Macrocyclic Gadolinium-based Contrast Agents Gadobutrol Research Articles

Clinical Safety of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations.

The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety. The aim of this study was to perform a thorough review and status update on gadobutrol's safety. Safety data from the clinical phase II-IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized. Forty-five clinical phase II-IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age ("elderly") were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol. More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations.

Susceptibility-Weighted Imaging of the Pediatric Brain after Repeat Doses of Gadolinium-Based Contrast Agent.

Gadolinium complexes have paramagnetic properties; thus, we aimed to determine the susceptibility changes in the globus pallidus and dentate nucleus following administration of linear or macrocyclic gadolinium-based contrast agents in children. Thirty-three patients with linear gadolinium-based contrast agent gadopentetate dimeglumine administration, 33 age- and sex-matched patients with macrocyclic gadolinium-based contrast agent gadobutrol administration, and 33 age- and sex-matched control subjects without gadolinium exposure were enrolled in this retrospective study. The signal intensity on SWI and T1WI was determined in the dentate nucleus, middle cerebellar peduncle, globus pallidus, and pulvinar of the thalamus in an ROI-based analysis to calculate dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios. A repeated measures ANOVA was performed to compare SWIminimum, SWImean, and T1WI signal intensity ratios between gadolinium-based contrast agent groups and control subjects. Pearson correlation analysis was performed to determine any correlation between signal intensity ratios and variables. Dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios for both SWImean and SWIminimum were lower for the linear gadolinium-based contrast agent group compared with macrocyclic gadolinium-based contrast agent and control groups (P < .05). No significant difference of the SWImean and SWIminimum ratios were noted between the macrocyclic gadolinium-based contrast agent group and the control group (P > .05). Both dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios on T1WI in the linear gadolinium-based contrast agent group were higher than in the control group and the macrocyclic gadolinium-based contrast agent group (P < .05). A negative correlation was identified between SWImean and SWIminimum ratios and the number of linear gadolinium-based contrast agent administrations (dentate nucleus-to-middle cerebellar peduncle ratio: SWImean, r = -0.43, P = .005; SWIminimum, r = -0.38, P = .011; globus pallidus-to-thalamus ratio: SWImean, r = -0.39, P = .009; SWIminimum, r = -0.33, P = .017). SWI analysis of the pediatric brain demonstrated a statistically significant decrease in SWIminimum and SWImean values for the dentate nucleus and globus pallidus after administration of linear gadolinium-based contrast agents but not macrocyclic gadolinium-based contrast agents.

The Macrocyclic Gadolinium-Based Contrast Agents Gadobutrol and Gadoteridol Show Similar Elimination Kinetics From the Brain After Repeated Intravenous Injections in Rabbits.

Male white New Zealand rabbits (2.4-3.1 kg) in 2 study groups (n = 21 each) received 3 injections of either gadobutrol or gadoteridol at 0.9 mmol Gd/kg within 5 days (total dose, 2.7 mmol Gd/kg). Animals in one control group (n = 9) received 3 injections of saline (1.8 mL/kg). After 2, 6, and 12 weeks, 7 animals from each study group and 3 from the control group were killed and the Gd concentrations in the cerebellum, cerebrum, in blood and in urine were determined by inductively coupled plasma mass spectrometry. The chemical species of excreted Gd in urine were determined by high pressure liquid chromatography. No significant (P > 0.05) differences in the Gd concentrations in the brain of rabbits were observed between the 2 macrocyclic GBCAs gadoteridol and gadobutrol at all time points. In the gadobutrol group, the mean Gd concentrations in the cerebellum and cerebrum decreased from 0.26 and 0.21 nmol Gd/g after 2 weeks, to 0.040 and 0.027 nmol Gd/g after 12 weeks, respectively, and in the gadoteridol group, from 0.25 and 0.21, to 0.037 and 0.023 nmol Gd/g, respectively. The plasma levels decreased from 0.11 and 0.13 nmol Gd/mL at 2 weeks for gadobutrol and gadoteridol to below the limit of quantification (<0.005 nmol Gd/mL) at 12 weeks. The urine concentration dropped in a biphasic course from 2 to 6 and from 6 to 12 weeks for both agents. The Gd excreted after 12 weeks was still present in the urine in the chemical form of the intact Gd complex for both agents. Contrary to what had been reported in rats, no significant differences in the elimination kinetics from brain tissue in rabbits were observed after intravenous injection of multiple doses of the macrocyclic GBCAs gadobutrol and gadoteridol.

The switch from Gd-DTPA to Gd-DOTA is not associated with decrease of the T1 signal intensity of the pallidus and dentate in a pediatric population.

The switch from the linear gadolinium-based contrast agent (GBCA) gadopentate dimeglumine (Gd_DTPA) to the macrocyclic GBCA gadobutrol is associated with a decrease of the T1 signal intensity (SI) in brain gray matter nuclei. The effects of the switch to other macrocyclic GBCAs are not yet established. To explore the effects of switching from Gd-DTPA to the macrocyclic GBCA gadoterate meglumine (Gd-DOTA) in pediatric patients. We measured the pallidus/middle cerebellar peduncle (MCP) SI ratio and the dentate/MCP SI ratio in pre-contrast sagittal T1-weighted spin-echo images in nine patients who had received ≥6 administrations of Gd-DTPA and then of Gd-DOTA, in 18 patients who had received ≥6 administrations of Gd-DOTA alone, and in nine age-matched controls without prior GBCA administrations. Serial assessment was performed in patients who switched from Gd-DTPA to Gd-DOTA. Finally, the rate of change of pallidal/MCP and dentate/MCP SI ratios between the first and last Gd-DOTA administrations was compared. The pallidal/MCP and dentate/MCP SI ratios were (P < 0.05) higher in patients with prior Gd-DTPA and Gd-DOTA administrations compared to the controls. After the switch, the pallidal/MCP SI ratio increased in nine patients and the dentate/MCP ratio in seven patients. The rate of change of pallidal/MCP SI ratio after Gd-DOTA was higher (P < 0.01) in patients who had previously received Gd-DTPA (mean 2.89 ± 2.6%) than in patients who had received Gd-DOTA alone (mean 0.53 ± 0.89%). T1 SI in gray matter nuclei does not decrease after switching from Gd-DTPA to Gd-DOTA. The switch effects from Gd-DTPA to each macrocyclic GBCA should be individually evaluated.

Signal Enhancement of the Dentate Nucleus at Unenhanced MR Imaging after Very High Cumulative Doses of the Macrocyclic Gadolinium-based Contrast Agent Gadobutrol: An Observational Study.

Purpose To test for measurable visual enhancement of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images in a cohort of patients with a primary brain tumor who had not received linear gadolinium-based contrast agents (GBCAs) but had received many injections of macrocyclic GBCAs. Materials and Methods Seventeen patients with high-grade gliomas who had received 10-44 administrations of the macrocyclic GBCA gadobutrol (0.1 mmol/kg of body weight) were retrospectively included in this regional ethics committee-approved study. Two neuroradiologists inspected T1-weighted MR images with optimized window settings to visualize small differences in contrast at the baseline and at the last examination for the presence of visual DN signal enhancement. Signal intensity (SI) in the DN was normalized to the SI of the pons, and a one-sample t test was used to test for differences between baseline normalized SI (nSI) in the DN (nSIDN) and the average change in nSIDN of all postbaseline MR imaging sessions (ΔnSIDNavg) or the change in nSIDN from baseline to the last MR imaging session (ΔnSIDN). Linear and quadratic correlation analyses were used to examine the association between the number of macrocyclic GBCA administrations and ΔnSIDN or ΔnSIDNavg. Results The mean ± standard deviation number of macrocyclic GBCA administrations was 22.2 ± 10.6 administered throughout 706 days ± 454. Visually appreciable signal enhancement was observed in two patients who had received 37 and 44 macrocyclic GBCA injections. Mean ΔnSIDN was greater than zero (0.03 ± 0.05; P = .016), and there was a significant linear association between the number of macrocyclic GBCA injections and ΔnSIDN (r = 0.69, P = .002) and ΔnSIDNavg (r = 0.77, P < .001). Conclusion A small but statistically significant dose-dependent T1-weighted signal enhancement was observed in the DN after multiple macrocyclic GBCA injections. Visually appreciable enhancement in the DN was observed on contrast-optimized images in two patients who had received 37 and 44 standard doses of macrocyclic GBCAs. © RSNA, 2017 Online supplemental material is available for this article.