Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bracco Imaging SPA, Via Egidio Folli, 50, 20134 Milan, Italy
Pharmacotherapeutic group: paramagnetic contrast media
ATC code: V08CA12
Gadopiclenol is a paramagnetic agent for Magnetic Resonance Imaging (MRI).
The contrast-enhancing effect is mediated by gadopiclenol which is a macrocyclic non-ionic complex of gadolinium, the active moiety which enhances the relaxation rates of water protons in its vicinity in the body, leading to an increase in signal intensity (brightness) of tissues.
When placed in a magnetic field (patient in MRI machine), gadopiclenol shortens the T1 and T2 relaxation times in targeted tissues. The extent to which a contrast agent can affect the relaxation rate of tissue water (1/T1 or 1/T2) is termed relaxivity (r1 or r2).
Gadopiclenol presents a high relaxivity in water (see Table 3) due to its chemical structure, because it can exchange two water molecules, which are linked to the gadolinium to complete its coordination number in addition to the four nitrogens and the three oxygens of the carboxylate functions of the gadopiclenol chelate. This explains that, gadopiclenol given at half dose of gadolinium compared to other non-specific gadolinium-containing contrast agents, may provide the same contrast enhancement.
Table 3. Relaxivity at 37°C for gadopiclenol:
| r1 (mmol-1.l.s-1) | r2 (mmol-1.l.s-1) | |||||
|---|---|---|---|---|---|---|
| Magnetic field | 0.47 T | 1.5 T | 3 T | 0.47 T | 1.5 T | 3 T |
| Relaxivity in water | 12.5 | 12.2 | 11.3 | 14.6 | 15.0 | 13.5 |
| Relaxivity in biological medium | 13.2 | 12.8 | 11.6 | 15.1 | 15.1 | 14.7 |
Two pivotal studies included adult patients undergoing MRI with gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) and MRI with gadobutrol at 0.1 mL/kg BW (equivalent to 0.1 mmol/kg BW). One study (Study 1; PICTURE) included 256 patients presenting with known or highly suspected CNS lesions with focal areas of disrupted BBB (e.g. primary and secondary tumors). The majority of patients (72%) presented with brain tumors, 20% had brain or spine metastases and 8% presented with other pathologies.
The other study (Study 2; PROMISE) included 304 patients with known or suspected abnormalities or lesions in other body regions (8% in head and neck, 28% in thorax, 35% in abdomen, 22% in pelvis and 7% in musculo-skeletal system) both based on results of a previous imaging procedure such as CT or MRI. The most frequent pathologies were breast tumors (23%) and liver tumors (21%).
The primary endpoint was the evaluation of lesion visualization, based on 3 co-criteria (border delineation, internal morphology and degree of contrast enhancement) by three independent blinded readers, using a 4-point scale. The mean of scores for each of the 3 lesion visualization co-criteria was calculated as the sum of scores for up to 3 most representative lesions divided by the number of lesions.
Both studies demonstrated:
The pooled analysis of the primary outcome over the three readers, and for each lesion visualization criterion also demonstrated the non-inferiority of gadopiclenol at 0.05 mmol/kg to gadobutrol at 0.1 mmol/kg in both studies, as shown in table 4 below.
Table 4. Lesion visualization – Off-site readings – Full analysis set:
| n patients | LS Mean (SE) | 95% CI difference | p-value | |||
|---|---|---|---|---|---|---|
| Gadopiclenol | Gadobutrol | Difference | ||||
| Study 1 (PICTURE) | ||||||
| Border delineation | 239 | 3.83 (0.02) | 3.82 (0.02) | 0.01 (0.02) | [-0.02; 0.05] | 0.5025 |
| Internal morphology | 239 | 3.83 (0.02) | 3.81 (0.02) | 0.02 (0.02) | [-0.01; 0.05] | 0.2006 |
| Degree of contrast enhancement | 239 | 3.73 (0.03) | 3.68 (0.03) | 0.05 (0.02) | [0.01; 0.09] | 0.0172 |
| Study 2 (PROMISE) | ||||||
| Border delineation | 273 | 3.60 (0.03) | 3.60 (0.03) | -0.00 (0.02) | [-0.05; 0.04] | 0.8987 |
| Internal morphology | 273 | 3.75 (0.02) | 3.76 (0.02) | -0.01 (0.02) | [-0.05; 0.03] | 0.6822 |
| Degree of contrast enhancement | 273 | 3.30 (0.04) | 3.29 (0.04) | 0.01 (0.03) | [-0.05; 0.07] | 0.8546 |
CI: Confidence Interval; LS: Least Squares; SE: Standard Error.
The secondary criteria evaluated included quantitative evaluations (Contrast to Noise Ratio, Lesion to Brain (background) Ratio and percentage of lesion enhancement), overall diagnostic preference and impact on patient management.
In Study 1, Lesion to Brain Ratio, and percentage of lesion enhancement were statistically significantly higher with gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) compared to gadobutrol at 0.1 mL/kg BW (equivalent to 0.1 mmol/kg BW) for all 3 readers. Contrast to Noise Ratio was statistically significantly higher for 2 readers. In Study 2, percentage of lesion enhancement was significantly higher with gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) compared to gadobutrol at 0.1 mL/kg BW (equivalent to 0.1 mmol/kg BW) and no statistically significant difference was observed for Lesion to Background Ratio.
Lesion visualisation parameters (e.g., co-primary endpoints and quantitative assessments, such as, Contrast to Noise Ratio, Lesion to Brain (background) Ratio and percentage of lesion enhancement) were assessed in all the lesions identified by the blinded readers, independently of their size, in more than 86% of patients in CNS study and in more than 81% of patients in Body study, who had no more than 3 lesions. In the remaining patients with more than 3 lesions visible, a subset of 3 most representative lesions were selected for assessment of the co-primary endpoints. Therefore, in those patients, the additional lesions were not assessed. Consequently, the technical capability of lesion visualisation for both contrast agents cannot be extrapolated for those non-selected lesions.
The overall diagnostic preference was assessed in a global matched-pairs fashion (reading of images from both MRI assessed side by side) by three additional blinded readers in each study. The results are summarized in the Table 5 below. In Study 1, in majority, the readers expressed a preference for images acquired with gadopiclenol. In Study 2, in majority, the readers expressed no diagnostic preference between images acquired with gadopiclenol and with gadobutrol.
Table 5. Results on overall diagnostic preference for Study 1 (CNS) and Study 2 (Body):
| Reader | N | gadopiclenol preferred | No preference | gadopiclenol preferred | p-value* | |
|---|---|---|---|---|---|---|
| Study 1 (CNS) | 4 | 241 | 108 (44.8%) | 98 (40.7%) | 35 (14.5%) | <0.0001 |
| 5 | 241 | 131 (54.4%) | 52 (21.6%) | 58 (24.1%) | <0.0001 | |
| 6 | 241 | 138 (57.3%) | 56 (23.2%) | 47 (19.5%) | <0.0001 | |
| Study 2 (Body) | 4 | 276 | 36 (13.0%) | 216 (78.3%) | 24 (8.7%) | 0.1223 |
| 5 | 276 | 40 (14.5%) | 206 (74.6%) | 30 (10.9%) | 0.2346 | |
| 6 | 276 | 33 (12.0%) | 228 (82.6%) | 15 (5.4%) | 0.0079 |
* Wilcoxon signed-rank test.
A change in patient treatment plan was reported after administration of gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) in 23.3% and 30.1% of patients in Study 1 and Study 2, respectively. Analysis per subgroups in Study 1 revealed that treatment plan could be changed for 64% of the 22 patients for whom the investigator considered that diagnosis was not assessable (or grade of glial tumor could not be determined) based on unenhanced MRI, 28% of 81 patients with malignant diagnosis and about 12% of 111 patients with non-malignant diagnosis.
In Study 2, treatment plan could be changed after MRI with gadopiclenol for 41% of the 22 patients with non-assessable diagnosis based on unenhanced MRI, 32% of 165 patients with malignant diagnosis and 14% of 64 patients with non-malignant diagnosis.
A post-hoc reading of all images from both pivotal studies for CNS and Body indications was conducted in a fully blinded, unpaired, randomised manner . A high level of concordance in lesion detectability between gadopiclenol at 0.05 mmol/kg and gadobutrol at 0.1 mmol/kg was observed at lesion and at patient level. The results are summarized in Table 6 below.
Table 6. Concordance in lesion detectability between gadopiclenol at 0.05 mmol/kg and gadobutrol at 0.1 mmol/kg:
| Perfect match at lesion level* | PPerfect match at patient level* | |
|---|---|---|
| Study 1 (CNS) | 88.0% to 89.8% | 84.3% to 86.0% |
| Study 2 (Body) overall | 92.3% to 95.5% | 81.3% to 85.0% |
| Head & Neck | 89.5% to 100% | 70.6% to 94.1% |
| Thorax | 88.3% to 93.2% | 69.8% to 73.2% |
| Pelvis | 91.7% to 100% | 87.5% to 94.6% |
| Abdomen | 94.6% to 95.2% | 84.0% to 87.2% |
| Musculoskeletal | 100% | 100% |
* Range of values according to the reader (3 readers per region)
One exploratory study (Study 3) with a single dose of gadopiclenol (0.1 mL/kg BW equivalent to 0.05 mmol/kg BW) included 80 paediatric patients aged 2 to 17 years old with 60 patients undergoing CNS MRI and 20 patients undergoing Body MRI. Diagnostic efficacy was evaluated and there was no difference among the paediatric age groups.
The European Medicines Agency has deferred the obligation to submit the results of studies with Vueway in one or more subsets of the paediatric population in the detection and visualisation of disorders or lesions with suspected abnormal vascularity in various body regions for diagnostic purposes. (see section 4.2 for information on paediatric use).
The absolute bioavailability of gadopiclenol (in humans) is 100%, as it is only administered via the intravenous route.
After an intravenous dose of 0.1 to 0.2 mL/kg BW (equivalent respectively to 0.05 and 0.1 mmol/kg BW), the Cmax was 525 ± 70 mcg/mL and 992 ± 233 mcg/mL, respectively.
The Cmax increased 1.1-fold, 1.1-fold and 1.4-fold and the AUCinf increased 1.5-fold, 2.5-fold and 8.7-fold in patients with mild, moderate and severe renal impairment, respectively after a dose of 0.2 mL/kg BW (equivalent to 0.1 mmol/kg BW).
In addition, the increase in Cmax and AUCinf is expected to be similar with a dose of 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) based on the results of population pharmacokinetic simulations.
After intravenous administration gadopiclenol is rapidly distributed in the extracellular fluids. After a dose of 0.1 ml/kg BW (equivalent to 0.05 mmol/kg BW) the distribution volume Vd was 12.9 ± 1.7 L.
The in vitro binding of 153Gd-gadopiclenol to human plasma proteins is negligible and independent of the gadopiclenol concentration, as 153Gd-gadopiclenol bound 0.0–1.8% to human plasma proteins and 0.0-0.1% to human red blood cells.
Gadopiclenol is not metabolised.
The lack of metabolism is confirmed by in vitro data using pooled human liver microsomes incubated with 153Gd-gadopiclenol. After 120 minutes ≥ 95% of the 153Gd-gadopiclenol remained in unchanged form. The results were similar when heat inactivated pooled human liver microsomes (negative controls) were incubated with 153Gd-gadopiclenol, indicating that 153Gd-gadopiclenol is not metabolised.
Gadopiclenol is eliminated rapidly in unchanged form through the kidneys by glomerular filtration. After a dose of 0.1 to 0.2 mL/kg BW (equivalent respectively to 0.05 and 0.1 mmol/kg BW), the mean plasma elimination half-life (t1/2) in healthy volunteers with a normal renal function was1.5 and 1.7 hour, respectively, and the clearance was 100 ± 10 mL/min and 96 ± 12 mL/min, respectively. 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.
The pharmacokinetic profile of gadopiclenol is linear in the studied dose range (0.05 to 0.6 mL/kg BW equivalent to 0.025 to 0.3 mmol/kg BW), without difference between males and females. Mean maximum concentration (Cmax) and Area Under the Curve (AUCinf) increased proportionally to the dose.
One Phase II study (Study 3) with a single dose of gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) was conducted and included 60 paediatric patients aged 2 to 17 years old undergoing CNS MRI.
Individual parameters predicted from the population pharmacokinetic model and normalised by BW were similar between adults and children. The terminal half-life was 1.77 hour for age group 12-17 years old, 1.48 hour for age group 7-11 years old and 1.29 hour for age group 2-6 years old. The median clearance ranged from 0.08 L/h/kg (for age group 12-17 years old) to 0.12 l/h/kg (for age group 2-11 years old).
The pharmacokinetics of gadopiclenol in children aged 2 to 17 years are comparable to the pharmacokinetics in adults.
The elimination half-life (t1/2) is prolonged in subjects with renal impairment, increasing with the degree of renal impairment. In patients with mild (60 ≤ eGFR < 90 mL/min), moderate (30 ≤ eGFR < 60 mL/min) and severe (15 ≤ eGFR < 30 mL/min) renal impairment, the mean t1/2 was 3.3, 3.8 and 11.7 hours, respectively and the clearance was 1.02, 0.62 and 0.17 mL/min/kg, respectively.
The Cmax increased 1.1-fold, 1.1-fold and 1.4-fold and the AUCinf increased 1.5-fold, 2.5-fold and 8.7-fold in patients with mild, moderate and severe renal impairment, respectively after a dose of 0.2 mL/kg BW (equivalent to 0.1 mmol/kg BW).
In addition, the increase in Cmax and AUCinf is expected to be similar with a dose of 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) based on the results of population pharmacokinetic simulations.
Urinary excretion is delayed with the progression of renal impairment level. In patients with mild or moderate renal impairment, more than 90% of the administered dose was recovered in the urine within 48 hours. In patients with severely impaired renal function about 84% of the administered dose was recovered in the urine within 5 days.
In patients with End Stage Renal Disease (ESRD), 4 hour haemodialysis effectively removed gadopiclenol from plasma as the percentage of decrease in blood concentrations was 95 to 98% at the end of the first haemodialysis session.
The effect of weight was investigated with population pharmacokinetic simulations of patients with a BW ranging from 40 kg to 150 kg receiving a gadopiclenol dose of 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW). The ratios of median AUCinf of gadopiclenol between a typical healthy subject of 70 kg and subjects weighing 40 kg and 150 kg was 0.86 and 2.06, respectively. The ratios of the plasma concentrations 10, 20 and 30 minutes after administration between a typical healthy subject of 70 kg and subjects weighing 40 kg and 150 kg ranged from 0.93 to 1.26.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
Juvenile animal toxicity studies have not revealed any relevant findings.
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