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

Abstract

Objectives The aim of this study was to determine a safe and effective dose of gadopiclenol, a new high relaxivity macrocyclic gadolinium-based contrast agent. Based on the contrast-to-noise ratio (CNR) as primary criterion, this new agent was compared with gadobenate dimeglumine in patients with contrast-enhancing central nervous system lesions. Methods and Materials This phase IIb international, multicenter, double-blind, randomized, controlled, parallel dose groups, and cross-over study included adult patients with known or highly suspected lesions with disrupted blood-brain barrier. Patients were randomized to 1 of 4 doses of gadopiclenol (0.025, 0.05, 0.1, 0.2 mmol/kg) and to 1 series of 2 magnetic resonance imaging scans: gadopiclenol then gadobenate dimeglumine at 0.1 mmol/kg or vice versa. The qualitative and quantitative efficacy evaluations were performed by 3 independent off-site blinded readers. Adverse events were monitored up to 1 day after second magnetic resonance imaging. Results The study population included 272 patients (58.5% females) with a mean (SD) age of 53.8 (13.6) years. The superiority of gadopiclenol over gadobenate dimeglumine was statistically demonstrated at 0.2 and 0.1 mmol/kg for all readers with an increase in CNR of more than 30% (P ≤ 0.0007). At 0.05 mmol/kg, gadopiclenol showed a CNR of similar magnitude as gadobenate dimeglumine at 0.1 mmol/kg, with no statistically significant difference. Similar results were obtained for lesion-to-brain ratio and contrast enhancement percentage, as secondary criteria. The relationship between CNR and dose of gadopiclenol was linear for all readers. Mean scores for lesion visualization variables, particularly lesion contrast enhancement, tended to be higher with gadopiclenol at 0.1 and 0.2 mmol/kg compared with gadobenate dimeglumine. All 3 readers mainly expressed an overall diagnostic preference for images with gadopiclenol at 0.1 mmol/kg (45.3%, 50.9%, or 86.8% of images) or expressed no preference (49.1%, 49.1%, or 9.4%, respectively), whereas preference for images with gadobenate dimeglumine was reported by 2 readers for 3.8% and 5.7% of the images. Predominantly, no preference was expressed when comparing images with gadopiclenol at 0.05 mmol/kg to those with gadobenate dimeglumine. Rates of adverse reactions were comparable for gadopiclenol (11.7%) and gadobenate dimeglumine (12.1%). Changes from baseline of more than 25% in serum creatinine and estimated glomerular filtration rate 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. No safety concerns were detected on centralized electrocardiography readings. Conclusions Between the doses of 0.025 and 0.2 mmol/kg of gadopiclenol, the increase in CNR is linear. Compared with gadobenate dimeglumine at 0.1 mmol/kg, the doses of 0.05 and 0.1 mmol/kg of gadopiclenol gave similar or significantly greater contrast enhancement, respectively, and thus both doses can be considered for future phase III studies.

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

“…Gadopiclenol had no effect on the action potential of rabbit Purkinje fibres nor did it prolong the QTc interval in vivo in conscious dogs (Guerbet, data on file). Further, no cardiac events were reported in the first‐in‐human study 13 and in a dose–response phase IIb study 14 …”

“…Further, no cardiac events were reported in the first-in-human study 13 and in a dose-response phase IIb study. 14 In the present study, the QT/QTc interval prolongation of gadopiclenol was investigated in a dedicated thorough QTc study, which was performed according to the ICH E14 guideline. 15…”

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

“…It was shown some time ago that lanthanide complexes of the heptadentate ligand PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), which contain a pyridine moiety fused to the cyclen ring, have surprisingly high kinetic inertness for a bishydrated chelate [ 55 ]. Both of these principles (pyridine fusion and sidearm substitution) were applied in the design of Gadopiclenol, a high relaxivity GBCA currently in human clinical trials [ 56 , 57 , 58 , 59 ] to achieve excellent kinetic stability. A 2- to 3-fold greater relaxivity enhancements compared with current GBCA were achieved through a combination of two coordinating water molecules and slower molecular motion [ 57 ].…”

“… a Based on the EMA recommendation [ 123 , 124 ]. b Low risk by design [ 57 , 58 , 125 , 126 , 127 , 128 ], no T 1 hyperintensity in animal models [ 56 , 126 , 129 ]. …”

Role of gadolinium-based contrast agents in neurological disorders

“…It is possible that machine learning could lead to a 10-fold reduction in the required contrast dose [90]. Recently published results of a phase IIb clinical study on the new high relaxivity macrocyclic GBCA gadopiclenol suggest that a reduced dose of gadopiclenol, compared to clinically used dosages, is possible without a reduction in CNS image quality [91]. Moreover, there are attempts to improve GBCAs by replacing the standard chelate agents with carbon nanomaterials.…”