Pharmacokinetics, Safety, and Tolerability of the Novel Tetrameric, High-Relaxivity, Macrocyclic Gadolinium-Based Contrast Agent Gadoquatrane in Healthy Adults

Invest Radiol. 2023 Nov 3. doi: 10.1097/RLI.0000000000001043. Online ahead of print.


Objectives: Gadolinium (Gd)-based contrast agents are well established in clinical routine and have been proven safe and effective. However, there is a need for "next-generation" Gd-based contrast agents that would allow lowering the Gd dose used for routine contrast-enhanced magnetic resonance imaging procedures. The objective of this first-in-human study was to investigate the pharmacokinetic profile, safety, and tolerability of gadoquatrane, a novel high-relaxivity Gd-based contrast agent.

Materials and methods: This study was conducted in 2018/2019 as a prospective, randomized, single-blind, single-dose, placebo-controlled, escalating-dose study. Healthy volunteers were randomly assigned (6:2) to intravenous administration of gadoquatrane (0.025 to 0.2 mmol Gd/kg body weight) or placebo. Study procedures included collection of blood samples and excreta for pharmacokinetic analyses and safety assessments.

Results: Forty-nine healthy study participants (mean age ± SD, 35 ± 6.3 years; 24 female) were evaluated. The effective half-life of gadoquatrane in plasma was short and similar in all dose groups (1.4-1.7 hours). Plasma concentrations around the lower quantitation limit (0.0318 μmol Gd/L) were reached 15-72 hours after administration. The volume of distribution at steady state was ~0.2 L/kg in all dose groups. The clearance (total and renal) was ~0.1 L/h per kilogram in all groups. Across dose groups, the exposure of gadoquatrane increased dose-proportionally. Metabolite profiling revealed no hint of degradation in vivo or release of free Gd. Seven of 36 participants (19.4%) receiving gadoquatrane and 4 of 13 participants (30.8%) receiving placebo experienced mild or moderate treatment-emergent adverse events. No serious adverse events occurred. The analysis of the Gd concentration-QTc interval relationship indicated no risk of QT/QTc prolongation (>10 milliseconds) with gadoquatrane at clinical dose levels.

Conclusions: Gadoquatrane with its high-relaxivity, pharmacokinetic similarity to established Gd-based contrast agents and high tolerability is a promising "next-generation" contrast agent for magnetic resonance imaging.