Gadavist

CLINICAL PHARMACOLOGY

Mechanism of Action

In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur 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 (gadobutrol) 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 (gadobutrol) , is based upon several factors including the concentration of Gadavist (gadobutrol) 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.

Pharmacodynamics

Gadavist (gadobutrol) 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 2). This may improve tissue visualization.

Table 2: Relaxivity (FI) of Gadolinium Chelates at 1.5 T

Gadolinium-Chelate r1 (L·mmol -1 ·s-1)
Gadobutrol 5.2
Gadoteridol 4.1
Gadobenate 6.3
Gadopentetate 4.1
Gadodiamide 4.3
Gadoversetamide 4.7
r1 relaxivity in plasma at 37°C

Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist (gadobutrol) results in half the volume of administration and a more compact contrast bolus.

Gadavist (gadobutrol) 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.

Pharmacokinetics

Distribution

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.

Metabolism

Gadobutrol is not metabolized.

Elimination

Gadobutrol is excreted in an unchanged form via the kidneys. Gadobutrol is eliminated from plasma with a mean terminal half-life of 1.81 hours (1.33-2.13 hours).

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. The extrarenal elimination is negligible.

Special populations

Gender

Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol.

Geriatric

A single IV dose of 0.1 mmol/kg Gadavist (gadobutrol) 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].

Pediatric

The pharmacokinetics of Gadavist (gadobutrol) were evaluated based on a population pharmacokinetic analysis in 130 pediatric subjects aged 2 to 17 years. Subjects received a single intravenous dose of 0.1 mmol/kg of Gadavist (gadobutrol) . The median AUC (mmol-h/L), clearance (L/hr/kg) and elimination half-life (hrs) of gadobutrol was similar across the age range of 2 - 17 years. The median AUC of gadobutrol in children 2-6 years (n=45) was 0.8 mmol-h/L, 1.0 mmol-h/L in children 7-11 years (n=39), and 1.2 mmol-h/L in children 12 - 17 years (n=46). The median clearance of gadobutrol in children 2-6 years was 0.13 L/hr/kg, 0.1 L/hr/kg in children 7-11 years, and 0.09 L/hr/kg in children 12 - 17 years, and the median elimination half-life of gadobutrol in children 2-6 years was 1.75 hours, 1.61 hours in children 7-11 years, and 1.65 hours in children 12 - 17 years. Approximately 99% (median value) of the dose was recovered in urine within 6 hours. [See Use In Specific Populations]

Renal Impairment

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 at least 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 (gadobutrol) in order to enhance the contrast agent's elimination. Sixty-eight % 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].

Clinical Studies

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 (gadobutrol) 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 (gadobutrol) 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 0 to 4, and for internal morphology using a scale of 0 to 3 (Table 3). Lesion counting was also performed to demonstrate non-inferiority of paired Gadavist (gadobutrol) image sets to pre-contrast MRI. Readers were blinded to clinical information.

Table 3: Primary Endpoint Visualization Scoring System

Score Visualization Characteristics
Contrast Enhancement Border Delineation Internal Morphology
1 None None Poorly visible
2 Weak Moderate Moderately visible
3 Clear Clear but incomplete Sufficiently visible
4 Clear and bright Clear and complete N/A

Diagnostic 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 4 shows a comparison of visualization results between paired images and pre-contrast images. Gadavist (gadobutrol) provided a statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study.

Table 4: Visualization Endpoint Results of Central Nervous System Adult MRI Studies with 0.1 mmol/kg Gadavist (gadobutrol)

Endpoint Study A
N=336
Study B
N=321
Pre-contrast Paired Difference* Pre-contrast Paired Difference
Contrast Enhancement 0.97 2.26 1.29^ 0.93 2.86 1.94^
Border Delineation 1.98 2.58 0.60^ 1.92 2.94 1.02^
Internal Morphology 1.32 1.93 0.60^ 1.57 2.35 0.78^
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 (gadobutrol) 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 (gadobutrol) 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 3 is shown in Table 5. 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 5: Primary Endpoint Visualization Categorical Improvement for Average Reader

Endpoint Study A
N=336
Study B
N=321
Categorical Improvement
(Paired - Pre-Contrast) %
Categorical Improvement
(Paired - Pre-Contrast) %
≤ 0 > 0 - < 1 l- < 2 ≥ 2 ≤ 0 > 0 - < 1 l- < 2 ≥ 2
Contrast Enhancement 1 30 55 13 3 6 34 57
Border Delineation 7 73 18 1 5 38 51 5
Internal Morphology 4 79 17 0 5 61 33 1

For both studies, the improvement of visualization endpoints in paired Gadavist (gadobutrol) images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy.

Last reviewed on RxList: 5/5/2011
This monograph has been modified to include the generic and brand name in many instances.

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