OBJECTIVE To assess the clinical safety and tolerability of the macrocyclic contrast agent gadobutrol (Gadovist/Gadavist) overall and in specific patient populations based on clinical trials and postmarketing experience. MATERIALS AND METHODS In total, 5545 patients enrolled in 34 prospective clinical studies were evaluated in an integrated analysis of safety. Of all enrolled patients, 4549 received gadobutrol at a dose of ≤ 0.09 mmol/kg body weight to a maximum of 0.51 mmol/kg body weight, with most patients (53.5%) receiving the recommended dose of >0.09 to 0.11 mmol/kg body weight. Data include comparisons with other extracellular contrast agents and subgroup analyses in pediatric patients, and patients with allergic disposition, renal impairment, hepatic impairment, or cardiovascular disease. Furthermore, worldwide postmarketing safety surveillance results, including nephrogenic systemic fibrosis reports, based on more than 5.7 million estimated applications are described. RESULTS One or more adverse events (AEs) assessed as related to the administration of gadobutrol were reported by 182 (4.0%) of the 4549 patients who participated in clinical trials. This is comparable to the incidence observed with the comparator contrast agents (74/1844 patients, 4.0%). The most common AEs, independent of drug relationship, were headache, nausea, feeling hot, and dysgeusia. The favorable safety profile of gadobutrol was also demonstrated in the following specific subpopulations in whom similar incidence rates were seen: pediatric patients aged 2 to 17 years (8/138 patients, 5.8%), patients with severe or moderate renal impairment (9/366 patients, 2.5%), patients with severe or moderate hepatic impairment (9/214 patients, 4.2%), and patients with cardiovascular disorders (42/1506 patients, 2.8%). Having been established in controlled clinical trials, this safety profile was also confirmed by postmarketing surveillance data. With more than 5.7 million estimated administrations of gadobutrol, a total of 1175 (0.02%) suspected adverse drug reactions have been reported. The most serious adverse reactions seen in postmarketing surveillance included rare reports of cardiac arrest, respiratory arrest, anaphylactoid shock, and nephrogenic systemic fibrosis. Incidence and type of AEs from postmarketing surveillance were consistent with the established safety profile. CONCLUSION The comprehensive analysis of safety data obtained from 34 clinical studies demonstrates that gadobutrol has an excellent safety profile and a positive benefit risk profile when used in patients in need of contrast-enhanced magnetic resonance imaging. Gadobutrol was well tolerated by adults, by children, by patients with impaired liver or kidney function, and by patients with cardiovascular disease. The favorable safety profile is confirmed by the available postmarketing surveillance data and is compared with that of other gadolinium-based contrast agents.

Safety of gadobutrol, a new generation of contrast agents: experience from clinical trials and postmarketing surveillance.

Evaluation of brain lesions using magnetic resonance imaging (MRI) provides information that is critical for accurate diagnosis, prognosis, therapeutic intervention and monitoring response. Conventional contrast-enhanced MR neuroimaging using gadolinium (Gd) contrast agents primarily depicts disruption of the blood-brain barrier, demonstrating location and extent of disease, and also the morphological details at the lesion site. However, conventional imaging results do not always accurately predict tumour aggressiveness. Advanced functional MRI techniques such as dynamic contrast-enhanced perfusion-weighted imaging utilise contrast agents to convey physiological information regarding the haemodynamics and neoangiogenic status of the lesion that is often complementary to anatomical information obtained through conventional imaging. Most of the Gd contrast agents available have similar T1 and T2 relaxivities, and thus their contrast-enhancing capabilities are comparable. Exceptions are gadobenate-dimeglumine, Gd-EOB-DTPA, Gadobutrol and gadofosveset, which, owing to their transient-protein-binding capability, possess almost twice (and more) the T1 and T2 relaxivities as other agents at all magnetic field strengths. Numerous comparative studies have demonstrated the advantages of the increased relaxivity in terms of enhanced image contrast, image quality and diagnostic confidence. Here we summarise the benefits of higher relaxivity for the most common neuroimaging applications including MRI, perfusion-weighted imaging and MRA for evaluation of brain tumours, cerebrovascular disease and other CNS lesions.

High-relaxivity contrast-enhanced magnetic resonance neuroimaging: a review

Since the introduction of the first gadolinium-based contrast agent (GBCA) approximately 25 years ago, magnetic resonance imaging (MRI) using GBCAs has revolutionized diagnostic and follow-up imaging of pathological lesions, with clinical applications expanded to encompass almost all fields of medicine. Intravenous gadobutrol (Gadovist™ [EU]; Gadavist® [USA]) is a second-generation extracellular non-ionic macrocyclic GBCA that is used in patients undergoing diagnostic contrast-enhanced MRI for visualization of pathological lesions in the CNS and all other body regions or for contrast-enhanced magnetic resonance angiography (MRA) to evaluate perfusion and flow-related abnormalities. Its unique physicochemical profile, along with the high thermostability of macrocyclic GBCAs, means gadobutrol is formulated at twice the gadolinium ion concentration of other currently licensed GBCAs. This reduces the injection volume and provides a narrower bolus, thereby improving image enhancement. Based on extensive clinical experience in a broad range of patients, including paediatric and adult patients (younger and elderly adults), and those with moderate to severe hepatic or renal impairment or cardiovascular disorders, gadobutrol is an effective and generally well tolerated extracellular GBCA for patients undergoing diagnostic contrast-enhanced MRI and contrast-enhanced MRA. As with all macrocyclic GBCAs, the potential for gadobutrol to cause nephrogenic systemic fibrosis appears to be lower than with linear GBCAs.

Gadobutrol: a review of its use for contrast-enhanced magnetic resonance imaging in adults and children.

Objectives This clinical study evaluated the pharmacokinetics (PK) and safety data of macrocyclic extracellular contrast agent gadobutrol in pediatric subjects aged younger than 2 years. Materials and methods Pediatric subjects (term newborns to those aged younger than 2 years) with normal renal function undergoing magnetic resonance imaging with gadobutrol (0.1 mmol/kg body weight [BW]) were prospectively enrolled in this open-label, multicenter clinical trial to evaluate PK as a primary end point. Plasma PK was analyzed using a population-based PK approach. Safety and qualitative efficacy (evaluation of images) were secondary end points. Safety and tolerability were assessed throughout study participation (approximately 7 days). Imaging efficacy variables were assessed by investigators. Results Forty-four subjects were evaluated for safety and efficacy; 43 subjects were eligible for PK evaluation including 9 term newborns and infants aged younger than 2 months. Gadobutrol PK in pediatric subjects aged younger than 2 years were adequately described by a linear 2-compartmental model with elimination from the central compartment. Total median systemic exposure (area under the curve) of gadobutrol was estimated at 776 μmol · h/L (range, 544-1470 μmol · h/L). Simulated median concentration at 20 minutes after injection of gadobutrol (C20) was 339 μmol/L (range, 230-456 μmol/L). Safety and tolerability profile were similar to older populations. In 1 subject (2.3%), vomiting was reported as a mild adverse event related to gadobutrol, and there were no reported serious adverse events. The evaluation of gadobutrol-enhanced images provided improved diagnosis, increased confidence in diagnosis, and contributed to subject clinical management. Conclusions The PK profile of gadobutrol in children aged younger than 2 years including newborns is similar to that in older children and adults. At the dose of 0.1 mmol/kg BW, gadobutrol had a favorable safety profile and was well tolerated with similar profile across the age range 0 to younger than 2 years and compared with older children and adults. Extrapolation of efficacy data from adults to the younger pediatric population, including term newborns, is justified. The recommended standard dose of gadobutrol (0.1 mmol/kg BW), as used in the population aged 2 years and older, is also appropriate in children aged younger than 2 years.

Pharmacokinetics and Safety of Macrocyclic Gadobutrol in Children Aged Younger Than 2 Years Including Term Newborns in Comparison to Older Populations.

What is described is a process for producing high-purity gadobutrol in a purity (according to HPLC) of more than 997or 998 or 999% and the use for preparing a pharmaceutical formulation for parenteral administration The process is carried out using specifically controlled crystallization conditions The more recent developments in the field of the gadolinium-containing MR contrast agents (EP 0448191 B1, CA Patent 1341176, EP 0643705 B1, EP 0986548 B1, EP 0596586 B1) include the MRT contrast agent gadobutrol (Gadovist® 10) which has been approved for a relatively long time in Europe and more recently also in the USA under the name Gadavist®

Preparation of high-purity gadobutrol

The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.

https://link.springer.com/content/pdf/10.1007%2Fs00330-008-1054-2.pdf

Comparison of 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine-enhanced MRI in 471 patients with known or suspected renal lesions: Results of a multicenter, single-blind, interindividual, randomized clinical phase III trial

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Comparison of 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine-enhanced MRI in 471 patients with known or suspected renal lesions: Results of a multicenter, single-blind, interindividual, randomized clinical phase III trial