Gadopiclenol 0.5mmol/ml solution for injection 7.5ml vials

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 r1 and r2 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 ZnCl2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled 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 (r1 = 12.2 mM·s at 1.41 T), and the r1 value in human serum at 37°C did not markedly change with increasing field (r1 = 12.8 mM·s at 1.41 T and 11.6 mM·s 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.

Abstract licence: CC BY-NC-ND 4.0

ABSTRACT: This review describes the pharmacokinetics, efficacy, and safety of gadopiclenol, a new macrocyclic gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration at the dose of 0.05 mmol/kg. Gadopiclenol is a high relaxivity contrast agent that shares similar pharmacokinetic characteristics with other macrocyclic GBCAs, including a predominant renal excretion. In pediatric patients aged 2-17 years, the pharmacokinetic parameters (assessed through a population pharmacokinetics model) were comparable to those observed in adults, indicating no need for age-based dose adjustment. For contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) and body indications, gadopiclenol at 0.05 mmol/kg was shown to be noninferior to gadobutrol at 0.1 mmol/kg in terms of 3 lesion visualization parameters (ie, lesion border delineation, internal morphology, and contrast enhancement). Moreover, for contrast-enhanced MRI of the CNS, compared with gadobenate dimeglumine at 0.1 mmol/kg, gadopiclenol exhibited superior contrast-to-noise ratio at 0.1 mmol/kg and comparable contrast-to-noise ratio at 0.05 mmol/kg. A pooled safety analysis of 1047 participants showed a favorable safety profile for gadopiclenol. Comparative studies showed that the incidence and nature of adverse drug reactions with gadopiclenol were comparable to those observed with other GBCAs. Importantly, no significant safety concerns were identified in pediatric and elderly patients, as well as in patients with renal impairment. Overall, these findings support the clinical utility and safety of gadopiclenol for MRI in adult and pediatric patients aged 2 years and older in CNS and body indications.

Abstract licence: CC BY-NC-ND 4.0

OBJECTIVES: Developing new high relaxivity gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) allowing dose reduction while maintaining similar diagnostic efficacy is needed, especially in the context of gadolinium retention in tissues. This study aimed to demonstrate that contrast-enhanced MRI of the central nervous system (CNS) with gadopiclenol at 0.05 mmol/kg is not inferior to gadobutrol at 0.1 mmol/kg, and superior to unenhanced MRI. MATERIALS AND METHODS: PICTURE is an international, randomized, double-blinded, controlled, cross-over, phase III study, conducted between June 2019 and September 2020. Adult patients with CNS lesions were randomized to undergo 2 MRIs (interval, 2-14 days) with gadopiclenol (0.05 mmol/kg) then gadobutrol (0.1 mmol/kg) or vice versa. The primary criterion was lesion visualization based on 3 parameters (border delineation, internal morphology, and contrast enhancement), assessed by 3 off-site blinded readers. Key secondary outcomes included lesion-to-background ratio, enhancement percentage, contrast-to-noise ratio, overall diagnostic preference, and adverse events. RESULTS: Of the 256 randomized patients, 250 received at least 1 GBCA administration (mean [SD] age, 57.2 [13.8] years; 53.6% women). The statistical noninferiority of gadopiclenol (0.05 mmol/kg) to gadobutrol (0.1 mmol/kg) was achieved for all parameters and all readers (n = 236, lower limit 95% confidence interval of the difference ≥-0.06, above the noninferiority margin [-0.35], P < 0.0001), as well as its statistical superiority over unenhanced images (n = 239, lower limit 95% confidence interval of the difference ≥1.29, P < 0.0001).Enhancement percentage and lesion-to-background ratio were higher with gadopiclenol for all readers ( P < 0.0001), and contrast-to-noise ratio was higher for 2 readers ( P = 0.02 and P < 0.0001). Three blinded readers preferred images with gadopiclenol for 44.8%, 54.4%, and 57.3% of evaluations, reported no preference for 40.7%, 21.6%, and 23.2%, and preferred images with gadobutrol for 14.5%, 24.1%, and 19.5% ( P < 0.001).Adverse events reported after MRI were similar for gadopiclenol (14.6% of patients) and gadobutrol (17.6%). Adverse events considered related to gadopiclenol (4.9%) and gadobutrol (6.9%) were mainly injection site reactions, and none was serious. CONCLUSIONS: Gadopiclenol at 0.05 mmol/kg is not inferior to gadobutrol at 0.1 mmol/kg for MRI of the CNS, confirming that gadopiclenol can be used at half the gadolinium dose used for other GBCAs to achieve similar clinical efficacy.

Abstract licence: CC BY-NC-ND 4.0

OBJECTIVES: Gadopiclenol is a q = 2 pyclen gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration, European Medicines Agency, and other European countries. The aim of this report is to demonstrate its stability in multiple stressed in vitro conditions and in vivo, in rat kidney, while maintaining its higher relaxivity compared with conventional GBCAs on the market. MATERIALS AND METHODS: Both gadopiclenol and its chemical precursor Pi828-Gd were characterized and compared with q = 1 gadolinium (Gd) complexes. The number of water molecules coordinated to the Gd (the hydration number, q) was determined by luminescence. 17 O NMR (Nuclear Magnetic Resonance) measurements gave access to the water residence time τ M . These parameters were used for the fitting of the nuclear magnetic relaxation dispersion profiles in water. Proton relaxivities of the complexes were determined in different media at 60 MHz (1.4 T), at different pH and temperature. The kinetic inertness was investigated in human serum, acidic media, under zinc competition in the presence of phosphate, and under ligand competition. The in vivo stability was evaluated in rat kidneys 12 months after repeated injections. RESULTS: The presence of 2 inner-sphere water molecules per Gd complex was confirmed for both pyclen derivatives. The high relaxivity of the complexes in water is maintained under physiological conditions, even under stressed conditions (ionic media, extreme pH, and temperature), which guarantees their efficiency in a large range of in vivo situations. Gd release from the q = 2 complexes was investigated in different potentially destabilizing conditions. Either no Gd release or a slower one than with "q = 1" stable macrocyclic GBCA (acidic conditions) was observed. Their kinetic inertness was demonstrated in physiological conditions, and the Gd release was below the lower limit of quantification of 0.1 μM after 12 days at 37°C in human serum. It was also demonstrated that gadopiclenol is stable in vivo in rat kidney 12 months after repeated injections. CONCLUSIONS: Thanks to its optimized structural design, gadopiclenol is a highly stable and effective macrocyclic q = 2 GBCA.

Abstract licence: CC BY-NC-ND 4.0

OBJECTIVE: Gadopiclenol is a new high-relaxivity macrocyclic gadolinium-based contrast agent for magnetic resonance imaging of the central nervous system and other body regions. The product has been approved by US Food and Drug Administration and is currently being evaluated by European Medicines Agency. For risk assessment of the single diagnostic use in humans, the safety profile of gadopiclenol was evaluated with a series of preclinical studies. MATERIALS AND METHODS: With exception of dose-ranging studies, all safety pharmacology and toxicology studies were performed in compliance with Good Laboratory Practice principles. Safety pharmacology studies were conducted to assess potential effects on cardiovascular (in vitro and in dogs), respiratory (in rats and guinea pigs), neurological (in rats), and renal endpoints (in rats). Toxicology studies were also performed to investigate acute toxicity (in rats and mice), extended single-dose (in rats and dogs) and repeated-dose toxicity (in rats and dogs), reproductive (in rats), developmental (in rats and rabbits) and juvenile toxicity (in rats), as well as genotoxicity (in vitro and in rats), local tolerance (in rabbits), potential immediate hypersensitivity (in guinea pigs), and potential tissue retention of gadolinium (in rats). RESULTS: Safety pharmacology studies conducted at high intravenous (IV) doses showed a satisfactory tolerance of gadopiclenol in the main body systems. After either single or repeated IV dosing (14 and 28 days) in rats and dogs, gadopiclenol was well tolerated even at high doses. The no-observed-adverse-effect level values (ie, the highest experimental dose without adverse effects) representing between 8 times in rats and 44 times in dogs (based on the exposure), the exposure achieved in humans at the intended diagnostic dose, provide a high safety margin. No or only minor and reversible effects on body weight, food consumption, clinical signs, clinical pathology parameters, or histology were observed at the highest doses. The main histological finding consists in renal tubular vacuolations (exacerbated after repeated exposure), which supports a well-known finding for this class of compounds that has no physiological consequence on kidney function. Reproductive toxicity studies showed no evidence of effects on reproductive performance, fertility, perinatal and postnatal development in rats, or reproductive development in rats or rabbits. The safety profile of gadopiclenol in juvenile rats was satisfactory like in adults. Gadopiclenol was not genotoxic in vitro in the Ames test, a mouse lymphoma assay, and a rat in vivo micronucleus test. There were no signs of local intolerance at the injection site after IV and intra-arterial administration in rabbits. However, because of minor signs of intolerance after perivenous administration, misadministration must be avoided. Gadopiclenol exhibited no signs of potential to induce immediate hypersensitivity in guinea pigs. CONCLUSIONS: High safety margins were observed between the single diagnostic dose of 0.05 mmol/kg in humans and the doses showing effects in animal studies. Gadopiclenol is, therefore, well tolerated in various species (mice, rats, dogs, rabbits, and guinea pigs). All observed preclinical data support the clinical approval.

Abstract licence: CC BY-NC-ND 4.0

ABSTRACT: Gadopiclenol is a novel, macrocyclic high-relaxivity gadolinium-based contrast agent recently approved for use in magnetic resonance imaging of the central nervous system and body organs at a dose of 0.05 mmol/kg body weight. Postmarketing surveillance of its first year of clinical use in the United States of America showed no serious adverse events (AEs) following over 882,550 administrations and a very low rate of nonserious AEs (1 case every 27,580 exposures). The types of observed AEs were similar to those reported for other gadolinium-based contrast agents in clinical use. Safety data from postmarketing surveillance of gadopiclenol further confirm its positive benefit-risk profile demonstrated in preapproval clinical studies.

Abstract licence: CC BY-NC-ND 4.0