Safety profile of gadoxetate disodium in elderly patients (≥65 years).

Background Safety data on routine clinical use of gadoxetate disodium in elderly patients is not reported yet. Purpose To assess the safety of liver specific gadoxetate disodium in contrast enhanced magnetic resonance imaging in elderly patients (≥65 years) in comparison to adults (18-64 years). Material and Methods Safety data on gadoxetate disodium were analyzed from 12 clinical phase II-III studies and from our pharmacovigilance database. A comparison between elderly (≥65 years) versus adults (18-64 years) was performed with respect to the frequency of drug-related adverse events (AEs) in clinical phase II-III studies and adverse drug reactions (ADRs) in the pharmacovigilance database. Results In clinical studies, 1989 patients were enrolled: 675 elderly and 1314 adults. Twenty-three elderly patients (3.4%) suffered at least one drug-related AE in contrast to 58 patients (4.4%) in the group of adults (odds ratio = 0.76; 95% confidence interval = 0.45-1.27). Since marketing authorization in 2004, more than 3.5 million patients have been exposed to gadoxetate disodium worldwide: 1.7 million (48.6%) in elderly and 1.8 million (51.4%) in adults. The number of patients with post-marketing ADRs (total n = 793) was 354 (0.021%) in the elderly group and 439 (0.024%) in the adult group. Thus, there were significantly fewer patients with ADRs reported in the group of elderly versus adults ( P = 0.028). Hypersensitivity/immune system disorders, gastrointestinal disorders, and respiratory disorders were the most frequent ADRs in both groups, elderly and adults. Conclusion The incidence of drug-related AEs in clinical studies was similar and that of patients with ADRs in the post-marketing setting was lower in elderly (≥65 years) compared with younger adults aged 18-64 years. Overall, gadoxetate disodium shows a favorable safety profile in both age groups.

Safety of gadoxetate disodium: results from six clinical phase IV studies in 8194 patients.

Background Safety data on routine clinical use of gadoxetate disodium for liver magnetic resonance imaging (MRI) is not reported yet. Purpose To assess the safety profile of gadoxetate disodium for liver MRI in the routine clinical setting. Material and Methods Six multicenter studies were performed in Europe, USA, Australia, and Asia to evaluate the safety and efficacy of gadoxetate disodium (Primovist®/Eovist®) enhanced liver MRI. Patients received a single intravenous bolus injection of the standard approved dose of 0.025 mmol/kg body weight (0.1 mL/kg). The number of patients, the characteristics of adverse events, related adverse events, and serious adverse events were analyzed. Results A total of 8194 patients were included in the database. A total of 141 patients (1.7%) reported 230 AEs of which 129 were considered being related to the use of gadoxetate disodium by the investigators. None of the AEs in the pediatric population ( n = 52) were related. The most frequent AEs independent of relationship to the drug included dyspnea (25/0.31%), nausea (22/0.27%), liver disorders (13/0.16%), and renal disorders (9/0.11%). Nine related SAEs were recorded. No patient died during the studies. Conclusion Gadoxetate disodium for liver MRI is safe and well tolerated in the routine clinical setting.

Safety of gadoxetate disodium: Results from the clinical phase II-III development program and postmarketing surveillance.

PURPOSE: To summarize the safety data of gadoxetate disodium, reported in 12 Phase II and III clinical development studies and in the postmarketing surveillance database. MATERIALS AND METHODS: Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. RESULTS: A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. CONCLUSION: Gadoxetate disodium for liver MRI has an excellent safety profile.

A multicenter, randomized, controlled, single-blind comparison phase III study to determine the efficacy and safety of gadobutrol 1.0 M versus gadopentetate dimeglumine following single injection in patients referred for contrast-enhanced MRI of the body regions or extremities.

PURPOSE: To demonstrate the noninferiority of gadobutrol-enhanced magnetic resonance imaging (MRI) compared with gadopentetate dimeglumine-enhanced MRI in Asian patients referred for contrast-enhanced imaging of the body or extremities. MATERIALS AND METHODS: A multicenter, parallel-group comparison study of Asian adults referred for contrast-enhanced MRI were randomized (1:1) to either gadobutrol or gadopentetate dimeglumine. Lesions were assessed for three primary visualization variables: degree of contrast enhancement, border delineation, and internal morphology. Secondary efficacy variables included number of lesions detected, match of MRI diagnosis with final clinical diagnosis, and sensitivity and specificity for malignant lesion detection. Safety was monitored for 24 ± 4 hours after contrast agent administration. RESULTS: A total of 363 patients received either gadobutrol (n = 168) or gadopentetate dimeglumine (n = 178). Mean total scores for three primary visualization variables were 9.39 and 9.34 for gadobutrol and gadopentetate dimeglumine, respectively. The proportion of patients with matched MRI and final diagnosis and sensitivity for malignant lesion detection was greater for unenhanced versus combined images (gadobutrol: 72.2% vs. 81.7%; gadopentetate dimeglumine: 76.2% vs. 82.2%, respectively). Both contrast agents were well tolerated. CONCLUSION: Gadobutrol (0.1 mmol/kg BW) was well tolerated and effective in Asian patients referred for contrast-enhanced MRI of the body or extremities.

Gadobutrol in the central nervous system at three doses: results from a phase II, randomized, multicenter trial.

PURPOSE: To investigate the efficacy and safety of three doses of gadobutrol and determine the minimum effective dose for contrast-enhanced MRI of the central nervous system (CNS). MATERIALS AND METHODS: This was a Phase II, multicenter, double-blind, parallel-group controlled study in subjects referred for contrast-enhanced MRI of the CNS. Subjects were randomized to receive gadobutrol 0.03, 0.1, or 0.3 mmol/kg body weight, and underwent unenhanced, gadobutrol-enhanced, and comparator-enhanced MRI scans. Three blinded readers assessed the images. Primary efficacy variables were number of lesions detected, border delineation, contrast enhancement, and internal morphology. RESULTS: Of the 229 randomized subjects, 173 were evaluated for efficacy. Clinically meaningful improvements in lesion border delineation, contrast enhancement, and internal morphology were observed for 0.1 mmol/kg gadobutrol. Pair-wise comparisons of a composite score of the four primary variables showed the 0.1 mmol/kg dose to be statistically superior to the 0.03 mmol/kg dose (P = 0.003). The 0.3 mmol/kg dose showed no statistically significant difference with the 0.1 mmol/kg dose. Twenty-two (9.8%) subjects reported at least one treatment-emergent adverse event (TEAE). No TEAE was reported at an incidence >3.5%. CONCLUSION: The 0.1 mmol/kg dose of gadobutrol was effective and well tolerated for contrast-enhanced MRI of the CNS.

Gd-EOB-DTPA-enhanced magnetic resonance imaging for focal liver lesions in Chinese patients: a multicenter, open-label, phase III study.

BACKGROUND: Contrast agents help to improve visibility in magnetic resonance (MR) imaging. However, owing to the large interstitial spaces of the liver, there is a reduction in the natural contrast gradient between lesions and healthy tissue. This study was undertaken to evaluate the efficacy and safety of the liver-specific MR imaging contrast agent gadoxetate disodium (Gd-EOB-DTPA) in Chinese patients. METHODS: This was a single-arm, open-label, multicenter study in patients with known or suspected focal liver lesions referred for contrast-enhanced MR imaging. MR imaging was performed in 234 patients before and after a single intravenous bolus of Gd-EOB-DTPA (0.025 mmol/kg body weight). Images were evaluated by clinical study investigators and three independent, blinded radiologists. The primary efficacy endpoint was sensitivity in lesion detection. RESULTS: Gd-EOB-DTPA improved sensitivity in lesion detection by 9.46% compared with pre-contrast imaging for the average of the three blinded readers (94.78% vs 85.32% for Gd-EOB-DTPA vs pre-contrast, respectively). Improvements in detection were more pronounced in lesions less than 1 cm. Gd-EOB-DTPA improved diagnostic accuracy in lesion classification. CONCLUSIONS: This open-label study demonstrated that Gd-EOB-DTPA improves diagnostic sensitivity in liver lesions, particularly in those smaller than 1 cm. Gd-EOB-DTPA also significantly improves the diagnostic accuracy in lesion classification, and furthermore, Gd-EOB-DTPA is safe in Chinese patients with liver lesions.

Evaluation of possible drug-drug interaction between gadoxetic acid and erythromycin as an inhibitor of organic anion transporting peptides (OATP).

PURPOSE: To evaluate if erythromycin compromises liver-specific enhancement of gadoxetic acid; both compounds competing in organic anion transporting peptides (OATP) -mediated hepatocytic uptake. MATERIALS AND METHODS: The study was approved by institutional review board. Twelve healthy subjects (nine men, three woman; mean age, 38.7 years) were examined twice by MR imaging with prior administration of NaCl solution (placebo) or 1000 mg of erythromycin following a randomized sequence. Gadoxetic acid (0.025 mmol/kg body weight) was administered 15 min after the end of infusions. Pre- and 20 min postcontrast two-dimensional gradient-recalled-echo sequences were acquired. Relative enhancements of liver parenchyma and ratio of means were calculated from signal intensity measurements. Plasma levels of gadoxetic acid and erythromycin were determined and given in geometric means and coefficients of variation (CV). RESULTS: Concentration of erythromycin directly after end of infusion was 13.9 mg/L (CV 14.9%). Gadolinium plasma concentrations 5 min after gadoxetic acid administration were 138.7 µmol/L (CV 20.4%) after erythromycin infusion and 129.6 µmol/L (CV 22.8%) after placebo. Mean relative enhancements of liver parenchyma were 88.1 (SD 24.9%) after erythromycin infusion and 92.6 (SD 17.9%) after placebo. Ratio of relative enhancements was 0.951 (95% confidence interval, 0.833; 1.061; statistically not significant). CONCLUSION: Coadministration of erythromycin has no effect on gadoxetic acid enhanced liver MR imaging.

Radiologists and Clinical Trials: Part 1 The Truth About Reader Disagreements.

The debate over human visual perception and how medical images should be interpreted have persisted since X-rays were the only imaging technique available. Concerns over rates of disagreement between expert image readers are associated with much of the clinical research and at times driven by the belief that any image endpoint variability is problematic. The deeper understanding of the reasons, value, and risk of disagreement are somewhat siloed, leading, at times, to costly and risky approaches, especially in clinical trials. Although artificial intelligence promises some relief from mistakes, its routine application for assessing tumors within cancer trials is still an aspiration. Our consortium of international experts in medical imaging for drug development research, the Pharma Imaging Network for Therapeutics and Diagnostics (PINTAD), tapped the collective knowledge of its members to ground expectations, summarize common reasons for reader discordance, identify what factors can be controlled and which actions are likely to be effective in reducing discordance. Reinforced by an exhaustive literature review, our work defines the forces that shape reader variability. This review article aims to produce a singular authoritative resource outlining reader performance's practical realities within cancer trials, whether they occur within a clinical or an independent central review.

Enhancement of liver parenchyma after injection of hepatocyte-specific MRI contrast media: a comparison of gadoxetic acid and gadobenate dimeglumine.

PURPOSE: To compare enhancement of liver parenchyma in MR imaging after injection of hepatocyte-specific contrast media. MATERIALS AND METHODS: Patients (n = 295) with known/suspected focal liver lesions randomly received 0.025 mmol gadoxetic acid/kg body weight or 0.05 mmol gadobenate dimeglumine/kg body weight by means of bolus injection. MR imaging was performed before and immediately after injection, and in the delayed phase at approved time points (20 min after injection of gadoxetic acid and 40 min after injection of gadobenate dimeglumine). The relative liver enhancement for the overall population and a cirrhotic subgroup was compared in T1-weighted GRE sequences. An independent radiologist performed signal intensity measurements. Enhancement ratios were compared using confidence intervals (CIs). RESULTS: The relative liver enhancement in the overall population was superior with gadoxetic acid (57.24%) versus gadobenate dimeglumine (32.77%) in the delayed-imaging phase. The enhancement ratio between the contrast media was statistically significant at 1.75 (95% CI: 1.46-2.13). In the delayed phase, the enhancement of cirrhotic liver with gadoxetic acid (57.00%) was comparable to that in the overall population. Enhancement with gadobenate dimeglumine was inferior in cirrhotic liver parenchyma (26.85%). CONCLUSION: In the delayed, hepatocyte-specific phase, liver enhancement after injection of gadoxetic acid was superior to that obtained with gadobenate dimeglumine.

Improved characterization of focal liver lesions with liver-specific gadoxetic acid disodium-enhanced magnetic resonance imaging: a multicenter phase 3 clinical trial.

OBJECTIVES: To evaluate the safety of gadoxetic acid disodium (Gd-EOB-DTPA) magnetic resonance imaging (MRI) and its efficacy in characterizing liver lesions. METHODS: Lesion characterization and classification using combined (unenhanced and Gd-EOB-DTPA-enhanced) MRI were compared with those using unenhanced MRI and contrast-enhanced spiral computed tomography (CT) using on-site clinical and off-site blinded evaluations for patients with focal liver lesions. RESULTS: Gadoxetic acid disodium was well tolerated in this study. For the clinical evaluation, more lesions were correctly characterized using combined (unenhanced and Gd-EOB-DTPA-enhanced) MRI than using unenhanced MRI and spiral CT (96% vs 84% and 85%, respectively; P < or = 0.0008). For the blinded evaluation, more lesions were correctly characterized using combined MRI compared with using unenhanced MRI (61%-76% vs 48%-65%, respectively; P < or = 0.0012 for 2/3 readers); when compared with spiral CT, a similar proportion of lesions were correctly characterized. CONCLUSIONS: Gadoxetic acid disodium-enhanced MRI is of clinical benefit relative to unenhanced MRI and spiral CT for a radiological diagnosis of liver lesions.

Safety of Gadobutrol: Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance After 29 Million Applications.

OBJECTIVE: The aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine. MATERIALS AND METHODS: Forty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998-2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups. RESULTS: In the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups.The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea.For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded. CONCLUSIONS: Gadobutrol is well tolerated and has a favorable safety profile for patients of all age groups.

A Japanese, Multicenter, Open-label, Phase 3 Study to Investigate the Safety and Efficacy of Gadobutrol for Contrast-enhanced MR Imaging of the Central Nervous System.

PURPOSE: Gadobutrol 1.0 M is macrocyclic gadolinium-based contrast agent for magnetic resonance imaging (MRI). This multicenter, open-label, phase 3 study aimed to investigate the efficacy and safety of gadobutrol-enhanced versus unenhanced MRI in the visualization and diagnosis of central nervous system (CNS) lesions in Japanese patients. METHODS: A total of 223 patients referred for contrast-enhanced MRI of the CNS underwent unenhanced and gadobutrol-enhanced (0.1 mmol/kg body weight) MRI. The unenhanced and combined (unenhanced and enhanced) images were evaluated by three independent readers in a blinded manner for degree of contrast enhancement, border delineation, internal morphology, and number of detected lesions (primary variables), and for primary diagnosis and diagnostic confidence. Final clinical diagnoses were established by an independent truth committee consisting of two neurosurgeons. Sensitivity, specificity, and accuracy were calculated for the detection of malignancy and the preciseness of diagnoses (secondary variables) by comparing the results obtained by the blinded readers and the truth committee. RESULTS: Gadobutrol enhancement significantly improved three visualization parameters in MR images: contrast enhancement, border delineation, and internal morphology (P < 0.0001). Non-inferiority was achieved for mean number of lesions detected. Gadobutrol-enhanced imaging provided significant improvements in sensitivity and accuracy for the detection of malignant disease with no loss in specificity, and also improvements in accuracy of exact match diagnosis and diagnostic confidence. Drug-related adverse events were reported in 6 out of 223 patients (2.7%); all were non-serious. CONCLUSION: Gadobutrol is an effective and well-tolerated contrast agent for MR imaging of the CNS.

Safety and Efficacy of Gadobutrol for Contrast-enhanced Magnetic Resonance Imaging of the Central Nervous System: Results from a Multicenter, Double-blind, Randomized, Comparator Study.

PURPOSE: Contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) with gadolinium-based contrast agents (GBCAs) is standard of care for CNS imaging and diagnosis because of the visualization of lesions that cause blood-brain barrier breakdown. Gadobutrol is a macrocyclic GBCA with high concentration and high relaxivity. The objective of this study was to compare the safety and efficacy of gadobutrol 1.0 M vs unenhanced imaging and vs the approved macrocyclic agent gadoteridol 0.5 M at a dose of 0.1 mmol/kg bodyweight. MATERIALS AND METHODS: Prospective, multicenter, double-blind, crossover trial in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol. Three blinded readers assessed the magnetic resonance images. The primary efficacy variables included number of lesions detected, degree of lesion contrast-enhancement, lesion border delineation, and lesion internal morphology. RESULTS: Of the 402 treated patients, 390 patients received study drugs. Lesion contrast-enhancement, lesion border delineation, and lesion internal morphology were superior for combined unenhanced/gadobutrol-enhanced imaging vs unenhanced imaging (P < 0.0001 for all). Compared with gadoteridol, gadobutrol was non-inferior for all primary variables and superior for lesion contrast-enhancement, as well as sensitivity and accuracy for detection of malignant disease. The percentage of patients with at least one drug-related adverse event was similar for gadobutrol (10.0%) and gadoteridol (9.7%). CONCLUSION: Gadobutrol is an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS. Gadobutrol demonstrates greater contrast-enhancement and improved sensitivity and accuracy for detection of malignant disease than gadoteridol, likely because of its higher relaxivity.

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

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.

Evaluation of the effect of two gadolinium-containing contrast-enhancing agents, gadobutrol and gadoxetate disodium, on colorimetric calcium determinations in serum and plasma.

OBJECTIVE: To determine the extent to which the gadolinium-containing contrast agents, gadobutrol (Gadovist) and gadoxetate disodium (Primovist/Eovist), interfere with the colorimetric measurement of calcium concentrations in serum and plasma. MATERIALS AND METHODS: Gadobutrol and gadoxetate disodium were added in various concentrations to serum and plasma from healthy volunteers; the calcium concentration in these samples was then measured by standard colorimetry methods and atomic absorption. RESULTS: At clinically relevant concentrations, neither gadobutrol nor gadoxetate disodium influenced the results of the calcium measurement in serum or plasma. Only at the highest concentrations tested (50 mM gadobutrol; 25 mM gadoxetate disodium), an effect was seen in some cases. Results were confirmed by atomic absorption spectroscopy as the reference method. CONCLUSIONS: At clinically relevant concentrations, gadobutrol and gadoxetate disodium did not interfere with standard colorimetric methods for calcium determination.

Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment.

OBJECTIVES: : The purpose of this study was to determine the pharmacokinetics (PKs), imaging properties, and safety of the liver-specific magnetic resonance (MR) imaging contrast agent gadoxetic acid disodium (Gd-EOB-DTPA) in subjects with various levels of hepatic impairment, renal impairment, or coexisting hepatic and renal impairment. MATERIALS AND METHODS: : In this single-center, open-label, parallel-group study, patients with varying degrees of renal and/or hepatic impairment were compared with healthy subjects matched for age, gender, and weight (control group). All subjects received a single intravenous bolus of Gd-EOB-DTPA (Primovist, Eovist, EOB-Primovist) 25 µmol/kg body weight. Samples of serum, urine, and feces were collected for PK analysis. MR imaging was performed before dosing and at preset times after dose administration to determine enhancement relative to predose signal intensity values. Safety was assessed by monitoring adverse events, laboratory values, vital signs, cardiac rhythm, oxygen saturation, and by physical examination findings. RESULTS: : Gd-EOB-DTPA was well tolerated by all subjects. Total clearance of Gd-EOB-DTPA did not significantly change in patients with mild and moderate hepatic impairment (Child-Pugh A and B), compared with the control group. Mean urinary excretion was increased and mean fecal excretion was decreased in patients with hepatic impairment. Renal excretion was increased to between 72% and 96% of the dose administered in patients with very high bilirubin levels (>3 mg/dL), compared with 48% in the control group. Total clearance of Gd-EOB-DTPA was significantly reduced to 140 ± 45 mL/min and terminal elimination half-life (t1/2) was slightly, but not significantly, increased to 2.6 ± 0.9 hours in patients with severe hepatic impairment (Child-Pugh C), compared with the control group (209 ± 37 mL/min and 1.8 ± 0.2 hours, respectively). Liver MR signal enhancement (area under the curve of relative enhancement [%] over time) was similar in patients with mild and moderate hepatic impairment and in those in the control group, but was decreased by 38% in patients with severe hepatic impairment, compared with control. Peak liver enhancement, however, was still at a high level (118% ± 57%). PK and imaging parameters were not significantly affected in patients with moderate renal impairment (creatinine clearance, 30-50 mL/min). In patients with end-stage renal failure (ESRF), however, the PK profile of Gd-EOB-DTPA was significantly different, with an increased t1/2 (20.0 ± 7.0 hours vs. 1.8 ± 0.2 hours in the control group). During a 3-hour dialysis session that started 1 hour after administration of the intravenous dose, the serum levels in patients with ESRF declined by between 71% and 88% as a result of elimination by hemodialysis and parallel hepatobiliary excretion. This is comparable with the decline observed in healthy subjects (85%) during the 1- to 4-hour interval after injection. CONCLUSIONS: : The results of the present study show that in humans with moderate renal impairment and mild-to-moderate hepatic impairment, no relevant changes in PK parameters, such as total clearance and t1/2, develop as a result of increased renal excretion to compensate in the case of hepatic impairment (or increased hepatic elimination in the case of renal impairment). The t1/2 of Gd-EOB-DTPA was markedly altered only in patients with ESRF. The high MR signal enhancement profile, observed even in patients with severe hepatic impairment, indicates that there is no need to adjust the dose of Gd-EOB-DTPA.

Magnetic resonance evaluation of brain metastases from systemic malignances with two doses of gadobutrol 1.0 m compared with gadoteridol: a multicenter, phase ii/iii study in patients with known or suspected brain metastases.

OBJECTIVES: To determine the efficacy and safety of 2 doses of gadobutrol 1.0 M (0.1 and 0.2 mmol/kg body weight [BW]), compared with gadoteridol 0.5 M (0.2 mmol/kg BW), in contrast-enhanced magnetic resonance imaging (CE-MRI) of brain metastases in patients with known or suspected brain metastases from systemic malignancies. The study also compared the usefulness of gadobutrol in treatment planning for stereotactic radiosurgery (SRS). MATERIALS AND METHODS: This was a Phase II/III, multicenter, single-blind, randomized, controlled, crossover, intraindividual comparison study. Each patient underwent one MRI study examination with gadobutrol and the other with gadoteridol, each at a dose of 0.1 mmol/kg BW, administered twice, for a total dose of 0.2 mmol/kg BW. Image acquisition was carried out after the first and second doses of gadobutrol, but only after the second dose of gadoteridol. Contrast agents were assigned in a randomized order and their administration separated by an interval of 1 to 14 days. Images were evaluated through blinded readings by 3 independent experienced radiologists. Treatment planning for SRS was assessed in a blinded manner, as a consensus between a diagnostic neuroradiologist and a radiation oncologist, in addition to the clinical investigator's assessment. The safety and tolerability of gadobutrol and gadoteridol were evaluated in all patients who received the study drugs. The primary efficacy variable was the number of lesions detected in CE-MRI images; the secondary efficacy variables were the degree of contrast enhancement and border delineation of lesions, and experts' confidence in treatment planning for SRS. RESULTS: A total of 175 patients were enrolled and randomized, with 164 (93.7%) included in the safety analysis set, and 151 (86.2%) evaluable in the efficacy analysis. The mean number of detected lesions per patient using the average of the 3 blinded readers was 6.28, 6.92, and 6.87 for gadobutrol 0.1 and 0.2 mmol/kg BW, and gadoteridol 0.2 mmol/kg BW, respectively. Noninferiority of gadobutrol (both doses) to gadoteridol 0.2 mmol/kg BW was demonstrated. The degree of contrast enhancement and the border delineation of each lesion were categorized as "good" or "excellent" for most lesions for both agents. Almost all enhanced images were rated as "confident" in treatment planning for SRS. Sixty-five (43%) and 62 (41%) patients in the gadobutrol 0.1 and 0.2 mmol/kg BW groups, respectively, were selected as eligible for SRS treatment. The percentage of images assessed as "gadobutrol was better than gadoteridol" was higher than that assessed as "gadoteridol was better than gadobutrol" for both doses of gadobutrol. Eight adverse events were reported as being related to the study drug in 7 patients (4.3%) in each group. CONCLUSION: In this study, a single dose of gadobutrol was shown to be noninferior to a double dose of gadoteridol at detecting brain metastases, and could be effectively used for treatment planning in patients eligible for SRS. A dose of gadobutrol 0.1 mmol/kg BW is recommended as the clinical dose for the detection of brain metastases.

Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.

OBJECTIVES: To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. MATERIALS AND METHODS: The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. RESULTS: Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter

Vascular enhancement in early dynamic liver MR imaging in an animal model: comparison of two injection regimen and two different doses Gd-EOB-DTPA (gadoxetic acid) with standard Gd-DTPA.

OBJECTIVES: To investigate the influence of 2 different doses and injection rates on the enhancement of liver vasculature in Gd-EOB-DTPA enhanced liver MRI compared with the standard dose Gd-DTPA. MATERIALS AND METHODS: This animal experimental study has been approved by the local authorities. In 5 pigs, a time-resolved T1w 3D GRE sequence, and in a second experiment, a single-slice turbo FLASH T1w sequence with 3 frames/s were started each with contrast agent application of Gd-EOB-DTPA and Gd-DTPA. Three sets with different doses were performed with an injection rate of 1 and 2 mL/s which are as follows: A, Standard dose: 25 [mu]mol Gd-EOB-DTPA/kg body-weight (bw); B, Double dose: 50 [mu]mol Gd-EOB-DTPA/kg bw; and C, Standard dose: 100 [mu]mol Gd-DTPA/kg bw. Signal intensities were measured in aorta, vena cava inferior, portal vein, and liver parenchyma, and time-signal-to-noise (SNR)-curves were generated. The increase in SNR from baseline and several perfusion parameters were calculated. Statistical significance was tested with the Wilcoxon rank test at a significance level of P = 0.05. RESULTS: Mean peak enhancement (SNR) in the aorta was not significantly different for set A, B, and C with the same injection rate. Mean peak enhancement in the aorta was significantly higher for set A at 1 mL/s than at 2 mL/s (159.1 vs. 144.4, P = 0.043). Mean peak enhancement in the PV, the vena cava inferior, and the liver parenchyma was significantly lower for set A compared with set B and set C, at both injection speeds. The full width at half max was significantly longer for injection protocols with 1 as compared with 2 mL/s for sets A and set B. Set A with 1 mL/s reached similar values as compared with set C with 2 mL/s for the full width at half max (8.92 vs. 9.40; P = 0.35), for the area-under-the curve (1736.64 vs. 1912.74; P = 0.69) and the maximal signal-to-noise ratio (25.21 vs. 25.37; P = 0.69). CONCLUSION: Despite the lower amount of gadolinium in the standard dose of Gd-EOB-DTPA, the results showed that the arterial enhancement in Gd-EOB-DTPA-enhanced dynamic liver MRI was comparable to Gd-DTPA. This result can be explained mainly by the higher relaxivity. Choosing a lower injection rate additionally supported to compensate for the lower injection volume by stretching the bolus without decreasing the peak. In this respect, an injection rate of 1 mL/s showed better results with regard to the arterial enhancement compared with 2 mL/s.