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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)

Hao, Jing, MD; Bourrinet, Philippe, PharmD, PhD; Desché, Pierre, MD

doi: 10.1097/RLI.0000000000000556
Original Articles

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 under the trial registration number NCT03603106.

From the Guerbet, Roissy CDG Cedex, France.

Received for publication December 14, 2018; and accepted for publication, after revision, January 25, 2019.

Conflicts of interest and sources of funding: J.H., P.B., and P.D. are employees of Guerbet. This work is part of the ISEULT project and was funded in part by Banque Publique d'Investissement (France) and by Guerbet.

Correspondence to: Jing Hao, MD, Guerbet, BP57400, 95943 Roissy CDG Cedex, France. E-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Online date: March 13, 2019

The use of gadolinium-based contrast agents (GBCAs) has revolutionized the radiologic field since their introduction almost 30 years ago. These contrast agents have been extensively used in a large range of indications, particularly magnetic resonance imaging (MRI) examinations of central nervous system. Contrast enhancement has enabled improving tissue visualization, lesion characterization, and more sensitive detection of even very small lesions.

Gadolinium-based contrast agents can be categorized by their chemical structures into linear and macrocyclic agents and further subdivided by their charge (ionic or nonionic). In vitro experiments have shown that the macrocyclic compounds are the most stable, with an undetectable release of Gd3+ ions under physiological conditions.1

Evidences from the literature have linked the exposure to gadolinium with 2 safety concerns: the development of nephrogenic systemic fibrosis in at-risk subjects with impaired renal function2–4 and the potential retention of gadolinium in tissues (bone, brain, and skin) even in subjects with normal renal function.5–10 Consequently, the use of some less stable linear GBCAs more prone to release free gadolinium has been recently restricted by the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency, whereas the US Food and Drug Administration requested changes in the package inserts, with the same wording for all marketed GBCAs and the availability to patients of a medication guide.11 All agencies requested that the lowest possible dose is used when contrast-enhanced MRI is needed.

One of the common strategies to increase MRI sensitivity for the detection of brain lesions is increasing the dose of the contrast agent. Although a standard dose of GBCA is considered to be 0.1 mmol/kg body weight (BW), many studies have been published demonstrating improved diagnostic performance with double (0.2 mmol/kg) or even triple (0.3 mmol/kg) doses.12–14 However, using higher doses of contrast agent is limited today, considering the concerns described previously. Another alternative approach is to reach an equivalent diagnostic performance with the use of a lower dose of GBCA with higher relaxivity.15

Gadopiclenol is a new nonspecific, non–protein-binding, nonionic macrocyclic GBCA discovered and developed by Guerbet. A particular feature of gadopiclenol is its very high relaxivity, at least 2-fold higher compared with other commercially available GBCAs, whereas its relaxivity does not change markedly with increasing field (r1 relaxivity values from 12.8 mM−1·s−1 at 1.5 T to 11.6 mM−1·s−1 at 3 T and r2 relaxivity values from 15.1 mM−1·s−1 at 1.5 T to 14.7 mM−1·s−1 at 3 T, in Seronorm at 37°C). Its macrocyclic structure guarantees a strong stability of the complex to avoid release of free gadolinium.

Several preclinical studies indicated a good tolerance and a low toxicity profile of gadopiclenol at dose levels and exposure much higher than the anticipated clinical dose (unpublished data). Preliminary results in an experimental rat model of hepatic colorectal cancer metastases have demonstrated significantly higher enhancement properties of gadopiclenol as compared with another GBCA gadobutrol at the identical dose of 0.1 mmol/kg BW.16

The purpose of this first-in-human study was to evaluate the pharmacokinetics, safety profile, and pharmacodynamics of gadopiclenol after single ascending dose levels in healthy subjects and in patients with brain lesions.

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This single-center, ascending dose phase I/IIa study was conducted in Belgium from November 2013 to April 2015 and included 2 parts: a double-blind, randomized, placebo-controlled phase I in healthy subjects and an open-label phase IIa in patients with brain lesions.

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Ethical Considerations

The study was conducted in accordance with the guidelines of International Conference on Harmonization for Good Clinical Practice and with applicable local requirements. The study protocol was approved by an Independent Ethics Committee, and written informed consent was obtained from each subject/patient at screening.

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Study Population

In phase I, male or female subjects with good health status between 18 and 45 years old with a body mass index of 18 to 30 kg/m2 were enrolled. Good health was determined by the investigator based on medical history, clinical examination including 12-lead electrocardiogram (ECG), vital signs (blood pressure, pulse rate, respiratory rate, and body temperature), and laboratory tests at selection and inclusion.

In phase IIa, adult patients having at least one brain lesion with a disruption of the blood-brain barrier (BBB) and/or with intracranial abnormal vascularity were enrolled. The lesion(s) must have been detected by a previous computed tomography or MRI assessment.

Overall, subjects or patients with acute or chronic renal insufficiency (ie, estimated creatinine clearance <90 mL/min), with known class III/IV congestive heart failure according to the New York Heart Association classification, with a history of severe allergic or anaphylactic reactions to any allergen including drugs and contrast agents, or who had received any contrast agent within 1 week before inclusion, who were going to receive any contrast agent within 1 week after inclusion, or who were going to have any interventions during the course of the study were excluded from the study.

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Contrast Agent Administration

In phase I, 54 subjects were randomized to receive 1 of the 6 doses (0.025, 0.05, 0.075, 0.1, 0.2, or 0.3 mmol/kg) of gadopiclenol (Guerbet, Aulnay sous Bois, France) or placebo (NaCl 0.9%) at a ratio of 2:1 using an Interactive Web Response System. Gadopiclenol and placebo were administered in one single intravenous administration at the same injection rate: 0.5 mL/s to the first 3 subjects of each group, 1 mL/s to the 3 following subjects, and 2 mL/s to the last 3 subjects. The injection rate was increased only if the tolerance was acceptable. After the injection of contrast agent, a saline flush of at least 20 mL at same injection rate was done. Subjects were confined from the night before dosing until 2 days after dosing with no permitted consumption of alcohol, tobacco, caffeine, or grapefruit juice and with a requested water intake of 2 L/d.

In phase IIa, 12 patients received 1 of the 4 doses (0.05, 0.075, 0.1, or 0.2 mmol/kg) of gadopiclenol. Dosing of patients started only when clinical safety data in phase I were confirmed to be satisfactory. An injection rate of 2 mL/s was used for all patients, based on the good tolerance in healthy subjects. The confinement period lasted 24 hours after dosing.

The volume to be administered was calculated according to subject/patient's BW.

For both parts of the study, dose escalation from one group to a next group was sequential and allowed only if all the clinical and biological data of all subjects/patients had been reviewed by the Data Safety Monitoring Board and were judged satisfactory with no major safety concern raised.

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Pharmacokinetics Assessments

A total of 13 blood samples of 6 mL each were collected into polypropylene tubes containing sodium heparinate over a 24-hour period for both phases: before administration and 2, 5, 10, 20, 30, 45 minutes, 1, 2, 4, 6, 8, and 24 hours postadministration. Phase I included an additional blood sample 12 hours postadministration. Urine specimen collection was done for phase I only: a sample was collected before administration, then total urine was collected during 3 intervals postadministration 0 to 6, 6 to 24, and 24 to 48 hours. An additional urine sample was collected 7 days postadministration at the safety visit. All plasma and urine samples were stored at −20°C.

Gadopiclenol assay in plasma and urine and pharmacokinetic analysis were performed by Eurofins ADME-Bioanalyses (Vergèze, France). The analytical methods in sodium heparin plasma and urine involved protein precipitation and dilution with methanol, respectively. Presence and concentration of the gadopiclenol molecule in samples were analyzed using a validated liquid chromatography–mass spectrometry/mass spectrometry detection method with a lower limit of quantitation of 5 μg/mL.

Pharmacokinetics assessments were performed using a noncompartmental approach with Kinetica Version 4.3 software (Thermo Electron Corporation, Philadelphia). An independent model method was chosen, with trapezoidal rules. The following pharmacokinetic parameters were calculated: maximum plasma concentration (Cmax), time to reach maximum plasma concentration (tmax), area under the plasma concentration-time curve from administration to the last measurable concentration (AUClast), AUC from administration to infinity (AUCinf), terminal elimination half-life (t1/2), total clearance (Cl), renal clearance (Clr), volume of distribution (Vd), and fraction excreted (Fe). Below the limit of quantitation (BLQ) values were substituted by zeros, except for the BLQ values between quantifiable concentrations, which were treated as missing values. BLQ values obtained at the last time points were excluded for the analysis.

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MRI Examination and Pharmacodynamics Assessments

Three subjects of the 4 dose groups 0.05, 0.075, 0.1, and 0.2 mmol/kg in phase I and all patients in phase IIa underwent MRI examination. Magnetic resonance imaging was performed at 1.5 T (GE Signa 1.5 T EchoSpeed Excite; Mobile MRI System). The protocol included axial T1-weighted, T2-weighted, and T2-weighted FLAIR sequences for precontrast images. T2-weighted FLAIR and axial, coronal, and sagittal T1-weighted sequences were mandatory for postcontrast images.

All images were read by an off-site experienced radiologist. In phase I, 4 normal structures (pineal gland, pituitary gland, choroid plexus, and nasal membrane) were evaluated. In phase IIa, up to 5 brain lesions were assessed. A qualitative evaluation of the visualization of brain structures or lesions was done on pre and paired (pre + post) contrast images through the scoring of 3 criteria (border delineation, internal morphology, and contrast enhancement) with a 3-point scale for each criterion (1, none; 2, moderate; 3, clear and complete for border delineation; 1, poor; 2, moderate; 3, sufficient for internal morphology; 1, none; 2, weak; 3, clear and bright for contrast enhancement). Signal intensity was measured on preimage and postimage using regions of interest. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and prepost variations in signal intensity, SNR, and CNR were calculated.

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Safety Evaluation

A safety visit was performed 7 days postinjection of gadopiclenol for phase I and 24 hours postinjection for phase IIa. Same safety assessments were done for both phases.

Biochemistry (sodium, potassium, chloride, glucose, blood urea nitrogen, creatinine, total protein, calcium, phosphorus, total bilirubin, conjugated bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, prothrombin time/International normalized ratio) and hematology tests (red blood cells, white blood cells, neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelet count, hemoglobin, hematocrit, and mean red blood cells volume) were performed on blood samples at inclusion and safety visits for both phases and additionally after 24 and 48 hours postadministration for phase I.

Cardiac function was monitored through 12-lead ECG measurements (heart rate [RR interval], PR interval, QRS duration, QT, QT Bazett [QTcB], and QT Fridericia [QTcF]) performed at inclusion visit, before (within 30 minutes) and after gadopiclenol administration (from 30 minutes to 48 hours for phase I and from 30 minutes to 8 hours for phase IIa), and at safety visit.

Renal function was assessed at inclusion and safety visits for both phases, and 24 and 48 hours after administration for phase I using creatinine clearance estimated according to the Cockcroft and Gault equation. Urinalysis via dipstick was done at inclusion and safety visits for both phases, and 24 hours after administration for phase I.

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) were measured in supine position at inclusion, before (within 30 minutes) and after gadopiclenol administration (from 5 minutes to 48 hours for phase I and from 5 minutes to 8 hours for phase IIa), and at safety visit.

Tolerance at the injection site was recorded during 24 hours after administration for both phases. Adverse events were collected throughout the subjects or patients' participation in the study and described by the investigator with regard to the nature, intensity (mild, moderate, severe), seriousness, outcome, and causal relationship to the treatment (not related, doubtfully related, possibly related).

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Statistical Methods

The statistical analysis of demographic, pharmacodynamics, and safety data was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC) separately on healthy subjects and patients at the end of each study phase. Descriptive statistics were used: sample size, mean, standard deviation (SD), minimum and maximum for quantitative variables; sample size, mean, SD, median, minimum, maximum, and percentiles for ordinal variables; and sample size and frequencies converted into percentages for qualitative variables.

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Study Population

In phase I, all 54 randomized healthy subjects completed the study: 36 subjects received gadopiclenol and 18 subjects, placebo. Demographic data and baseline characteristics were similar in the different treatment groups. Half of the subjects were male. The median of subjects' overall age was 26.0 years with a median age in the treatment groups ranging between 23 and 33.5 years. The median weight ranged from 65.00 to 81.65 kg.

Twelve patients were included and completed the phase IIa. Among them, 7 (58.3%) were male. A lower median age was observed for the 0.05 mmol/kg group (40.0 vs 56.0 years for the 0.075 and 0.1 mmol/kg groups and 53.0 years for the 0.2 mmol/kg group). The median weight ranged from 80.40 to 87.20 kg in the different dose groups. Patients presented with 1 to 9 lesions, disruption of the BBB in 75.0% of the patients and abnormal vascularity in 25.0%.

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The mean pharmacokinetics parameters of gadopiclenol measured in healthy subjects and patients with brain lesions after a single administration are displayed in Table 1.



For phase I, the gadopiclenol plasma concentration-time curves by dose group is presented in Figure 1. Maximum concentrations of gadopiclenol in plasma were achieved in an interval of 0.03 to 0.08 hours after administration. Mean Cmax and AUCinf increased proportionally to dose, with mean Cmax values increasing from 248.7 μg/mL (0.025 mmol/kg dose) to 3916.4 μg/mL (0.3 mmol/kg dose). Gadopiclenol was not quantifiable in both plasma and urine samples for the 18 subjects who received placebo.



The distribution volume ranged from 182 to 254 mL/kg and was consistent with the volume of extracellular water. Mean values of t1/2 were estimated between 1.50 and 2.09 hours. Urinary excretion is the major route of elimination of gadopiclenol with approximately 98% of the dose excreted in urine after 48 hours regardless of the dose administered. At 7 days postadministration, no gadopiclenol could be detected (values <lower limit of quantitation) in urine of subjects of the lowest dose groups (0.025 and 0.05 mmol/kg). For 2 subjects of the 0.1 mmol/kg group, 3 subjects of the 0.2 mmol/kg group and 4 subjects of the 0.3 mmol/kg group, quantifiable values were detected, ranging from 6 to 33 μg/mL. The gadopiclenol molecule was found under unchanged form in plasma and urine chromatographic profiles. Both total and renal clearances were independent of the dose administered with mean total clearance ranging from 91.7 to 106.4 mL/min.

In phase IIa, mean Cmax values ranged from 370.8 (0.05 mmol/kg dose) to 1434.9 μg/mL (0.2 mmol/kg dose) and were reached in an interval of 0.03 to 0.21 hours. As for healthy subjects, mean Cmax and AUCinf values increased proportionally with dose. Mean values of t1/2 were estimated between 1.79 and 2.04 hours.

Overall, similar concentrations and pharmacokinetic parameters were observed in patients versus healthy subjects at corresponding doses, and no differences in the pharmacokinetic parameters were seen between male and female.

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Pharmacodynamic Assessments (Qualitative and Quantitative)

In phase I, MRIs were not performed in the 3 subjects of the 0.2 mmol/kg group due to a technical problem with the MR machine. Therefore, 9 patients (75.0%) actually underwent the MRI examination.

The precontrast + postcontrast assessment of border delineation score was the same as the precontrast score in the 4 brain structures for all subjects of the placebo, 0.05 and 0.075 mmol/kg groups. For the 2 subjects who received the dose of 0.1 mmol/kg, the border delineation score of the choroid plexus and pituitary gland increased from “moderate” to “clear and complete” after gadopiclenol administration.

An improvement of the internal morphology score between precontrast and precontrast + postcontrast evaluations was shown in 1 subject of the 0.05 mmol/kg group for the pineal gland, in 1 subject of the 0.075 mmol/kg group for the choroid plexus, and in the 2 subjects of the 0.1 mmol/kg group for the choroid plexus, pineal, and pituitary glands. No other changes in internal morphology scores from the precontrast evaluation to the precontrast + postcontrast evaluation were observed.

For the 4 brain structures, a higher score in contrast enhancement was observed in all subjects who received gadopiclenol, whereas no contrast enhancement was shown with placebo. The contrast enhancement was “clear and bright” for half of the patients of the 0.05 and 0.075 mmol/kg groups and all patients of the 0.1 mmol/kg group in choroid plexus, for all patients in nasal membrane, and for all but 1 patient (of the 0.05 mmol/kg group) in pituitary gland. A “weak” contrast enhancement was observed in the pineal gland regardless of the dose of gadopiclenol administered.

In phase IIa, results of the qualitative evaluation of lesion visualization in patients are presented in Table 2. The precontrast scores of border delineation and internal morphology were maximum for most (≥50%) of the evaluated lesions. Consequently, no clear differences between preimages and preimages + postimages were observed for these 2 scores in the 4 dose groups.



After gadopiclenol administration, a “clear and bright” contrast enhancement was observed for 5/14 lesions (35.7%) in the 0.05 mmol/kg group, 10/12 lesions (83.3%) in the 0.075 mmol/kg, 2/2 lesions (100%) in the 0.1 mmol/kg, and 2/3 (66.7%) lesions in the 0.2 mmol/kg group. It should be noted that 9 nonenhancing lesions in the 0.05 mmol/kg group were inactive multiple sclerosis plaques, 1 nonenhancing lesion in the 0.075 mmol/kg group was cyst, and enhancement for 1 lesion in the group of 0.2 mmol/kg was not sufficiently visualized due to poor quality of images caused by MR technical issues.

All median pre-post variations in CNR, SNR, and SI were positive (see Table 3), with an increase proportional to dose.



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The frequencies of postinjection adverse events (AEs) for phase I and phase IIa are displayed in Table 4.



In phase I, the same proportion of subjects (50%) experienced at least one postinjection AE after gadopiclenol administration or after placebo administration, and these postinjection AEs were assessed as related to the treatment for 36.1% of subjects with gadopiclenol and 33.3% with placebo. No serious postinjection AEs were reported. The majority of postinjection AEs were mild in intensity and none were severe. The most frequent treatment-related AEs were injection site pain (gadopiclenol, 11.1%; placebo, 11.1%), headache (gadopiclenol, 11.1%; placebo, 11.1%), and injection site edema (gadopiclenol, 5.6%; placebo, 5.6%) (Table 5). No clear relationship between the increasing dose of gadopiclenol and incidence of postinjection AEs was observed.



No clinically relevant modifications of laboratory parameters were reported, and no treatment-emergent QTcB or QTcF values greater than 500 milliseconds or increases in QTcB or QTcF interval from baseline greater than 60 milliseconds were observed. Among vital signs, one case of body temperature increase was reported as an AE of mild intensity in one patient of the 0.05 mmol/kg group. This event was considered possibly related to gadopiclenol by the investigator and resolved after 1 hour without treatment. No other clinically relevant modifications of vital signs were observed. Injection site pain within 24 hours after injection was spontaneously reported by one subject in the placebo group.

In phase IIa, a total of 5 postinjection AEs were reported in 4 patients (33.3%) after administration of gadopiclenol (Table 4). Among them, one (mild decreased appetite) was assessed as doubtfully related to the contrast agent. A serious AE was reported in a 25-year-old woman with congenital cavernous hemangioma who was exposed to a dose of 0.075 mmol/kg of gadopiclenol before pregnancy. Genetic testing during pregnancy was positive for congenital hemangioma. The patient elected to undergo therapeutic abortion, which was reported as a serious AE of severe intensity and not considered related to the contrast agent.

No clinically relevant modifications of laboratory parameters, vital signs, and ECG measurements were reported, and a good tolerance at injection site was observed within 24 hours after injection.

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Six ascending doses were tested in this first-in-human study. Based on prerequisite toxicology studies in rats and dogs, the very low dose of 0.025 mmol/kg was chosen as a starting dose for the very first injection of gadopiclenol in human before escalating to 0.05 mmol/kg, and 0.3 mmol/kg was considered as the highest dose potentially used for certain indications. The pharmacokinetic profile of gadopiclenol is dose-independent (linear) in the dose range 0.025 to 0.3 mmol/kg as single dose in healthy volunteers and in the dose range 0.05 to 0.2 mmol/kg as single dose in patients with brain lesions, without difference between males and females. After intravenous injection, gadopiclenol is distributed within the extracellular fluid space as indicated by the small volume of distribution (ca 200–250 mL/kg). A rapid plasmatic clearance (approximately 100 mL/min) was observed, and the mean elimination half-life ranged from 1.5 to 2 hours. Renal clearance represented the immense majority of the total clearance, correlated with approximately 98% of the administered dose recovered in urine within 48 hours after administration. At 7 days postadministration, amounts of gadopiclenol in urine were below the detection limit for the 2 lowest dose groups (0.025 and 0.5 mmol/kg) or slightly above for some subjects in the highest dose groups (0.1 to 0.3 mmol/kg), suggesting a residual slow elimination from the body, as already described with other GBCA.17 The gadopiclenol molecule was found under unchanged form by liquid chromatography–mass spectrometry/mass spectrometry on plasma and urine chromatographic profiles, demonstrating the absence of biotransformation. All these pharmacokinetic features are typical of extracellular GBCA, and parameter values are fully consistent with those reported in the literature for other macrocyclic GBCA.18,19

An assessment of fecal excretion was not done because pharmacokinetic studies performed in rats and dogs after administration of a single intravenous dose showed that this elimination pathway was negligible (4.8%–8.7% and 4.8%–6.3% of the dose found in feces 168 hours after administration for rats and dogs, respectively). The pharmacokinetic profile observed in human was similar to that seen in these 2 species (unpublished data).

The potential effectiveness of gadopiclenol as a contrast agent was demonstrated by qualitative and quantitative evaluation of MR images in healthy subjects and patients with brain lesions. In healthy subjects, scores of contrast enhancement for choroid plexus, nasal membrane, pineal gland, and pituitary gland were all improved on precontrast + postcontrast images from the dose of 0.05 mmol/kg. In patients with brain lesions, qualitative evaluation revealed an improvement in the scores of contrast enhancement on the precontrast + postcontrast images for the majority of lesions. The contrast enhancement was scored “none” for 11/31 lesions. This lack of enhancement could be explained by the nature of the lesions, such as inactive multiple sclerosis plaques or cysts, in which the BBB is intact. Quantitative assessments showed positive variation in SI, CNR, and SNR of the lesions between precontrast and precontrast + postcontrast images in the dose range tested (from 0.05 to 0.2 mmol/kg), with a median increase proportional to dose. Overall, these are the preliminary evidences that, at lower dose than the standard dose of 0.1 mmol/kg, gadopiclenol could induce sufficient contrast enhancement.

Promising enhancement properties of gadopiclenol were also observed in a first in vivo animal study that aimed to compare gadopiclenol and gadobutrol at the identical dose of 0.1 mmol/kg BW. In a rat model of hepatic colorectal cancer metastases, approximately 2-fold higher values of CNR, SNR, and lesion enhancement were observed with gadopiclenol as compared with gadobutrol at all examination timepoints.16

Among the 8 currently available GBCAs, gadoxetate disodium (Primovist) and gadobenate dimeglumine (MultiHance) exhibit the highest T1 and T2 relaxivities.20 Gadobenate dimeglumine (r1 of 6.3 mM−1·s−1 and r2 of 8.7 mM−1·s−1 in plasma at 37°C and 1.5 T)20 is indicated for central nervous system and body imaging (restricted use to delayed liver imaging in Europe according to European Medicines Agency decision11), whereas gadoxetate disodium (r1 of 6.9 mM−1·s−1 and r2 of 8.7 mM−1·s−1 in plasma at 37°C and 1.5 T)20 is specifically used for liver imaging according to its pharmacokinetic properties. Greater relaxivity properties of these 2 linear GBCAs are due to their ability to interact with serum proteins, notably with human serum albumin.20,21 Consequently, relaxivity properties of these protein-binding GBCAs are dependent on the concentration of serum proteins,22 especially gadobenate dimeglumine for which relaxation rates are influenced by serum albumin concentration.23,24 A more pronounced decrease of relaxivity with increasing strength field have also been observed for protein-binding GBCAs than for extracellular GBCAs without protein binding.25

According to in vitro experiments showing a negligible binding of gadopiclenol to human plasma proteins, gadopiclenol is the first GBCA combining macrocyclic structure with high relaxivity properties not dependent on protein-binding capability. If these preliminary pharmacodynamic results are further confirmed by a larger phase IIb dose-response study, comparing gadopiclenol to another high relaxivity agent such as gadobenate dimeglumine, then, gadopiclenol could lead to a new paradigm in the dose-response relationship of GBCAs.

After gadopiclenol administration, a good clinical and biochemical safety profile was observed in healthy subjects as well as in patients with brain lesions. No serious AE related to contrast agent and no clinically relevant change in renal/liver function and hematology tests were reported. Electrocardiogram data showed no impact of this new contrast agent on the cardiac conduction or repolarization and no QT prolongation. Most frequent AEs assessed as related to gadopiclenol by the investigator were injection site pain (11.1%), headache (11.1%), and injection site edema (5.6%), all observed in an equivalent number of patients between gadopiclenol and placebo groups in phase I. The nature and intensity of AEs was consistent with that reported for other extracellular GBCAs.26–29 The product was well-tolerated at all doses tested, and no dose-related effect was observed on any safety data collected.

Limitations of that study are those inherent to first-in-human studies (phase I/IIa). The sample size was limited in both phases I and IIa, but the design of phase I was placebo-controlled, and a whole set of pharmacokinetic, pharmacodynamics, and safety measurements was performed overall. Pharmacokinetics evaluation was only assessed in healthy volunteers and patients with normal function. Because gadopiclenol is excreted via the kidneys, a dedicated study in patients with various degrees of renal impairment should be carried out during the development of the product. Regarding the pharmacodynamics evaluation, limited imaging results were obtained in a very small sample size. Furthermore, the technical conditions were not optimal (use of a mobile MRI), leading to a moderate quality of the majority of images. Consequently, these preliminary data need to be confirmed by a robust dose-response study with centralized image reading.

In conclusion, 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 GBCAs. Preliminary pharmacodynamic results in patients suggest that gadopiclenol is a promising contrast agent with the potential use of lower dose for clinical routine MRIs.

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The authors thank Professor Martin Bendszus (Universitätsklinikum Heidelberg, Germany) for reading the images and Anne-Coline Laurent for providing editorial support.

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gadopiclenol; GBCA; MRI; pharmacokinetics; phase I; phase IIa

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