A Comprehensive Overview of the Efficacy and Safety of Gadopiclenol: A New Contrast Agent for MRI of the CNS and Body.

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.

Preclinical Safety Assessment of Gadopiclenol: A High-Relaxivity Macrocyclic Gadolinium-Based MRI Contrast Agent.

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.

Pharmacokinetics, Dialysability, and Safety of Gadopiclenol, a New Gadolinium-Based Contrast Agent, in Patients With Impaired Renal Function.

OBJECTIVES: The aims of this study were to evaluate the pharmacokinetics (PK) of gadopiclenol, a new macrocyclic gadolinium based-contrast agent, in subjects with impaired renal function, and to assess its dialysability in subjects with end-stage renal disease (ESRD). METHODS AND MATERIALS: This 2-center, open-label, phase 1 study included 5 successive cohorts of 8 adult subjects: healthy subjects (cohort 1), subjects with mild (cohort 2), moderate (cohort 3), severe (cohort 4) renal impairment, or ESRD (cohort 5), who received a single intravenous injection of gadopiclenol (0.1 mmol/kg). Blood and urine samples were collected at different time points in cohorts 1 to 4, and blood and dialysate samples were collected at each hemodialysis session (4-hour session on day 1, day 3, and day 5) in cohort 5. Gadopiclenol elimination and safety were assessed for up to 6 months. Pharmacokinetics parameters were calculated using noncompartmental analysis. RESULTS: A total of 40 subjects were included, with a mean age of 51.5 years (range, 18-71 years). No significant difference in the mean maximum concentration values and the distribution volume was observed among cohorts 1 to 4. Urinary excretion of unchanged gadopiclenol was delayed with the degree of renal impairment and ranged between 96% and 84% in subjects with mild to severe renal impairment. Compared with that of healthy subjects, the mean area under the plasma concentration curve was 54%, 148%, and 769% higher in subjects with mild, moderate, or severe renal impairment, respectively. The mean terminal half-life was prolonged with the degree of renal impairment (1.9, 3.3, 3.8, and 11.7 hours for cohorts 1-4). In ESRD subjects, gadopiclenol was effectively removed from the plasma (95% to 98%) after the first hemodialysis session. Gadopiclenol concentration in plasma was below the limit of quantification for all subjects after the second hemodialysis session. Gadopiclenol concentration was below limit of quantification in all plasma and urine samples collected at 1, 3, and 6 months. Five subjects (12.5%) experienced adverse events related to gadopiclenol, none serious and all resolved. Laboratory measurements, vital signs, and electrocardiography did not raise any safety concern. CONCLUSIONS: Gadopiclenol elimination half-life was prolonged in subjects with mild to severe renal impairment, yet its renal clearance remains complete or nearly complete. In ESRD subjects, gadopiclenol was effectively removed from the plasma after 1 hemodialysis session, and up to 3 hemodialysis sessions were sufficient to completely clear it. No safety concern was raised. Therefore, no dose adjustment seems necessary in this patient population.

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol: A New Macrocyclic Gadolinium Chelate With High T1 Relaxivity.

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.

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.

A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years.

OBJECTIVES: The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. MATERIAL AND METHODS: This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium-enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. RESULTS: Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2ß) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 µmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2.2%) experienced 1 rash of moderate intensity considered as related to gadoterate meglumine. CONCLUSIONS: The pharmacokinetic profile of gadoterate meglumine after a single intravenous injection of 0.1 mmol/kg was appropriately described in newborns and infants younger than 2 years, for whom no dose adjustment is required. The improved efficacy of gadoterate meglumine for contrast-enhanced MRI examination of brain, spine, and associated tissues, as well as its good safety profile, was also demonstrated in this population.

The European Registered Toxicologist (ERT): Current status and prospects for advancement.

Following its inception in 1994, the certification of European Registered Toxicologists (ERT) by EUROTOX has been recognized as ensuring professional competence as well as scientific integrity and credibility. Criteria and procedures for registration are contained in the ERT "Guidelines for Registration 2012". The register of ERT currently has over 1900 members. In order to continue the harmonisation of requirements and processes between national registering bodies as a prerequisite for official recognition of the ERT title as a standard, and to take account of recent developments in toxicology, an update of the ERT Guidelines has been prepared in a series of workshops by the EUROTOX subcommittees for education and registration, in consultation with representatives of national toxicology societies and registers. The update includes details of topics and learning outcomes for theoretical training, and how these can be assessed. The importance of continuing professional development as the cornerstone of re-registration is emphasised. To help with the process of harmonisation, it is necessary to collate and share best practices of registration conditions and procedures across Europe. Importantly, this information can also be used to audit compliance with the EUROTOX standards. As recognition of professionals in toxicology, including specialist qualifications, is becoming more important than ever, we believe that this can best be achieved based on the steps for harmonisation outlined here together with the proposed new Guidelines.

Non-clinical safety assessment of gadoterate meglumine (Dotarem(®)) in neonatal and juvenile rats.

The purpose of this study was to assess the safety of gadoterate meglumine, a gadolinium-based contrast agent used in magnetic resonance imaging, in neonatal and juvenile rats. Rats received a single intravenous administration on postnatal day (PND) 10 or 6 administrations (from PND 10 to 30), at doses of 0, 0.6, 1.25, and 2.5 mmol/kg/administration, i.e. equivalent to approximately 1, 2 and 4-times the usual human dose. The animals were sacrificed at the end of the treatment period or after a 60-day treatment-free period. No mortality and no significant treatment-related effect on clinical signs, macroscopic and histopathological findings, development, behavior, sexual maturation and hematology parameters were observed. Minor non-adverse changes were observed in clinical biochemistry and urinary parameters. Based on AUC0-t, gadoterate meglumine was more rapidly eliminated at PND 30 vs. PND 10, reflecting maturation of kidney function. At the end of the treatment period, Gd was measurable in all organs sampled after single or repeated dosing and levels were dose-dependent as expected, the highest ones being found in kidneys. The total Gd concentrations were similar in all the organs following a single or repeated dosing. At the end of the treatment-free period, only traces of gadolinium were quantifiable, almost exclusively in kidneys, reflecting the excretory function of this organ. In conclusion, single or repeated administration of gadoterate meglumine to juvenile rats was well tolerated.

Cardiovascular safety of gadoterate meglumine (Gd-DOTA).

OBJECTIVES: Gadolinium complexes are not considered to be a drug class at high risk for prolonging cardiac repolarization, which can lead to potentially life-threatening arrhythmias such as torsade de pointes. However, only limited robust data are available on these compounds despite their extensive use as contrast enhancers in magnetic resonance imaging. We present an overview of recent cardiovascular safety data obtained on gadoterate meglumine (Gd-DOTA). MATERIALS AND METHODS: Cardiovascular safety was evaluated by "state-of-the-art" nonclinical ex vitro (dog Purkinje fibers) and in vivo studies in both normal (dogs) and sensitized animal models (rabbits) and in patients with various diseases in a specific clinical trial. RESULTS: In all of these studies, Gd-DOTA did not show any direct deleterious effect on cardiac electrophysiology and especially on ventricular repolarization. CONCLUSION: These results confirmed the good safety profile of Gd-DOTA derived from postmarketing evaluations. Nonspecific gadolinium complexes used for magnetic resonance contrast enhancement do not constitute a class-at-risk for drug-related arrhythmias.

Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent.

OBJECTIVES: This report presents an overview of preclinical data available on ferumoxtran-10, an ultrasmall superparamagnetic iron oxide nanoparticular contrast agent proposed for lymph node magnetic resonance imaging. MATERIALS AND METHODS: Pharmacokinetic, safety pharmacology, single- and repeat-dose toxicity, reproduction toxicity, and genotoxicity studies were performed with ferumoxtran-10 given intravenously (bolus injection) in mice, rats, rabbits, dogs, and monkeys. RESULTS: Ferumoxtran-10 was taken up by macrophages, mostly in liver, spleen, and lymph nodes, within 24 hours after bolus injection and underwent progressive metabolism. Toxicity was observed only at very high exposure levels and mainly was linked to a massive iron load after repeated injections. Ferumoxtran-10 was not mutagenic but was teratogenic in rats and rabbits. DISCUSSION: 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.

Multi-slice DCE-MRI data using P760 distinguishes between metastatic and non-metastatic rodent prostate tumors.

An intermediate molecular weight contrast agent P760 was used to investigate the ability of multi-slice dynamic contrast-enhanced MRI (DCE-MRI) to distinguish metastatic from non-metastatic rodent prostate tumors. Non-metastatic AT2.1 and metastatic AT3.1 prostate tumors originally derived from the Dunning prostate cancer model were implanted on the hind leg of Copenhagen rats. Multi-sliced DCE-MRI data were acquired on a SIGNA 1.5 T scanner and analyzed using a recently developed empirical mathematical model. The P760 multi-slice DCE-MRI data in combination with the empirical mathematical model successfully distinguished between metastatic and non-metastatic rodent prostate tumors. Specifically, fitting the data with the empirical model showed that metastatic tumors had significantly faster contrast media uptake (p<0.001) and slower washout rates (p<0.01) than non-metastatic tumors.

New model for analysis of dynamic contrast-enhanced MRI data distinguishes metastatic from nonmetastatic transplanted rodent prostate tumors.

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.