased risk of a prolonged presence of gadolinium in tissues in this study after administration of gadoquatrane compared with the comparator products. Metabolite profiling confirmed the metabolic stability of gadoquatrane.