Safety Evaluation of Linear and Macrocyclic Gadolinium-Based Contrast Agents for Patients With Mild to Moderate Renal Insufficiency Undergoing Enhanced Magnetic Resonance Imaging (Interventional Prospective Study) Clinical Trial Protocol

The purpose of this study is to evaluate the safety of linear and macrocyclic gadolinium-based contrast agents for patients with mild to moderate renal insufficiency. The study will compare the incidence of adverse events of gadodiamide and gadoteric Acid Meglumine Salt for patients with mild to moderate renal insufficiency undergoing enhanced magnetic resonance imaging.

Start Date01 Mar 2021

Sponsor / Collaborator

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

NCT02599844 / WithdrawnNot ApplicableIIT

Long Term Impact of Pediatric Acute Renal Injury in Severe Sepsis in Young Adults - IMPRESS YA

Sepsis is the most common cause of childhood death worldwide. Millions of children survive, but are left with impaired health. Sepsis-related Acute Kidney Injury (sAKI) is increasingly recognized as a significant factor associated with long-term mortality among different patient populations. Renal dysfunction and subsequent chronic kidney disease is implicated in the development of hypertension and cardiovascular disease. The investigators overall hypothesis is that, in the pediatric population, sepsis-related AKI will have unrecognized, long-term consequences with regard to kidney function, endothelial function, blood pressure control, and overall health.

Start Date01 Dec 2015

Sponsor / Collaborator

University of Florida

[+1]

NCT02597543 / CompletedPhase 4IIT

Stress Cardiac MRI Using Regadenoson for Evaluation of Nonspecific Allograft Dysfunction

The investigators will use cardiac MRI to measure the myocardial perfusion reserve and amount of myocardial edema and fibrosis in heart-transplant patients with nonspecific allograft dysfunction in contrast to those with normal graft function. The investigators hypothesize that patients with nonspecific allograft dysfunction will demonstrate decreased myocardial perfusion reserve, related to microvascular allograft vasculopathy, compared to those with normal graft function.

Start Date01 Nov 2015

Sponsor / Collaborator

Stanford University

[+1]

100 Clinical Results associated with Gadopentetate Dimeglumine

100 Translational Medicine associated with Gadopentetate Dimeglumine

100 Patents (Medical) associated with Gadopentetate Dimeglumine

5,922

Literatures (Medical) associated with Gadopentetate Dimeglumine

01 Mar 2024·Journal of magnetic resonance imaging : JMRI

MRI for Hepatitis B‐Associated Intrahepatic Cholangiocarcinoma: A Multicenter Comparative Study

Article

Author: Sun, Wei ; Jin, Kaipu ; Zhou, Jianjun ; Zeng, Mengsu ; Dai, Yongming ; Zhang, Yunfei ; Sheng, Ruofan ; Wang, Heqing ; Zhang, Weiguo

Background:

The diagnosis of intrahepatic cholangiocarcinoma (iCCA) is challenging in hepatitis B virus (HBV)‐infected patients, due to the overlapping clinical manifestations and atypical imaging patterns compared to patients without HBV.

Purpose:

To investigate the preoperative imaging characteristics of iCCA in patients with HBV in comparison to those without HBV.

Study Type:

Retrospective.

Subjects:

431 patients with histopathologically confirmed iCCA (143 HBV‐positive and 288 HBV‐negative patients) were retrospectively enrolled from three institutes, and patients were allocated to the training (n = 302) and validation (n = 129) cohorts from different institutes or time period; 100 matching HBV‐positive hepatocellular carcinoma (HCC) patients were also enrolled.

Field Strength/Sequence:

1.5‐T and 3‐T, including T1‐ and T2‐weighted, diffusion‐weighted and dynamic gadopentetate dimeglumine‐enhanced imaging.

Assessment:

Clinical and MRI features were analyzed and compared between HBV‐positive and HBV‐negative patients with iCCA, and between HBV‐positive patients with iCCA and HCC.

Statistical Tests:

Univariate and multivariate logistic regression analyses with odds ratio (OR) to identify independent features for discriminating HBV‐associated iCCA. Diagnostic model generation by incorporating independent features, and the performance for discrimination was evaluated by receiver operating characteristics with the area under the curve (AUC) and 95% confidence interval (CI). AUCs were compared by the DeLong's method. A P‐value <0.05 was considered statistically significant.

Results:

Compared to patients without HBV, washout or degressive enhancement pattern (OR = 51.837), well‐defined tumor margin (OR = 8.758) and no peritumoral bile duct dilation (OR = 4.651) were independent significant features for discriminating HBV‐associated iCCAs. All these features were also the predominant MRI manifestations for HBV‐associated HCC. The combined index showed an AUC of 0.798 (95% CI 0.748–0.842) in the training cohort and an AUC of 0.789 (95% CI 0.708–0.856) in the validation cohort for discrimination. The sensitivity, specificity, and accuracy were all >70%, which was superior to each single feature alone in both cohorts. [Correction added after first online publication on 29 June 2023. The Field Strength/Sequence has been updated from 5‐T to 1.5‐T.]

Data Conclusion:

Preoperative MRI may help to discriminate HBV‐associated iCCA.

Evidence Level:

Technical Efficacy Stage:

01 Jan 2024·Theranostics

Inactivation of ERK1/2 signaling mediates dysfunction of basal meningeal lymphatic vessels in experimental subdural hematoma

Article

Author: Gao, Chuang ; Li, Shenghui ; Nie, Meng ; Quan, Wei ; Huang, Jinhao ; Sha, Zhuang ; Yuan, Jiangyuan ; Xiang, Tangtang ; Wang, Dong ; Zhang, Xinjie ; Jiang, Weiwei ; Liu, Mingqi ; Gong, Zhitao ; Wu, Chenrui ; Liu, Xuanhui ; Jiang, Rongcai ; Zhang, Jianning ; Chen, Yupeng

Rationale: Meningeal lymphatic vessels (MLVs) are essential for the clearance of subdural hematoma (SDH). However, SDH impairs their drainage function, and the pathogenesis remains unclear. Herein, we aimed to understand the pathological mechanisms of MLV dysfunction following SDH and to test whether atorvastatin, an effective drug for SDH clearance, improves meningeal lymphatic drainage (MLD). Methods: We induced SDH models in rats by injecting autologous blood into the subdural space and evaluated MLD using Gadopentetate D, Evans blue, and CFSE-labeled erythrocytes. Whole-mount immunofluorescence and transmission electron microscopy were utilized to detect the morphology of MLVs. Phosphoproteomics, western blot, flow cytometry, and in vitro experiments were performed to investigate the molecular mechanisms underlying dysfunctional MLVs. Results: The basal MLVs were detected to have abundant valves and play an important role in draining subdural substances. Following SDH, these basal MLVs exhibited disrupted endothelial junctions and dilated lumen, leading to impaired MLD. Subsequent proteomics analysis of the meninges detected numerous dephosphorylated proteins, primarily enriched in the adherens junction, including significant dephosphorylation of ERK1/2 within the meningeal lymphatic endothelial cells (LECs). Subdural injection of the ERK1/2 kinase inhibitor PD98059 resulted in dilated basal MLVs and impaired MLD, resembling the dysfunctional MLVs observed in SDH. Moreover, inhibiting ERK1/2 signaling severely disrupted intercellular junctions between cultured LECs. Finally, atorvastatin was revealed to protect the structure of basal MLVs and accelerate MLD following SDH. However, these beneficial effects of atorvastatin were abolished when combined with PD98059. Conclusion: Our findings demonstrate that SDH induces ERK1/2 dephosphorylation in meningeal LECs, leading to disrupted basal MLVs and impaired MLD. Additionally, we reveal a beneficial effect of atorvastatin in improving MLD.

01 Jan 2024·Birth defects research

Evaluation of gadolinium‐based contrast agents in pregnant CD‐1 mice and subsequent in utero exposure of the developing offspring, including behavioral evaluations

Article

Author: Czupalla, Oliver ; Clemens, Guenther ; Tedoldi, Fabio ; Bourrinet, Phillipe ; Lewis, Elise M ; Jones, Paul ; Bussi, Simona ; Fretellier, Nathalie ; Hoberman, Alan M ; Hirani, Ella

Abstract:

Introduction:

The offspring of CD‐1 mice exposed during pregnancy to one of seven gadolinium‐based contrast agents (GBCAs) were evaluated for potential effects on postnatal development and behavior. The GBCAs, comprising four linear (gadopentetate dimeglumine, gadodiamide, gadobenate dimeglumine, and gadoxetate disodium) and three macrocyclic (gadoterate meglumine, gadoteridol, and gadobutrol), were administered via intravenous injection once daily from Gestation Day 6 through 17 following confirmed mating (Day 0) at doses of at least twice the human equivalent recommended clinical dose (i.e., 0.63 mmol Gd/kg for gadoxetate disodium and 2.5 mmol Gd/kg for the other GBCAs). All dams were allowed to deliver naturally. F0 generation females were monitored for maternal toxicity and gadolinium (Gd) levels in blood and brain. Offspring were evaluated for Gd levels in blood and brain at birth and on Day 70 postpartum. F1 generation mice were evaluated for survival and growth preweaning. Selected pups/litter were evaluated postweaning for sexual maturation, growth, and behavior. Gd was quantifiable in the brain of the F1 offspring on PND 1, with levels declining over time. There was no long‐term effect of any GBCA on the growth and development of any offspring. There was no impact on neurodevelopment, as assessed by brain histology and validated neurobehavioral tests, including a battery of functional observational tests, motor activity, and learning and memory as evaluated in the Morris water maze.

Conclusion:

At the end of the postweaning period, the highest dose tested was considered the no‐observable‐adverse‐effect level (NOAEL) in the F0 and F1 offspring for all tested GBCAs.

News (Medical) associated with Gadopentetate Dimeglumine

19 Jul 2023

·www.prnewswire.com

Data Reinforcing Efficacy and Safety of Gadopiclenol in Contrast-Enhanced MRI of Certain Body Regions Published in Radiology

The results of the multicenter, international PROMISE clinical trial demonstrate that gadopiclenol provides similar lesion visualization and contrast enhancement at a gadolinium dose of 0.05 mmol/kg versus a full dose of gadobutrol (0.1 mmol/kg). [i] Bracco has launched gadopiclenol as VUEWAY® (gadopiclenol) solution for injection and VUEWAY® (gadopiclenol) Pharmacy Bulk Package, following the 2022 approval of gadopiclenol by the United States Food and Drug Administration (U.S. FDA). [ii] Gadopiclenol is highly stable and shows the highest relaxivity among the gadolinium-based contrast agents available for clinical use.ii,[iii],[iv],[v],[vi],[vii],[viii] MONROE TOWNSHIP, N.J., July 19, 2023 /PRNewswire/ -- Bracco Imaging, an innovative world leader delivering end-to-end products and solutions through a comprehensive portfolio inclusive of precision diagnostic imaging modalities, announced today the publication of the PROMISE trial in Radiology.i The PROMISE study was a prospective, multinational, crossover (within-patient), double-blind comparison of the safety and efficacy of 0.05 mmol/kg gadopiclenol (VUEWAY) with 0.1 mmol/kg gadobutrol (Gadavist®) in adult patients referred for contrast-enhanced magnetic resonance imaging (MRI) of head and neck, thorax (including breast), abdomen (including liver, pancreas, and kidneys), pelvis (including ovaries, uterus, and prostate), and musculoskeletal (including extremities). Despite being administered at half the dose of gadobutrol, gadopiclenol provided a comparable degree of contrast enhancement and quality of morphologic assessment of lesions. The type and severity of adverse events (AEs) were similar with the two gadolinium-based contrast agents, with VUEWAY (4.2%) having a slightly lower rate to that of Gadavist (5.5%).i The publication of the results of the PROMISE Study comes on the heels of those of the PICTURE clinical trial, which were published in Investigative Radiology and showed non-inferior quality of morphologic assessment of lesions of the brain and spine with 0.05 mmol/kg VUEWAY compared with 0.1 mmol/kg gadobutrol (Gadavist).[ix] The combined results of the PROMISE and PICTURE trials, and additional clinical evidence, supported the regulatory application for gadopiclenol submitted to the U.S. FDA, resulting in Priority Review and subsequent approval in 2022. Bracco has launched gadopiclenol in the U.S. market as VUEWAY (gadopiclenol) injection and VUEWAY (gadopiclenol) Pharmacy Bulk Package, with a series of hospitals leading first clinical usage. "Before gadopiclenol, most of the GBCAs available for clinical use were indicated for the brain, spine, or central nervous system with narrow indications for the body, such as the breast, liver, and heart,i" said Fulvio Renoldi Bracco, Vice-Chairman and CEO of Bracco Imaging. "The publication of this data reinforces VUEWAY injection as a boundary-pushing and novel MRI contrast agent across the central nervous system (the brain, spine, and surrounding tissues) and body (the head and neck, thorax, abdomen, pelvis, and musculoskeletal system).ii" The PROMISE trial included 273 adult patients suspected of having an enhancing abnormality in one of three different body regions (head/neck, breast/thorax/abdomen/pelvis, or musculoskeletal). Off-site blinded readers with expertise in the respective body regions rated border delineation, internal morphology, and visual contrast enhancement. All primary and secondary endpoints of the study were achieved. For all blinded readers, 0.05 mmol/kg gadopiclenol was non-inferior to 0.1 mmol/kg gadobutrol for all visualization parameters and all readers (P<.001), and superior to unenhanced images (P<.001). Two of three readers yielded higher percentage enhancement for gadopiclenol (P<.001). Lesion-to-background ratio did not differ. For most participants (75%–83%), readers reported no preference between 0.05 mmol/kg gadopiclenol and 0.1 mmol/kg gadobutrol images.i "The results of the PROMISE Study led to the approval of the use of gadopiclenol with MRI of the head and neck, thorax, abdomen, pelvis, and the musculoskeletal system,ii" said Alberto Spinazzi, MD, Chief Medical and Regulatory Officer at Bracco. "Of note, gadopiclenol was approved for both MRI of the central nervous system and of the body at the dose of 0.05 mmol/kg, which showed to provide similar contrast enhancement efficacy compared with a dose of 0.1 mmol/kg of Gadavist. This is thanks to the high relaxivity of gadopiclenol, the highest among all the available GBCAs.ii,iii,IV,V,VI,VII,VIII" VUEWAY injection is a Group II agent within the American College of Radiology's classification of gadolinium-based agents relative to the risk of nephrogenic systemic fibrosis (NSF), indicating association with few if any, unconfounded cases.[x] It is approved for use in adult and pediatric patients aged 2 years and older with magnetic resonance imaging (MRI) of the CNS (brain, spine, and surrounding tissues) and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system).ii VUEWAY injection is now available to order from Bracco Diagnostics Inc. Visit VUEWAY.com for more information, including its full Prescribing Information. VUEWAY® (gadopiclenol) solution for injection Indications VUEWAY injection is indicated in adults and children aged 2 years and older for use with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in: the central nervous system (brain, spine and surrounding tissues), the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system). IMPORTANT SAFETY INFORMATION WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m 2 ), or Acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. For patients at highest risk for NSF, do not exceed the recommended VUEWAY dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration. Contraindications VUEWAY injection is contraindicated in patients with history of hypersensitivity reactions to VUEWAY. Warnings Risk of nephrogenic systemic fibrosis is increased in patients using GBCA agents that have impaired elimination of the drugs, with the highest risk in patients with chronic, severe kidney disease as well as patients with acute kidney injury. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. Hypersensitivity reactions, including serious hypersensitivity reactions, could occur during use or shortly following VUEWAY administration. Assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders, administer VUEWAY only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, and observe patients for signs and symptoms of hypersensitivity reactions after administration. Gadolinium retention can be for months or years in several organs after administration. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (brain, skin, kidney, liver and spleen). Minimize repetitive GBCA imaging studies, particularly closely spaced studies, when possible. Acute kidney injury requiring dialysis has occurred with the use of GBCAs in patients with chronically reduced renal function. The risk of acute kidney injury may increase with increasing dose of the contrast agent. Ensure catheter and venous patency before injecting as extravasation may occur, and cause tissue irritation. VUEWAY may impair the visualization of lesions seen on non-contrast MRI. Therefore, caution should be exercised when VUEWAY MRI scans are interpreted without a companion non-contrast MRI scan. The most common adverse reactions (incidence ≥ 0.5%) are injection site pain (0.7%), and headache (0.7%). You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. Please click here for full Prescribing Information for VUEWAY, including BOXED WARNING on Nephrogenic Systemic Fibrosis. Manufactured for Bracco Diagnostics Inc. by Liebel-Flarsheim Company LLC - Raleigh, NC, USA 27616. VUEWAY is a registered trademark of Bracco Imaging S.p.A. All other trademarks and registered trademarks are the property of their respective owners. About Bracco Imaging Bracco Imaging S.p.A. ("Bracco Imaging"), part of the Bracco Group, is an innovative world leader delivering end-to-end products and solutions through its comprehensive portfolio across diagnostic imaging modalities. Headquartered in Milan, Italy, Bracco Imaging's purpose is to improve people's lives by shaping the future of prevention and precision diagnostic imaging. The Bracco Imaging portfolio includes products and solutions for all key diagnostic imaging modalities: X-ray imaging, magnetic resonance imaging (MRI), Contrast Enhanced Ultrasound (CEUS), and Nuclear Medicine through radioactive tracers and novel PET imaging agents. Bracco Imaging has approximately 3,600 employees and operates in more than 100 markets globally. Bracco Imaging has a well-skilled and innovative Research and Development (R&D) organization with an efficient process-oriented approach and track record in the diagnostic imaging industry. R&D activities are located in four centers based in Italy, Switzerland, the United Kingdom and the United States. Bracco Group global revenues were 1.4 billion Euros in 2020. To learn more about Bracco Imaging, visit . Bracco Diagnostics Inc. Media Relations (USA) Kimberly Gerweck Senior Manager, Marketing Communications [email protected] D: +1 609-524-2777 [i] Kuhl C, Csőszi T, Piskorski W et al. Efficacy and Safety of Half-Dose Gadopiclenol versus Full-Dose Gadobutrol for Contrast-enhanced Body MRI Radiology: Volume 308: Number 1—July 2023 [ii] Vueway® (gadopiclenol) solution for injection, 485.1 mg/mL/ Full Prescribing Information and Patient Medication Guide. Monroe Twp., NJ: Bracco Diagnostics Inc.; September 2022. [iii] 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. [iv] GADAVIST® (gadobutrol) Injection. Full Prescribing Information and Patient Medication Guide. Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ; April 2022. [v] DOTAREM® (gadoterate meglumine) Injection. Full Prescribing Information. Guerbet LLC. Princeton, NJ. April 2022. [vi] CLARISCAN™ (gadoterate meglumine) injection for intravenous use. Full Prescribing Information and Patient Medication Guide. GE Healthcare. Chicago, IL; February 2020. [vii] ProHance® (Gadoteridol) Injection, 279.3 mg/mL. Full Prescribing Information and Patient Medication Guide. Monroe Twp., NJ: Bracco Diagnostics Inc.; June 2022. [viii] MultiHance® (gadobenate dimeglumine) injection, 529 mg/mL. Full Prescribing Information and Patient Medication Guide. Monroe Twp., NJ: Bracco Diagnostics Inc.; August 2018. [ix] Loevner L, Kolumban B, Hutoczki G, et al. Efficacy and Safety of Gadopiclenol for Contrast-Enhanced MRI of the Central Nervous System. The PICTURE Randomized Clinical Trial. Invest Radiol. 2022 Dec. [x] American College of Radiology. ACR Manual on Contrast Media. 2023. SOURCE Bracco

Drug ApprovalClinical Result

11 Jul 2023

·www.sciencedaily.com

Copper could help create clearer MRI images and improved diagnosis

Scientists have found a new use for copper in magnetic resonance imaging (MRI) contrast agent design, that could help to create better images which help doctors diagnose patients' conditions more easily and safely. Scientists have found a new use for copper in magnetic resonance imaging (MRI) contrast agent design, that could help to create better images which help doctors diagnose patients' conditions more easily and safely. Researchers discovered a novel copper protein binding site, which does not occur in nature, that has real potential for use in MRI contrast agents used to improve the visibility of internal body structures in scans. The discovery overturns conventional medical wisdom that copper is unsuitable for use in MRI contrast agents and could help to develop new imaging agents with potentially fewer risks and side effects than exist with current commonly used contrast agents. Researchers from the Universities of Birmingham and St Andrews, as well as Diamond Light Source, published their findings in PNAS after creating a highly elusive abiological copper site bound to oxygen donor atoms within a protein scaffold. The experts found that the new structure displayed highly effective levels of relaxivity -the ability of a contrast agent to influence the relaxation times of protons, which helps create clearer and more informative images during an MRI scan. Co-author Dr Anna Peacock, Reader in Bioinorganic Chemistry at the University of Birmingham, commented: "We prepared a new-to-biology copper-binding site which shows real potential for use in contrast agents and challenges existing dogma that copper is unsuitable for use in MRI." "Despite copper largely being disregarded for use in MRI contrast agents, our binding site was shown to display extremely promising contrast agent capabilities, with relaxivities equal and superior to the Gd(III) agents used routinely in clinical MRI. Our discovery showcases a powerful approach for accessing new tools or agents for imaging applications." The researchers note that imaging agents based on copper could also be used in Positron emission tomography (PET) scans, which produce detailed 3-dimensional images of the inside of the body. Their study shows use of an artificial coiled coil to create the copper site within a protein scaffold has achieved function and performance not normally associated with copper. "Metal sites that are not part of the repertoire of biology are vital in providing protein designers with an expanded toolbox of chemistries they can use to design new functional systems such as the promising imaging capabilities reported here," added Dr Peacock. "This opens up applications beyond what biology is currently capable of and showcases some of the advantages of using simple miniature protein scaffolds as a means with which we can engineer new, and maybe currently unknown, metal-binding sites." In MRI scanners, sections of the body are exposed to a strong magnetic field causing hydrogen nuclei of water in tissues to be polarised in the direction of the magnetic field. The magnitude of the spin polarisation detected is used to form the MR image but decays with a characteristic time constant known as the T1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons -- altering contrast in the image and improving the visibility of internal body structures, with the most used compounds being gadolinium-based contrast agents (GBCAs). Gadolinium (in the form of Gd3+) is often used as a contrast agent, but there are environmental and patient safety concerns making exploration of new contrast agents an important and active research area. Although more work needs to be done to secure the stability of this new copper protein site, the study authors believe their work is a promising first step towards designing new copper-based contrast agents for clinical MRI scanning.

09 May 2023

·www.biospace.com

Guerbet Announces ACR Committee on Drugs and Contrast Media Classifies Elucirem™ (Gadopiclenol) Injection a Group II Agent

Elucirem™, a Novel New Macrocyclic GBCA for Use in Contrast-Enhanced Magnetic Resonance Imaging (MRI), has the highest relaxivity compared to other non-specific GBCAs (gadolinium-based contrast agents) 1 Elucirem™ requires only half the gadolinium dose of conventional non-specific GBCAs, addressing practitioners' concerns about gadolinium exposure. 2,3 PRINCETON, N.J., May 9, 2023 /PRNewswire/ -- Guerbet, a global leader in medical imaging with more than 30 years of experience in MRI, announced today that based on the most recent scientific and clinical evidence, the ACR Committee on Drugs and Contrast Media has classified Elucirem™ (gadopiclenol) as a Group II agent.6 This next generation GBCA from Guerbet, highly stable macrocyclic gadolinium-based contrast agent (GBCA), has the highest relaxivity in its class for magnetic resonance imaging (MRI) and is indicated for use in adults and children aged 2 years and older.1,4 Elucirem™ requires only half the gadolinium dose of conventional non-specific GBCAs, addressing practitioners' concerns about gadolinium exposure.2,3 "This new classification from the ACR is a real game changer for the future of Elucirem™," said Jared Houk, Commercial Vice President at Guerbet. "This is an important moment for our team as it really shows the benefit of this product and its potential in the market." The classification states that gadopiclenol "demonstrates kinetic stability and a long dissociation half-life that are comparable to other Group II macrocyclic agents. Based on the most recent scientific and clinical evidence, the ACR Committee on Drugs and Contrast Media considers the risk of NSF among patients exposed to standard or lower than standard doses of Gadopiclenol is sufficiently low or possibly nonexistent such that it has been classified as a Group II agent."6 Elucirem™ (Gadopiclenol) injection is used to detect and visualize lesions with abnormal vascularity in the central nervous system (brain, spine, and associated tissues) and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system).1 Guerbet received FDA approval of Elucirem™ (NDA 216986) on September 21, 2022 after priority review, a designation assigned to applications for drugs that provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions compared to available therapies.5 GBCAs improve the contrast between lesions and surrounding tissues by accelerating the relaxation of protons thanks to interaction with gadolinium atoms. Gadopiclenol, the active drug substance of Elucirem™, has been designed to enable twice as much interaction, resulting in the highest relaxivity among all non-specific GBCAs.4 This allows use at half the conventional gadolinium dose to reveal high quality images. Elucirem is manufactured by Liebel-Flarsheim™ Company LLC, a Guerbet Group company, in Raleigh, North Carolina. About Guerbet At Guerbet, we build lasting relationships so that we enable people to live better. That is our purpose. We are a global leader in medical imaging, offering a comprehensive range of pharmaceutical products, medical devices, and digital and AI solutions for diagnostic and interventional imaging. As pioneers in contrast products for over 95 years, with more than 2,600 employees worldwide, we continuously innovate and devote 8%-10% of our revenue to research and development in five centers in France, Israel, and the United States. Guerbet (GBT) is listed on Euronext Paris (segment B – mid caps) and generated €732 million in revenue in 2021. For more information, please visit . About Gadopiclenol Gadopiclenol, initially invented by Guerbet with subsequent contribution of Bracco intellectual property, is a new macrocyclic gadolinium-based contrast agent (GBCA) with high relaxivity. The efficacy and safety of Gadopiclenol have been evaluated in MRI of the central nervous system (brain, spine, and associated tissues) and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system) in adult and pediatric patients aged 2 years and older. (refer to the approved USPI for full information). Details on Phase III clinical trials are available on : Efficacy and Safety of Gadopiclenol for Central Nervous System (CNS) Magnetic Resonance Imaging (MRI) Full Text View - ClinicalTrials.gov Efficacy and Safety of Gadopiclenol for Body Magnetic Resonance Imaging (MRI) - Full Text View - ClinicalTrials.gov Gadopiclenol is currently in the process of examination by the European Medicines Agency. Forward-looking statements This press release may contain statements of a forward-looking nature, based on assumptions and predictions made by the management of Guerbet group. Various known and unknown risks, uncertainties and other factors could lead to marked differences between the future results, financial situation, development and performances of the company, and the estimates made here. These factors include those mentioned in the public reports of Guerbet, available on its website . The company assumes no responsibility whatsoever in relation to the updating of these forward-looking statements, or how they correspond to future events or developments. ELUCIREM™ (gadopiclenol) injection Important Safety Information Indications and Usage ELUCIREM™ (gadopiclenol) injection is indicated in adult and pediatric patients aged 2 years and older for use with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in the central nervous system (brain, spine, and associated tissues), and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system). Contraindications History of hypersensitivity reactions to ELUCIREM Warnings and Precautions Nephrogenic Systemic Fibrosis: GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease as well as patients with acute kidney injury. Hypersensitivity Reactions: With GBCAs, serious hypersensitivity reactions have occurred. In most cases, initial symptoms occurred within minutes of GBCA administration and resolved with prompt emergency treatment. Before ELUCIREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to ELUCIREM. Gadolinium Retention: Gadolinium is retained for months or years in several organs. Linear GBCAs cause more retention than macrocyclic GBCAs. Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function. While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible Acute Kidney Injury: In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent. Do not exceed the recommended dose. Extravasation and Injection Site Reactions: Injection site reactions such as injection site pain have been reported in the clinical studies with ELUCIREM. Extravasation during ELUCIREM administration may result in tissue irritation. Ensure catheter and venous patency before the injection of ELUCIREM. Interference with Visualization of Lesions Visible with Non-Contrast MRI: As with any GBCA, ELUCIREM may impair the visualization of lesions seen on non-contrast MRI. Therefore, caution should be exercised when Gadopiclenol MRI scans are interpreted without a companion non-contrast MRI scan. Adverse Reactions: In clinical trials, the most frequent adverse reactions that occurred in > 0.2% of patients who received ELUCIREM included: injection site pain, headache, nausea, injection site warmth, injection site coldness, dizziness, and localized swelling. Adverse reactions that occurred with a frequency ≤ 0.2% in patients who received 0.05 mmol/kg BW ELUCIREM included: maculopapular rash, vomiting, worsened renal impairment, feeling hot, pyrexia, oral paresthesia, dysgeusia, diarrhea, pruritus, allergic dermatitis, erythema, injection site paresthesia, Cystatin C increase, and blood creatinine increase. Use in Specific Populations Pregnancy: GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. There are no available data on ELUCIREM use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Lactation: There are no data on the presence of ELUCIREM in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in breast milk. Pediatric Use: The safety and effectiveness of ELUCIREM have not been established in pediatric patients younger than 2 years of age. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Renal Impairment: In patients with renal impairment, the exposure of gadopiclenol is increased compared to patients with normal renal function. This may increase the risk of adverse reactions such as nephrogenic systemic fibrosis (NSF). Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. No dose adjustment of ELUCIREM is recommended for patients with renal impairment. ELUCIREM can be removed from the body by hemodialysis You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. Please see the full Prescribing Information, including the Medication Guide, for additional important safety information. Contacts: Guerbet Leeann Essai, Head of Marketing, North America 609-480-9850/ leeann.essai@guerbet.com Syneos Health Edie Elkinson, Media Relations 310-430-6838/ edie.elkinson@syneoshealth.com

Phase 3Drug ApprovalNDAPriority Review

100 Deals associated with Gadopentetate Dimeglumine

External Link

KEGG	Wiki	ATC	Drug Bank
D01707	Gadopentetate Dimeglumine	V08CA01	DB00789

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Contrast agents	US	Bayer HealthCare Pharmaceuticals, Inc.	02 Jun 1988

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Abnormalities	Phase 3	-	Bayer AG	01 Dec 2003
Constriction, Pathologic	Phase 3	-	Bayer AG	01 Dec 2003
Renal Artery Obstruction	Phase 3	-	Bayer AG	01 Dec 2003
Peripheral Vascular Diseases	Phase 3	-	Bayer AG	01 Mar 2003
Brain Cancer	Phase 3	JP	Bayer AG	01 Feb 2003
Primary Immunodeficiency Diseases	Phase 2	US	Asis Co., Ltd.	01 Jan 2016
Myocardial Infarction	Phase 2	US	Bayer AG	01 Mar 2006
Myocardial Infarction	Phase 2	AR	Bayer AG	01 Mar 2006
Peripheral Arterial Disease	Phase 2	JP	Bayer AG	01 Jul 2004

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02057874 (CTgov)	Not Applicable	Hepatocellular Carcinoma \| Liver Cancer	2	3 Tesla Magnetic Resonance Imaging+Magnevist® (Intravenous (IV) administration of MRI contrast agent)	rdywmtmmfh(fyubduifdu) = xawhldxqsh xqkckjcgcc (agbugasowr, hmdevahxbd - nqfbwwgmdj) View more	-	11 Jul 2018
NCT02597543 (CTgov)	Phase 4	Acute cellular graft rejection	14	gadolinium+Regadenoson (Nonspecific Allograft Dysfunction)	yzmzmvhfyd(ruvmsfamyi) = gqtvdrtgjh wuedadrvpm (lgcgphlzyw, qtkrpieuxe - lqqxapmibb) View more	-	22 Aug 2017
NCT02597543 (CTgov)	Phase 4	Acute cellular graft rejection	14	gadolinium+Regadenoson (Normal Graft Function)	yzmzmvhfyd(ruvmsfamyi) = dvothuxxcx wuedadrvpm (lgcgphlzyw, wssyudhyrl - mfaitfdmmn) View more	-	22 Aug 2017
NCT00537056 (CTgov)	Not Applicable	Renal Cell Carcinoma	17	FDG PET CT+F-18 Fluoro-deoxi-glucose+sunitinib+Gadolinium-DTPA	mzairktbvt(sbkiyqmaky) = jinwsbmryn gxwolcgkfl (jkevdgypte, dsaenployo - izzlxzeocn) View more	-	14 Jun 2017
NCT02080312 (CTgov)	Not Applicable	Meniere Disease	6	Magnevist (gadopentetate dimeglumine)	iebunkvvfp(rtrtieiugy) = gxkdczsjeo jbrgzntlxk (zdmymuogie, ckwllzfavr - svonhropln) View more	-	12 Feb 2016
NCT01234870 (CTgov)	Phase 2/3	Coronary Artery Disease	40	gadolinium+Adenosine	bqbodafcmv(edowtkatxc) = ckgekexsuu gytupuqcun (guvkrioyyk, xxdjyyrgaj - kvkboifkns) View more	-	26 Sep 2014
NCT01260636 (Supra-Aortic VALUE, Pubmed \| AJNR Am J Neuroradiol)	Phase 3	-	46	Single-dose gadobenate dimeglumine	klxdqkorsq(khipiczxua) = ayaoljstmo iynwclwcrb (hhiuruhxrb ) View more	Positive	01 Apr 2013
	Phase 3	-	46	Double-dose gadopentetate dimeglumine	klxdqkorsq(khipiczxua) = zbohmolqzy iynwclwcrb (hhiuruhxrb ) View more	Positive	01 Apr 2013

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