The preclinical pharmacokinetic and safety profile of ferumoxtran-10 appears to be satisfactory in view of its proposed use as a single-dose diagnostic agent in human for MR imaging of lymph nodes.

Dynamic contrast-enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low-molecular-weight contrast agent (Gd-DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two-compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd-DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in "normal" tissue immediately adjacent to the tumors were evident: Gd-DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd-DTPA and P792 provides information regarding the microenvironment of tumors.

Objectives We aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging. Methods We described the molecular structure of gadopiclenol and measured the r 1 and r 2 relaxivity properties at fields of 0.47 and 1.41 T in water and human serum. Nuclear magnetic relaxation dispersion profile measurements were performed from 0.24 mT to 7 T. Protonation and complexation constants were determined using pH-metric measurements, and we investigated the acid-assisted dissociation of gadopiclenol, gadodiamide, gadobutrol, and gadoterate at 37°C and pH 1.2. Applying the relaxometry technique (37°C, 0.47 T), we investigated the risk of dechelation of gadopiclenol, gadoterate, and gadodiamide in the presence of ZnCl 2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled 153 Gd-gadopiclenol were performed in Beagle dogs, and protein binding was measured in rats, dogs, and humans plasma and red blood cells. Results Gadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid); registry number 933983-75-6] is based on a pyclen macrocyclic structure. Gadopiclenol exhibited a very high relaxivity in water (r 1 = 12.2 mM −1 ·s −1 at 1.41 T), and the r 1 value in human serum at 37°C did not markedly change with increasing field (r 1 = 12.8 mM −1 ·s −1 at 1.41 T and 11.6 mM −1 ·s −1 at 3 T). The relaxivity data in human serum did not indicate protein binding. The nuclear magnetic relaxation dispersion profile of gadopiclenol exhibited a high and stable relaxivity in a strong magnetic field. Gadopiclenol showed high kinetic inertness under acidic conditions, with a dissociation half-life of 20 ± 3 days compared with 4 ± 0.5 days for gadoterate, 18 hours for gadobutrol, and less than 5 seconds for gadodiamide and gadopentetate. The pharmacokinetic profile in dogs was typical of extracellular nonspecific GBCAs, showing distribution in the extracellular compartment and no metabolism. No protein binding was found in rats, dogs, and humans. Conclusions Gadopiclenol is a new extracellular and macrocyclic Gd chelate that exhibited high relaxivity, no protein binding, and high kinetic inertness. Its pharmacokinetic profile in dogs was similar to that of other extracellular nonspecific GBCAs.

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.