Current and Future MR Contrast Agents: Seeking a Better Chemical Stability and Relaxivity for Optimal Safety and Efficacy.

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.

Future of Diagnostic Computed Tomography: An Update on Physicochemical Properties, Safety, and Development of X-ray Contrast Media.

Iodinated contrast media (CM) are utilized in approximately 40% of the 300 million computed tomography (CT) scans undertaken annually. This review focuses on the physicochemical properties and safety of iodinated CM, and the development of new x-ray CM, and it explores methods to optimize CT scanning parameters. It concludes that good x-ray CM should have high structural stability, hydrophilicity, and CT attenuation; low viscosity, osmolality, and protein binding; no metabolism and tissue accumulation; and a complete elimination.

Randomized study of the effect of gadopiclenol, a new gadolinium-based contrast agent, on the QTc interval in healthy subjects.

AIMS: We investigated the effect of gadopiclenol, a new gadolinium-based contrast agent, on the QTc interval at clinical and supraclinical dose, considering the relative hyperosmolarity of this product. METHODS: This was a single centre, randomized, double-blind, placebo- and positive-controlled, 4-way crossover study. Forty-eight healthy male and female subjects were included to receive single intravenous (i.v.) administrations of gadopiclenol at the clinical dose of 0.1 mmol kg-1 , standard for current gadolinium-based contrast agents, the supraclinical dose of 0.3 mmol kg-1 , placebo and a single oral dose of 400 mg moxifloxacin. RESULTS: The largest time-matched placebo-corrected, mean change from-baseline in QTcF (ΔΔQTcF) was observed 3 hours after administration of 0.1 mmol kg-1 gadopiclenol (2.39 ms, 90% confidence interval [CI]: 0.35, 4.43 ms) and 5 minutes after administration of 0.3 mmol kg-1 (4.81 ms, 90%CI: 2.84, 6.78 ms). The upper limit of the 90% CI was under the threshold of 10 ms, demonstrating no significant effect of gadopiclenol on QTc interval. From 1.5 to 4 hours postdose moxifloxacin, the lower limit of the 90% CI of ΔΔQTcF exceeded 5 ms demonstrating assay sensitivity. Although there was a positive slope, the concentration-response analysis estimated that the values of ΔΔQTcF at the maximal concentration of gadopiclenol at 0.1 and 0.3 mmol kg-1 were 0.41 and 2.23 ms, respectively, with the upper limit of the 90% CI not exceeding 10 ms. No serious or severe adverse events or treatment discontinuations due to adverse events were reported. CONCLUSION: This thorough QT/QTc study demonstrated that gadopiclenol did not prolong the QT interval at clinical and supraclinical doses and was well tolerated in healthy volunteers. The positive slope of the QTc prolongation vs concentration relationship suggests that hyperosmolarity could be associated with QTc prolongation. However, the amplitude of this effects is unlikely to be associated with proarrhythmia.

Gadolinium Retention as a Safety Signal: Experience of a Manufacturer.

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.

Assessment of Pharmacokinetic, Pharmacodynamic Profile, and Tolerance of Gadopiclenol, A New High Relaxivity GBCA, in Healthy Subjects and Patients With Brain Lesions (Phase I/IIa Study).

OBJECTIVES: 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 Cmax 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 (t1/2) 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.

Adverse Reactions to Gadoterate Meglumine: Review of Over 25 Years of Clinical Use and More Than 50 Million Doses.

OBJECTIVE: The aim of this study was to evaluate the safety profile of gadoterate meglumine from clinical trials, postmarketing observational studies, and pharmacovigilance reports of adverse drug reactions (ADRs) encompassing 25 years of clinical use and over 50 million administered doses. MATERIALS AND METHODS: Assessment of the safety of gadoterate meglumine through processing and review of all safety data was collected after magnetic resonance imaging procedures. All ADRs originated from 3 major sources: (1) a clinical study database including 50 phase I to IV studies involving 2822 patients, (2) a safety database including 8 postmarketing safety studies (PMSs) involving 151,050 patients, and (3) a pharmacovigilance database compiling safety experience following over 50 million doses administered between March 1989 and September 2015. RESULTS: Among the 2822 patients receiving gadoterate meglumine in the clinical trials, 241 (8.5%) experienced 405 postinjection adverse events (AEs), considered related to the contrast agent for 113 patients (4.0%). Serious AEs were reported for 27 patients (1.0%) and assessed as related to gadoterate meglumine for 2 patients (0.07%). None of the PMS studies showed evidence of unexpected safety issues, with a very low rate of AEs (<1%). Postmarketing safety experience with over 50 million doses of gadoterate meglumine prescribed for 25 years of approved use worldwide compiled spontaneous reports for 3797 patients who experienced 8397 ADRs, yielding a very low reported incidence of ADRs of 0.007% of patients. There was no single-agent case of confirmed nephrogenic systemic fibrosis with gadoterate meglumine either from clinical development programs or from postmarketing experience. CONCLUSIONS: Based on clinical trials, postmarketing observational studies and pharmacovigilance data, a very low incidence of ADRs was reported with gadoterate meglumine, which has no impact on its favourable benefit-risk ratio.

Effects of gadolinium-based contrast agent concentrations (0.5 M or 1.0 M) on the diagnostic performance of magnetic resonance imaging examinations: systematic review of the literature.

Background To date there is no agreement as to what is the optimal concentration for gadolinium-based contrast agents (GBCAs). Purpose To assess whether diagnostic performance differences exist between 0.5 M and 1.0 M GBCAs used for magnetic resonance imaging (MRI). Material and Methods A PubMed literature search identified 21 clinical studies published between 2005 and 2013 which evaluated the diagnostic efficacy of both types of GBCAs. Study design, type of procedure, GBCA administration mode, imaging performances, impact on patient management, study limitations, and biases were analyzed. No statistical test was performed on pooled data. Results Sixteen comparative and five non-comparative studies were analyzed, involving 2183 patients who underwent MRI procedures for various indications. In 67% of the studies, 0.5 M and 1.0 M GBCAs were injected at equimolar gadolinium amounts per kg body weight. Only 33% applied the same molar flow rate for delivery of the GBCAs. No significant differences between GBCAs were reported for 23 out of 27 qualitative endpoints (mainly image quality, lesion, and vessel visualization) and 29 out of 40 quantitative endpoints. Three out of four studies with non-equimolar delivery rates showed better contrast-to-noise and signal-to-noise ratios for 1.0 M gadobutrol, without showing an impact on diagnostic performance. Methodological biases were identified in several studies impairing the interpretation of comparisons. Conclusion Imaging differences between 0.5 M and 1.0 M GBCAs were essentially observed under non-equimolar delivery rates. However, they did not result into greater diagnostic efficacy when performed under equimolar conditions.