The aim of this study was to evaluate the pharmacokinetics, safety profile, and pharmacodynamics of gadopiclenol, a new high relaxivity macrocyclic gadolinium-based contrast agent, in healthy subjects and patients with brain lesions. Materials and Methods: This was a single ascending dose phase I/IIa study. Phase I was double-blind, randomized, placebo-controlled and included 54 healthy subjects. In each dose group (0.025, 0.05, 0.075, 0.1, 0.2, and 0.3 mmol/kg), 6 subjects received gadopiclenol and 3 received placebo (NaCl 0.9%) in intravenous injection. Phase IIa was open-label and included 12 patients with brain lesions, 3 per dose group (0.05, 0.075, 0.1, and 0.2 mmol/kg). Concentrations were measured in plasma samples collected before administration and over a 24-hour period postadministration and in urine specimens (phase I) collected until 7 days after administration. A noncompartmental approach was used for pharmacokinetic analysis. Pharmacodynamic assessments included a qualitative evaluation of the visualization of brain structures/lesions and quantitative measurements (signal-to-noise ratio, contrast-to-noise ratio) on magnetic resonance imaging. A clinical and biological safety follow-up was performed up to 7 days after administration for phase I and up to 1 day after administration for phase IIa. Results: In healthy subjects (male, 50%; median age, 26.0 years), the pharmacokinetics of gadopiclenol is considered linear with mean maximum concentration C max values ranging from 248.7 to 3916.4 μg/mL. Gadopiclenol was excreted in an unchanged form via the kidneys, eliminated from plasma with a terminal elimination half-life (t 1/2 ) of 1.5 to 2 hours. There was no difference in the pharmacokinetics between males and females. After administration of gadopiclenol, the contrast enhancement scores in brain structures were improved in all dose groups. Similar rates of related adverse events were observed with gadopiclenol (36.1%) and placebo (33.3%). No clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, and vital signs were reported.In patients (male, 58%; median age, 53.0 years), a similar pharmacokinetic and safety profile was observed, and sufficient contrast enhancement was seen at all tested doses. Conclusions: The pharmacokinetics of gadopiclenol is dose-independent in healthy subjects and patients with brain lesions. Its good safety profile is in line with that reported for other macrocyclic gadolinium-based contrast agents. Preliminary pharmacodynamic results in patients suggest that gadopiclenol is a promising macrocyclic contrast agent with the potential use of lower dose for clinical routine magnetic resonance imaging scans.The study is registered on ClinicalTrials.gov under the trial registration number NCT03603106.

Crossbridge properties of cardiomyopathic Syrian hamster (CSH) diaphragm from the dilated Bio 53-58 strain were analyzed after 5-mo of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/d by oral gavage). Three groups were studied: control F1B hamsters (C; n = 14); CSH given placebo (PL; n = 11 ); and perindopril-treated CSH (PE; n = 11). Peak isometric tension was lower in PL than in C, in both twitch (21.4 +/- 1.5 versus 46.9 +/- 1.5 mN/mm2; p < 0.001) and tetanus (41.0 +/- 2.7 versus 90.5 +/- 3.3 mN/mm2; p < 0.001). In PE, peak isometric tension was intermediate between C and PL, and was significantly lower than in C and higher than in PL. The single force of one crossbridge (pi), the number (m) of crossbridges, the turnover rate of myosin adenosine triphosphatase (ATPase) (kcat), and peak mechanical efficiency (Effmax) were calculated from A.F. Huxley's equations; m was lower in PL than in C, in both twitch (3.4 +/- 0.2 versus 4.9 +/- 0.2 10(9)/mm2; p< 0.001) and tetanus (4.0 +/- 0.3 versus 8.9 +/- 0.7 10(9)/mm2; p < 0.001); m was higher in PE than in PL, in both twitch 4.3 +/- 0.5 versus 3.4 +/- 0.2 10(9)/mm2; NS) and tetanus (6.2 +/- 0.4 versus 4.0 +/- 0.3 10(9)/mm2; p < 0.01), with no change in pi. In the three groups, Effmax correlated linearly with kcat (r = 0.93; p = 0.001) and showed a negative linear correlation with pi (r = 0.996; p = 0.001). In conclusion, our results show that in experimental cardiomyopathy, ACE inhibitor mainly helps to prevent a decrease in the number of diaphragm muscle crossbridges, resulting in preserved peak isometric tension.

This review summarizes 30 years of experience in the development and clinical use of magnetic resonance (MR) contrast agents. Despite their undisputable usefulness for disease diagnosis, gadolinium (Gd)-based contrast agents (GBCAs) have gone through 2 major safety crises. Approximately 10 years ago, the regulatory agencies decided to restrict the use of GBCAs to minimize the risk of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Yet, following the recent discovery of Gd retention in brain, the same agencies adopted different positions ranging from suspension of marketing authorizations, changes in GBCA safety labeling, and performing preclinical and clinical studies to assess the potential long-term consequences of Gd accumulation on motor and cognitive functions. Besides, magnetic resonance imaging (MRI) has benefited from MR technological advances, which provide alternative solutions to increase the MR signal, generate new contrasts on MRI scans, and accelerate their acquisition and analysis. Altogether, GBCAs in combination with new MR techniques have found their place in the diagnostic pathway of various diseases. Despite the large research efforts to identify and develop alternative Gd-free MR agents, manganese- and iron-based contrast agents have failed to reach market approval. In this context, the development of next-generation MR contrast agents should focus on high-stability and high-relaxivity GBCAs, such as gadopiclenol, which offer the possibility to adapt the administered Gd dose to each indication while ensuring an optimal patient safety.

Objectives The purpose of this manuscript is to review the successive regulatory actions and decisions following the initial publication by Kanda and colleagues in 2014 regarding gadolinium retention in the human brain after multiple gadolinium-based contrast agents (GBCAs) administrations. Materials and Methods Starting from 2014, the actions and decisions made by all regulatory authorities were collected and summarized region by region. Volumes of GBCA sales in 2018 per region and main countries are also presented as an indicator of patients’ exposure to those products. Results All regulatory authorities agreed on the absence of evidence of any harmful effect of gadolinium retention in humans. However, based on the same amount of preclinical and clinical evidence available in adults and children, regulatory authorities used different approaches resulting in different actions and decisions regarding the labeling and market authorizations of GBCAs, as well as the specific actions requested to the manufacturers. Conclusions The manufacturers of GBCAs had to face different situations according to the countries, due to the different positions and expectations from regulatory agencies. They have adapted their responses to the different positions of the regulatory agencies and conducted specific preclinical and clinical investigations to provide the expected evidence. It is also their responsibility to continuously monitor the benefit-risk balance of the products and to propose risk minimization measures to the regulatory agencies.