"The US Food and Drug Administration (FDA) today approved the first nucleic acid-based test of cerebrospinal fluid (CSF) that can simultaneously detect 14 pathogens responsible for central nervous system (CNS) infections.
Mechanism Of Action
In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with:
- Differences in proton density
- Differences of the spin-lattice or longitudinal relaxation times (T1)
- Differences in the spin-spin or transverse relaxation time (T2)
When placed in a magnetic field, Gadavist shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from Gadavist, is based upon several factors including the concentration of Gadavist in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1-weighted magnetic resonance sequences. In T2*-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.
Gadavist leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37°C and 1.5 T, the relaxivity (r1) -determined from the influence on the relaxation times (T1) of protons in plasma -is 5.2 L/(mmol·sec) and the relaxivity (r2) -determined from the influence on the relaxation times (T2) -is 6.1 L/(mmol·sec). These relaxivities display only slight dependence on the strength of the magnetic field. The T1 shortening effect of paramagnetic contrast agents is dependent on concentration and r1 relaxivity (see Table 3). This may improve tissue visualization.
Table 3: Relaxivity (r1) of
Gadolinium Chelates at 1.5 T
|Gadolinium-Chelate||r1 (L-mmol -1 -s-1)|
|r1 relaxivity in plasma at 37°C|
Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist results in half the volume of administration and a more compact contrast bolus.
Gadavist is a highly water-soluble, extremely hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006.
After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. In rats, gadobutrol does not penetrate the intact blood-brain barrier.
Gadobutrol is not metabolized.
Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below.
Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min•kg) and thus comparable to the renal clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration.
Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible.
Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol.
A single IV dose of 0.1 mmol/kg Gadavist was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects [see Use In Specific Populations].
The pharmacokinetics of gadobutrol were evaluated in two studies in a total of 130 patients age 2 to less than 18 years and in 43 patients less than 2 years of age (including term neonates). Patients received a single intravenous dose of 0.1 mmol/kg of Gadavist. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to less than 18 year old age group).
Table 4: Pharmacokinetics by Age Group (Median
|0 to < 2 years
|2 to 6 years
|7 to 11 years
|12 to < 18 years
In patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance.
After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half-life was 5.8 ± 2.4 hours in mild to moderately impaired patients (80 > CLCR > 30 mL/min) and 17.6 ± 6.2 hours in severely impaired patients not on dialysis (CLCR < 30 mL/min). The mean AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol•h/L, compared to 4.0 ± 1.8 mmol•h/L in patients with mild to moderate renal impairment and 11.5 ± 4.3 mmol•h/L in patients with severe renal impairment.
Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days.
For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of Gadavist in order to enhance the contrast agent's elimination. Sixty-eight percent (68%) of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session. [See WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Animal Toxicology And/Or Pharmacology
Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting [see WARNINGS AND PRECAUTIONS].
MRI Of The CNS
Patients referred for MRI of the central nervous system with contrast were enrolled in two clinical trials that evaluated the visualization characteristics of lesions. In both studies, patients underwent a baseline, pre-contrast MRI prior to administration of Gadavist at a dose of 0.1 mmol/kg, followed by a post-contrast MRI. In study A, patients also underwent an MRI before and after the administration of gadoteridol. The studies were designed to demonstrate superiority of Gadavist MRI to non-contrast MRI for lesion visualization. For both studies, pre-contrast and pre-plus-post contrast images (paired images) were independently evaluated by three readers for contrast enhancement and border delineation using a scale of 1 to 4, and for internal morphology using a scale of 1 to 3 (Table 5). Lesion counting was also performed to demonstrate non-inferiority of paired Gadavist image sets to pre-contrast MRI. Readers were blinded to clinical information.
Table 5: Primary Endpoint Visualization Scoring System
|Contrast Enhancement||Border Delineation||Internal Morphology|
|3||Clear||Clear but incomplete||Sufficiently visible|
|4||Clear and bright||Clear and complete||N/A|
Efficacy was determined in 657 subjects. The average age was 49 years (range 18 to 85 years) and 42% were male. The ethnic representations were 39% Caucasian, 4% Black, 16% Hispanic, 38% Asian, and 3% of other ethnic groups.
Table 6 shows a comparison of visualization results between paired images and pre-contrast images. Gadavist provided a statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study.
Table 6: Visualization
Endpoint Results of Central Nervous System Adult MRI Studies with 0.1 mmol/kg Gadavist
|Endpoint||Study A N=336||Study B N=321|
|Contrast Enhancement||0.97||2.26||1.29^||0.93||2.86||1.94 ^|
|Average # Lesions Detected||8.08||8.25||0.17**||2.65||2.97||0.32^^|
|* Difference of means = (paired
mean) – (pre-contrast mean)
^ p < 0.001
^^ Met noninferiority margin of -0.35
** Did not meet noninferiority margin of -0.35
Performances of Gadavist and gadoteridol for visualization parameters were similar. Regarding the number of lesions detected, study B met the prespecified noninferiority margin of -0.35 for paired read versus pre-contrast read while in Study A, Gadavist and gadoteridol did not.
For the visualization endpoints contrast enhancement, border delineation, and internal morphology, the percentage of patients scoring higher for paired images compared to pre-contrast images ranged from 93% to 99% for Study A, and 95% to 97% for Study B. For both studies, the mean number of lesions detected on paired images exceeded that of the pre-contrast images; 37% for Study A and 24% for Study B. There were 29% and 11% of subjects in which the pre-contrast images detected more lesions for Study A and Study B, respectively.
The percentage of patients whose average reader mean score changed by ≤ 0, up to 1, up to 2, and ≥ 2 scoring categories presented in Table 5 is shown in Table 7. The categorical improvement of ( ≤ 0) represents higher ( < 0) or identical (= 0) scores for the pre-contrast read, the categories with scores > 0 represent the magnitude of improvement seen for the paired read.
Table 7: Primary Endpoint
Visualization Categorical Improvement for Average Reader
|Categorical Improvement (Paired - Pre-Contrast) %||Categorical Improvement (Paired - Pre-Contrast) %|
|≤ 0||> 0 - < 1||1 - < 2||≥ 2||≤ 0||> 0 - < 1||1 - < 2||≥ 2|
For both studies, the improvement of visualization endpoints in paired Gadavist images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy.
Two studies in 44 pediatrics patients age younger than 2 years and 135 pediatric patients age 2 to less than18 years with CNS and non-CNS lesions supported extrapolation of adult CNS efficacy findings. For example, comparing pre vs paired pre-and post-contrast images, investigators selected the best of four descriptors under the heading, “Visualization of lesion-internal morphology (lesion characterization) or homogeneity of vessel enhancement” for 27/44 (62% = pre) vs 43/44 (98% = paired) MR images from patients age 0 to less than 2 years and 106/135 (78% = pre) vs 108/135 (80% = paired) MR images from patients age 2 to less than 18 years.
MRI Of The Breast
Patients with recently diagnosed breast cancer were enrolled in two identical clinical trials to evaluate the ability of Gadavist to assess the presence and extent of malignant breast disease prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to Gadavist (0.1 mmol/kg) breast MRI. BMR images and Gadavist BMR (combined contrast plus non-contrast) images were independently evaluated in each study by three readers blinded to clinical information. In separate reading sessions the BMR images and Gadavist BMR images were also interpreted together with X-ray mammography images (XRM).
The studies evaluated 787 patients: Study 1 enrolled 390 women with an average age of 56 years, 74% were white, 25% Asian, 0.5% black, and 0.5% other; Study 2 enrolled 396 women and 1 man with an average age of 57 years, 71% were white, 24% Asian, 3% black, and 2% other.
The readers assessed 5 regions per breast for the presence of malignancy using each reading modality. The readings were compared to an independent standard of truth (SoT) consisting of histopathology for all regions where excisions were made and tissue evaluated. XRM plus ultrasound was used for all other regions.
The assessment of malignant disease was performed using a region based within-subject sensitivity. Sensitivity for each reading modality was defined as the mean of the percentage of malignant breast regions correctly interpreted for each subject. The within-subject sensitivity of Gadavist BMR was superior to that of BMR. The lower bound of the 95% Confidence Interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for Study 1 and from 12% to 27% for Study 2. The within-subject sensitivity for Gadavist BMR and BMR as well as for Gadavist BMR plus XRM and BMR plus XRM is presented in Table 8.
Table 8: Sensitivity of Gadavist BMR for Detection of
Malignant Breast Disease
|Study 1||Study 2|
|Reader||BMR||BMR + XRM||Gadavist BMR||Gadavist BMR +XRM||Reader||BMR||BMR + XRM||Gadavist BMR||Gadavist BMR +XRM|
Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant. The lower limit of the 95% confidence interval for specificity of Gadavist BMR was greater than 80% for 5 of 6 readers. (Table 9)
Table 9: Specificity of
Gadavist BMR in Non-Malignant Breasts
|Study 1||Study 2|
|Reader||Gadavist BMR||Lower Limit 95% CI||Reader||Gadavist BMR||Lower Limit 95% CI|
Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94%.
In breasts with malignancy, a false positive detection rate was calculated as the percentage of subjects for which the readers assessed a region as malignant which could not be verified by SoT. The false positive detection rates for Gadavist BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%).
Last reviewed on RxList: 1/15/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Gadavist Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.