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Dose Finding Study of Gadopiclenol, a New Macrocyclic Contrast Agent, in MRI of Central Nervous System

Bendszus, Martin MD*; Roberts, Donna MD; Kolumban, Balint MD; Meza, José Alfonso MD§; Bereczki, Daniel MD, PhD; San-Juan, Daniel MD; Liu, Benjamin P. MD#; Anzalone, Nicoletta MD**; Maravilla, Kenneth MD††

Author Information
doi: 10.1097/RLI.0000000000000624

Abstract

More than 30 years after their introduction, gadolinium-based contrast agents (GBCAs) have revolutionized magnetic resonance imaging (MRI) and are widely used for a large range of indications, including brain, spinal, abdominal, cardiac, and vascular MRI.1 Their use has improved lesion detection and characterization with a great impact on treatment planning. Moreover, many studies have shown that increasing the dose of GBCAs could improve lesion detection and diagnostic performance.2–4 Nevertheless, despite their undisputed benefits, major concerns have been raised in recent years, regarding the safety of these contrast agents.

In 2006, a publication described the first study that showed an association between GBCAs use and the development of nephrogenic systemic fibrosis (NSF), a rare disorder that occurs in patients with impaired renal function.5 More recently, high signal intensity was identified in the dentate nucleus and the globus pallidus of patients with multiple previous administrations of linear GBCAs, and postmortem studies demonstrated gadolinium accumulation in the brain.6,7 An increase in signal intensity on unenhanced T1-weighted images after multiple administrations of linear GBCAs was also shown in other deep brain structures.8,9 After these reports and others, the use of linear GBCAs, characterized by a lower kinetic stability than macrocyclic GBCAs,10 was restricted by the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency. Hence, developing a new contrast agent, with both high relaxivity permitting diagnostic efficacy at a lower dose and macrocyclic structure offering stability, is more important and pertinent in this context.11

In vitro experiments showed that gadopiclenol, a new GBCA under development, is the first GBCA combining macrocyclic structure with very high relaxivity properties independent of protein-binding capability. Indeed, gadopiclenol shows very high relaxivity data in water, and no protein binding is found in rats, dogs, and humans. Moreover, increasing field strength from 1.41 to 3 T does not markedly change the relaxivity value in human serum.12

The study of the pharmacokinetic profile of gadopiclenol in dogs showed that it had an extracellular compartment distribution and no metabolism.12 Gadopiclenol has the highest kinetic stability under acidic conditions compared with gadoterate, gadobutrol, gadodiamide, and gadopentetate, ensuring a reduced risk of gadolinium deposition.12

In a recently published phase I/IIa clinical study, it has been shown that gadopiclenol has a dose-independent pharmacokinetic profile and is excreted in an unchanged form via the kidneys. Moreover, a similar pharmacokinetic, clinical, and biochemical safety profile was observed between healthy patients and patients with central nervous system (CNS) lesions.13

The purpose of this phase IIb study was to determine the effective and safe clinical dose(s) of gadopiclenol to be considered for further phase III studies, by comparing its effects with a standard dose of the GBCA approved for CNS indications with the highest relaxivity (gadobenate dimeglumine). The dose selection was based on the superiority of gadopiclenol in terms of contrast-to-noise ratio (CNR) compared with gadobenate dimeglumine in patients with CNS lesions.

MATERIALS AND METHODS

Study Design

This phase IIb study, conducted between June 2016 and January 2018, was an international, multicenter, double-blind, randomized, controlled, parallel dose groups, and cross-over study. The study was initiated after having received, for each participating center, approval from an Independent Ethics Committee and authorization from the National Regulatory Authority. All recruited patients provided written informed consent. The study was registered on ClinicalTrials.gov (registration no. NCT02633501).

Male and female adult patients presenting with lesion(s) with disruption of the blood-brain barrier, including at least one previously detected enhancing lesion, were eligible for inclusion. Patients with acute or chronic renal insufficiency (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) or congestive heart failure (class III/IV, New York Heart Association classification) were excluded.

The first subset involving the first recruited patient of each center was used to train off-site readers, and validate the imaging protocol/acquisition sequences and the safety assessment. Patients of this subset were randomly assigned (in a 1:1 ratio) using an interactive web response system to receive first a single intravenous injection of 0.05 or 0.1 mmol/kg of gadopiclenol (Guerbet, Aulnay-sous-Bois, France) then, after a washout period, 0.1 mmol/kg of gadobenate dimeglumine (MultiHance; Bracco Imaging, Milan, Italy) or vice versa. Both contrast agents were injected at a rate of 2 mL/second, followed by a saline flush to ensure complete injection.

The other recruited patients composing the second subset were randomly assigned by interactive web response system in a 1:1:1:1 ratio to receive 1 of the 4 doses of gadopiclenol (0.025, 0.05, 0.1, 0.2 mmol/kg) and to undergo 1 series of 2 MRIs (in a 1:1 ratio) performed first with gadopiclenol then with gadobenate dimeglumine after a washout period (2 to 14 days) or vice versa. Patients with brain metastases were included at a minimum of 20% in this second subset.

Imaging Protocol

Magnetic resonance imaging examination was performed at 1.5 T or 3 T magnetic field strength, depending on the center, with consistent intraindividual field strength. Sequence parameters varied within predefined ranges necessitated by the use of different imaging systems. However, the same MRI scanner, imaging planes, section prescriptions, and sequence parameters were used for both examinations in each patient. Two sets of MRI scans, including an unenhanced axial 3-dimensional (3D) T1-weighted gradient echo (GRE), 2-dimensional T2-weighted fluid attenuated inversion recovery, T2-weighted turbo spin echo (TSE), and 1 contrast-enhanced 2-dimensional T1-weighted spin echo (SE)/TSE and 3D T1-weighted GRE images, were acquired for the brain. Unenhanced sagittal T2-weighted TSE, T1-weighted SE/TSE, and contrast-enhanced axial T1-weighted SE/TSE and sagittal T1-weighted SE/TSE images were acquired for spine. Contrast-enhanced sequences were acquired right after injection without delay.

Scan parameters were as follows: TR = 400–800 milliseconds, TE <30 milliseconds, flip angle = 90 degrees, section thickness = 3–5 mm, FOV = 240 mm or more for the T1 SE/TSE sequence; TR < 100 milliseconds, TE = 2–5 milliseconds, flip angle <60 degrees, section thickness ≤1.5 mm, FOV = 256 mm or more for the T1 GRE sequence. Axial scans were all acquired along the inferior callosal plane to ensure image comparability between scans within patient and across patients.

Quantitative and Qualitative Evaluation

Magnetic resonance images were evaluated by on-site investigators and by 3 independent off-site blinded readers. To allow exact matching of lesions between the 2 MRI examinations for a given patient, an independent radiologist performed the “lesion tracking” based on the available CNS diagrams.

Training sessions were organized for the readers to ensure less variability in image interpretations. During these sessions, the conditions of observation (including calipers, zoom, pan, adjustment of window/level, and speed of images scrolling) were extensively explained and discussed among readers to get a consensus on the image review process.

The displays were liquid crystal displays. Each reader evaluated all images independently on a multimonitor. The ambient lighting in the reading room should not be turned off, nor should it be left completely on.

The primary criterion to evaluate diagnostic efficacy was the CNR assessed by off-site readers and calculated based on the background noise, using the following formula:

Figure
Figure

Additional secondary criteria of particular relevance were also assessed: lesion-to-brain ratio (LBR) and contrast enhancement percentage according to the following formulas:

Figure
Figure
Figure
Figure

where SIlesion is the signal intensity (SI) in the region of interest (ROI) in the lesion, SIht is the SI in the ROI in the healthy tissue, SDnoise is the standard deviation of background noise (for CNR), and SIpre and SIpost are the SI in the lesion ROI pre and post contrast agent administration, respectively. Signal intensity was measured on the axial 3D T1-weighted GRE sequence for brain and sagittal T1-weighted SE/TSE sequence for spine.

These variables were calculated for each patient, averaging the results on a maximum of 3 lesions. Only lesions that matched on both MRIs after lesion tracking were considered. The results for these variables were presented per independent blinded reader.

Intrareader variability was assessed for each independent reader by analyzing CNR in a subgroup of 10% of images randomly reintroduced and reread. Interreader variability was assessed on the whole set of images.

Technical adequacy of combined preinjection and postinjection MRI scans was evaluated before recording of the number, size, and location of enhancing lesions detected and the presence or absence of enhancement. For the 3 most representative enhancing lesions, lesion border delineation, internal morphology, and degree of contrast enhancement were graded on a 4-point scale. Each investigator/independent blinded reader recorded the diagnosis and the confidence assigned to the diagnosis graded on a 5-point scale (from 1 to 5) for each patient. Three other independent off-site blinded readers were involved in reading of images in a global matched-pairs fashion to assess the overall diagnostic preference.

Safety Evaluation

The safety set included all patients who had received at least 1 injection. Vital signs and electrocardiography (ECG) measurements were performed before and at 45 minutes, 2 to 4 hours, and 24 hours after each contrast agent injection. Tolerance at injection site was assessed 45 minutes, 2 to 4 hours, and 24 hours postinjection. Collection of blood and urine samples for subsequent laboratory analysis was performed before and 24 hours after each MRI examination. Adverse events (AEs) were monitored from signature of informed consent to last follow-up evaluation.

Statistical Methods

Statistical analyses and descriptive summaries were performed using SAS (Version 9.2, SAS Institute Inc, Cary, NC). All statistical tests were one-sided at the significance level of 0.025.

Student t test with Holm's step-down method for multiple comparison was used to analyze CNR, LBR, and contrast enhancement percentage. The Holm's step-down testing procedure started with the most significant comparison and continued till a nonsignificant comparison occurred.

Lesion visualization scores were compared using a mixed model for correlated data based on the sum of scores obtained from each lesion visualization variable. Overall diagnostic preference comparison was performed using a Wilcoxon signed-rank test.

RESULTS

Overall, 280 patients were randomized, 272 received at least the first injection (safety set) and 240 received the 2 injections. The mean (SD) age of patients of the safety set was 53.8 (13.6) years, mean (SD) weight was 75.7 (17.6) kg, and no differences were observed between the different groups. Overall, 58.5% were women, and the majority of patients were white. Brain metastases, mainly from lung, breast, or bladder cancer, were present in 22.5% of the patients. The other patients presented mostly with meningioma (27.5%), acoustic neuroma (10.8%), benign pituitary tumor (9.2%), and primary intra-axial tumor (4.6%).

The MRIs were performed with machines at 1.5 T for 72% of the patients and 3 T for 28% of the patients.

Quantitative Evaluation

The primary criterion, CNR, was calculated on a maximum of 3 enhanced lesions per patient and by 3 independent blinded readers. For all independent readers, gadopiclenol at 0.1 and 0.2 mmol/kg demonstrated a statistically significant superiority for CNR as compared with gadobenate dimeglumine at 0.1 mmol/kg (P ≤ 0.0007), with a percentage increase of 32% to 45% and 40% to 71%, respectively. Gadopiclenol at 0.05 mmol/kg showed a CNR of similar magnitude as gadobenate dimeglumine at 0.1 mmol/kg, with no statistically significant difference (Table 1). When expressed as a function of gadopiclenol dose for each independent reader, CNR showed a linear relationship with the different doses of gadopiclenol (Fig. 1).

TABLE 1
TABLE 1:
Primary Criterion—Contrast-to-Noise Ratio
FIGURE 1
FIGURE 1:
Dose-response relationship between contrast-to-noise ratio (CNR) and the dose of gadopiclenol used. Each shape (round, square, and triangle) represents the arithmetic mean for each gadopiclenol dose and independent reader and the error bars the standard deviation, whereas the dotted lines are the corresponding linear model for each independent reader.

For the intrareader variability, results showed a fair to good correlation with an intraclass correlation coefficient of 0.43, 0.76, and 0.66 for reader 1, 2, and 3, respectively (see Table, Supplemental Digital Content 1, which illustrates intra-off-site reader variability in the evaluation CNR, http://links.lww.com/RLI/A489). A good interreader correlation was also observed with an intraclass correlation coefficient of 0.68 between readers 1 and 2, 0.72 between readers 2 and 3, and 0.66 between readers 1 and 3 (see Table, Supplemental Digital Content 2, which illustrates inter-off-site reader variability in the evaluation CNR, http://links.lww.com/RLI/A490).

Similar results were obtained for LBR and contrast enhancement percentage, as secondary criteria. Gadopiclenol at 0.1 and 0.2 mmol/kg demonstrated a statistically significant superiority as compared with gadobenate dimeglumine at 0.1 mmol/kg (P < 0.0002), whereas it was of similar magnitude at 0.05 mmol/kg, with no statistically significant difference (Tables 2 and 3).

TABLE 2
TABLE 2:
Secondary Criterion—Lesion-to-Brain Ratio
TABLE 3
TABLE 3:
Secondary Criterion—Contrast Enhancement Percentage

Qualitative Evaluation

Overall, 98.2% of images were considered as adequate and no major imbalance in the number of technically inadequate images with the 2 contrast agents was observed. For reader 1 and 3, 14 and 8 images, respectively, were considered as not adequate, mainly for artifacts due to patient, whereas for reader 2, only 2 images were not adequate for artifacts due to patient and injection technical failure. For the on-site reading by the investigators, 6 images were not adequate, mainly for artifacts due to patient with gadopiclenol and injection technical failure with gadobenate dimeglumine.

The number of patients with more than one enhancing lesion was not sufficient to draw any conclusion regarding the difference in number of enhancing lesions detected by each contrast agent.

Regarding lesion visualization variables (Table 4), the mean sum of scores for lesion contrast enhancement was higher with gadopiclenol at 0.1 and 0.2 mmol/kg compared with gadobenate dimeglumine at 0.1 mmol/kg, with statistical significance (P < 0.025) for 2 of 3 off-site readers for gadopiclenol at 0.1 mmol/kg. For lesion border delineation and visualization of lesion internal morphology variables, the mean sum of scores tended to be higher with gadopiclenol at 0.1 and 0.2 mmol/kg, with statistical significance at 0.2 mmol/kg for reader 1.

TABLE 4
TABLE 4:
Lesion Visualization Variables (Lesion Border Delineation, Visualization of Lesion Internal Morphology, and Lesion Contrast Enhancement)

The median level of diagnostic confidence on a scale from 1 (nil) to 5 (excellent) was 4 (high) for readers 1 and 2, and 5 for reader 3 for all gadopiclenol doses and for gadobenate dimeglumine. Likewise, the median level of confidence was 5 for on-site investigators for both contrast agents.

Overall diagnostic preference was expressed as gadopiclenol is preferred to gadobenate dimeglumine, no difference between the 2 contrast agents or gadobenate dimeglumine is preferred to gadopiclenol (Fig. 2). All 3 readers expressed a large preference for gadopiclenol at 0.2 mmol/kg compared with gadobenate dimeglumine (58.3% to 85.4% of cases). They also mostly preferred images with gadopiclenol at 0.1 mmol/kg (45.3% to 86.8% of images) or expressed no preference (9.4% to 49.1%). Moreover, the 3 readers predominantly reported no preference when comparing images with gadopiclenol at 0.05 mmol/kg to those with gadobenate dimeglumine (46.6% to 77.6%). Images with gadobenate dimeglumine were mostly preferred to images with gadopiclenol at 0.025 mmol/kg (61.8% to 90.9%).

FIGURE 2
FIGURE 2:
Overall diagnostic preference. Analysis was performed by 3 other independent readers on data available for the 2 MRI examinations, and data are presented as stacked bar graphs. The number of patients for each group is 48 for 0.2 mmol/kg, 53 for 0.1 mmol/kg, 58 for 0.05 mmol/kg, and 55 for 0.025 mmol/kg. Statistical significance is indicated on each bar as **** for P < 0.0001 or not significant (ns).

Examples of brain contrast-enhanced MRI scans of patients with brain metastases after gadopiclenol administration (0.05 mmol/kg or 0.1 mmol/kg) or gadobenate dimeglumine administration at 0.1 mmol/kg are shown in Figure 3 and Figure 4.

FIGURE 3
FIGURE 3:
Examples of contrast-enhanced MRI scans of patients after gadopiclenol or gadobenate dimeglumine administration in patients with brain lesions. A and B, Images show brain MRI scans (3D GRE) of a 65-year-old female patient with brain metastasis from lung cancer, obtained after gadopiclenol administration at 0.05 mmol/kg (A) or gadobenate dimeglumine at 0.1 mmol/kg (B). C and D, Images show brain MRI scans (3D GRE) of a 38-year-old male patient with brain metastasis from lung cancer, obtained after gadopiclenol administration at 0.1 mmol/kg (C) or gadobenate dimeglumine at 0.1 mmol/kg (D). White arrows are pointing toward the corresponding lesion of each MRI scan.
FIGURE 4
FIGURE 4:
Example of MRI scans before and after gadopiclenol or gadobenate dimeglumine administration in a 54-year-old male patient with brain metastasis from lung cancer. A–C, Images refer to T2-weighted (A), T1-weighted SE before (B), and 3D GRE after (C) gadopiclenol administration at 0.1 mmol/kg. D–F, Images refer to T2-weighted (D), T1-weighted SE before (E), and 3D GRE after (F) gadobenate dimeglumine administration at 0.1 mmol/kg. White arrows are pointing toward the corresponding lesion of each MRI scan, except for panel F where no enhancing lesion was present.

Safety Evaluation

Postinjection AEs considered by the investigator as related to gadopiclenol and gadobenate dimeglumine were reported in 11.7% and 12.1% of the patients, respectively. No differences were shown between gadopiclenol and gadobenate dimeglumine with regard to the number, nature, seriousness, and severity of AEs. Overall, the most frequent postinjection AEs considered related to the contrast agent were injection site pain, headache, injection site coldness, and fatigue (with both agents); diarrhea (with gadopiclenol); and nausea (with gadobenate dimeglumine).

Adverse events were assessed as related to gadopiclenol in 5.4% of patients who received a dose of 0.025 or 0.05 mmol/kg, 14.3% of the patients who received a dose of 0.1 mmol/kg, and 23.2% of the patients who received a dose of 0.2 mmol/kg, suggesting a possible dose-effect relationship for injection site pain and gastrointestinal disorders.

Four postinjection serious adverse events (SAEs) were reported, 2 for each contrast agent. One SAE was assessed as related to gadopiclenol, involving a patient who experienced an increase in creatinine >25% within 24 hours (0.71 to 0.90 mg/dL) but with values of blood creatinine and eGFR (91.2 to 69.3 mL/min/1.73 m2) that remained in the normal ranges. One SAE was assessed as related to gadobenate dimeglumine (seizure). All SAEs resolved and no deaths were reported.

No safety concerns were detected in the laboratory results. Values of serum creatinine and eGFR measured 1 day after first or second MRI were similar to baseline values, with no more than 15% change for more than 80% of the patients, whereas changes of more than 25% occurred in less than 2% of patients, equally for gadopiclenol and gadobenate dimeglumine. Changes from baseline for the values of blood urea nitrogen and cystatin C were also similar between gadopiclenol and gadobenate dimeglumine.

Vital signs remained mostly stable during the study, and no safety concerns were detected on centralized ECG readings, especially no QT prolongation.

DISCUSSION

The utility of GBCAs in the initial diagnosis and follow-up of numerous diseases is undisputable. Yet, there is increasing concern that these agents accumulate in various organs, in particular, the brain and bones, with uncertain clinical consequences. Accumulation in tissue has been shown to be dependent on the chemical structure of the agent.14 Several nonclinical and clinical studies showed that use of linear but not macrocyclic GBCAs was associated with gadolinium deposition into specific areas of the brain.8,9,15–17 Moreover, multiple administrations of macrocyclic GBCAs in pediatric patients was not associated with brain hyperintensity.18,19

As a result of these multiple reports, linear contrast agents were largely abandoned in Europe and Japan. For all agents in clinical practice, the ALARA principle (as low as reasonably achievable) should be applied, which means to use as little gadolinium as possible to achieve diagnostic MRI scans. The current study demonstrates that at 0.05 mmol/kg of gadolinium, gadopiclenol, the new high relaxivity macrocyclic agent, shows a similar diagnostic efficacy to gadobenate dimeglumine (Multihance, the approved GBCA at the time of the study with the highest relaxivity) at 0.1 mmol/kg, in patients with contrast-enhancing cerebral lesions. Likewise, this new contrast agent was superior at the same and double dose of gadolinium. These findings were consistent both with quantitative and qualitative analyses. Most importantly, there were no safety concerns for all groups, in clinical events, ECG, or laboratory findings.

Most of the GBCAs available have similar T1 relaxivity, and thus their contrast-enhancing capabilities are comparable. Exception is gadobenate dimeglumine, due to its weak and transitive interaction with human serum proteins. This feature results in an r1 relaxivity that is approximately 2- to 3-fold higher than the relaxivity of other agents measured in human plasma at 37°C.20–23 Gadopiclenol has no human plasma protein binding and exhibits a very high relaxivity in water (r1 = 12.2 mM−1·s−1 at 1.41 T), compared with other GBCAs including gadobenate dimeglumine (r1 = 4 mM−1·s−1 at 1.5 T). Moreover, r1 value in human serum at 37°C did not markedly change between the clinical field strengths of 1.41 T (r1 = 12.8 mM−1·s−1) and 3 T (r1 = 11.6 mM−1·s−1)12 and remained notably high at ultrahigh field strength (r1 = 10.7 mM−1·s−1 at 7 T and 8.6 mM−1·s−1 at 9.4 T),24 thereby overcoming the issues associated with the currently available GBCAs in high fields.

This study comes with some limitations. This multicenter trial applied both 1.5 T and 3 T MRI machines. However, due to the cross-over design and within-patient consistency in field strength this should not affect the findings. Subgroup analyses according to field strength may be presented in the future. Second, we only tested 1 GBCA comparator, but this is the substance with the highest relaxivity overall, therefore similar or even better results should be expected when comparing gadopiclenol to other GBCAs. Third, the endpoints of the study (quantitative and qualitative assessment of contrast enhancement) should only be regarded as surrogates for improvement in patient management. Future studies will need to show that, in particular, improved conspicuity at 0.1 mmol/kg also confers a better patient management and clinical outcome.

Only patients with CNS contrast-enhancing lesions were included in this study. It can be expected, although that findings in the body may be similar.

In summary, this phase IIb study showed a linear dose-response relationship for CNR between the doses of 0.025 and 0.2 mmol/kg of gadopiclenol, a new high relaxivity contrast agent. Compared with gadobenate dimeglumine at 0.1 mmol/kg, gadopiclenol showed similar results at 0.05 mmol/kg and superiority at the same and double dose (0.1 and 0.2 mmol/kg, respectively) for the quantitative and qualitative efficacy endpoints. The results of this study showed that gadopiclenol, a new macrocyclic contrast agent, with very high relaxivity at 1.5 and 3 T, allows the same clinical efficacy while using a lower dose. If used at the current standard dose (0.1 mmol/kg), gadopiclenol could also improve diagnostic efficacy through better lesion detection and characterization. Future phase III clinical trials will be essential to determine the full potential of gadopiclenol.

REFERENCES

1. van der Molen AJ. Diagnostic efficacy of gadolinium-based contrast media. In: Thomsen HS, Webb JAW, eds. Contrast Media: Safety Issues and ESUR Guidelines [Internet]. Berlin, Heidelberg: Springer Berlin Heidelberg; 2014:181–191. Available at: https://doi.org/10.1007/174_2013_896.
2. Yuh WT, Fisher DJ, Runge VM, et al. Phase III multicenter trial of high-dose gadoteridol in MR evaluation of brain metastases. AJNR Am J Neuroradiol. 1994;15:1037–1051.
3. Sze G, Johnson C, Kawamura Y, et al. Comparison of single- and triple-dose contrast material in the MR screening of brain metastases. AJNR Am J Neuroradiol. 1998;19:821–828.
4. Katakami N, Inaba Y, Sugata S, et al. Magnetic resonance evaluation of brain metastases from systemic malignances with two doses of gadobutrol 1.0 m compared with gadoteridol: a multicenter, phase ii/iii study in patients with known or suspected brain metastases. Invest Radiol. 2011;46:411–418.
5. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21:1104–1108.
6. Kanda T, Ishii K, Kawaguchi H, et al. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology. 2014;270:834–841.
7. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275:772–782.
8. Zhang Y, Cao Y, Shih GL, et al. Extent of signal hyperintensity on unenhanced T1-weighted brain MR images after more than 35 administrations of linear gadolinium-based contrast agents. Radiology. 2017;282:516–525.
9. Marie GPO, Pozeg P, Meuli RA, et al. Spatiotemporal pattern of gadodiamide-related T1 hyperintensity increase within the deep brain nuclei. Invest Radiol. 2018;53:748–754.
10. Port M, Idée JM, Medina C, et al. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals. 2008;21:469–490.
11. Runge VM, Heverhagen JT. Advocating the development of next-generation high-relaxivity gadolinium chelates for clinical magnetic resonance. Invest Radiol. 2018;53:381–389.
12. Robic C, Port M, Rousseaux O, et al. Physicochemical and pharmacokinetic profiles of gadopiclenol: a new macrocyclic gadolinium chelate with high T1 relaxivity. Invest Radiol. 2019;54:475–484.
13. Hao J, Bourrinet P, Desché P. 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). Invest Radiol. 2019;54:396–402.
14. Robert P, Lehericy S, Grand S, et al. T1-weighted hypersignal in the deep cerebellar nuclei after repeated administrations of gadolinium-based contrast agents in healthy rats: difference between linear and macrocyclic agents. Invest Radiol. 2015;50:473–480.
15. Boyken J, Frenzel T, Lohrke J, et al. Gadolinium accumulation in the deep cerebellar nuclei and globus pallidus after exposure to linear but not macrocyclic gadolinium-based contrast agents in a retrospective pig study with high similarity to clinical conditions. Invest Radiol. 2018;53:278–285.
16. Rasschaert M, Emerit A, Fretellier N, et al. Gadolinium retention, brain T1 hyperintensity, and endogenous metals: a comparative study of macrocyclic versus linear gadolinium chelates in renally sensitized rats. Invest Radiol. 2018;53:328–337.
17. Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology. 2015;275:783–791.
18. Pozeg P, Forget J, Meuli RA, et al. Age, but not repeated exposure to gadoterate meglumine, is associated with T1- and T2-weighted signal intensity changes in the deep brain nuclei of pediatric patients. Invest Radiol. 2019;54:537–548.
19. Radbruch A, Haase R, Kickingereder P, et al. Pediatric brain: no increased signal intensity in the dentate nucleus on unenhanced T1-weighted MR images after consecutive exposure to a macrocyclic gadolinium-based contrast agent. Radiology. 2017;283:828–836.
20. Rohrer M, Bauer H, Mintorovitch J, et al. Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol. 2005;40:715–724.
21. Cavagna FM, Maggioni F, Castelli PM, et al. Gadolinium chelates with weak binding to serum proteins. A new class of high-efficiency, general purpose contrast agents for magnetic resonance imaging. Invest Radiol. 1997;32:780–796.
22. Giesel FL, von Tengg-Kobligk H, Wilkinson ID, et al. Influence of human serum albumin on longitudinal and transverse relaxation rates (r1 and r2) of magnetic resonance contrast agents. Invest Radiol. 2006;41:222–228.
23. Pintaske J, Martirosian P, Graf H, et al. Relaxivity of gadopentetate dimeglumine (Magnevist), gadobutrol (Gadovist), and gadobenate dimeglumine (MultiHance) in human blood plasma at 0.2, 1.5, and 3 Tesla. Invest Radiol. 2006;41:213–221.
24. Fries P, Massmann A, Robert P, et al. Evaluation of gadopiclenol and P846, 2 high-relaxivity macrocyclic magnetic resonance contrast agents without protein binding, in a rodent model of hepatic metastases: potential solutions for improved enhancement at ultrahigh field strength. Invest Radiol. 2019;54:549–558.
Keywords:

gadopiclenol; GBCA; MRI; phase IIb; dose-response; relaxivity; safety

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