"Today, the U.S. Food and Drug Administration approved Kanuma (sebelipase alfa) as the first treatment for patients with a rare disease known as lysosomal acid lipase (LAL) deficiency.
Patients with LAL deficiency (also known as Wolman disea"...
Mechanism of Action
Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.
In magnetic resonance imaging (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, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.
Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2-1.5 T).
Gadoterate does not cross the intact blood-brain barrier and, therefore, does not enhance normal brain or lesions that have a normal blood-brain barrier, e.g. cysts, mature post-operative scars. However, disruption of the bloodbrain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.
The pharmacokinetics of total gadolinium following an intravenously administered 0.1 mmol/kg dose of DOTAREM in normal subjects conform to a one-compartment open-model with a mean elimination half-life (reported as mean ± SD) of about 1.4 ± 0.2 hr and 2.0 ± 0.7 hr in female and male subjects, respectively. Similar pharmacokinetic profile and elimination half-life values were observed after intravenous injection of 0.1 mmol/kg of DOTAREM followed 20 minutes later by a second injection of 0.2 mmol/kg (1.7 ± 0.3 hr and 1.9 ± 0.2 hr in female and male subjects, respectively).
The volume of distribution at steady state of total gadolinium in normal subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water.
Gadoterate does not undergo protein binding in vitro. The extent of blood cell partitioning of gadoterate is not known.
Gadoterate is not known to be metabolized.
Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0% and 85.4 ± 9.7% (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2% and 92.0 ± 12.0% recovered in urine within 48 hrs in female and male subjects respectively.
In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear.
A single intravenous dose of 0.1 mmol/kg of DOTAREM was administered to 8 patients (5 men and 3 women) with impaired renal function (mean serum creatinine of 498 ± 98 μmol/L in the 10-30 mL/min creatinine clearance group and 192 ± 62 μmol/L in the 30-60 mL/min creatinine clearance group). Renal impairment delayed the elimination of total gadolinium. Total clearance decreased as a function of the degree of renal impairment. The distribution volume was unaffected by the severity of renal impairment (Table 5). No changes in renal function test parameters were observed after DOTAREM injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48 hrs in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hrs in patients with severe renal impairment and 93.3 ± 4.7% in 24 hrs for subjects with normal renal function.
Table 5: Pharmacokinetic Profile of Total Gadolinium
in Normal and Renally Impaired Patients
|Population||Elimination Half-life (hr)||Plasma Clearance (L/h/kg)||Distribution Volume (L/kg)|
|Healthy volunteers||1.6 ± 0.2||0.10 ± 0.01||0.246 ± 0.03|
|Patients with moderate renal impairment||5.1 ± 1.0||0.036 ± 0.007||0.236 ± 0.01|
|Patients with severe renal impairment||13.9 ± 1.2||0.012 ± 0.001||0.234 ± 0.01|
Animal Toxicology and/or Pharmacology
Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting [see WARNINGS AND PRECAUTIONS].
Efficacy and safety of DOTAREM were evaluated in a multi-center clinical trial (Study A) that enrolled 364 adult and 38 pediatric patients (aged ≥ 2 years) with known or suspected CNS lesions. Adults were randomized 2 to 1 to receive either DOTAREM or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received DOTAREM, also at a dose of 0.1 mmol/kg. In the trial, patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MR examination. The images (pre-contrast, post-contrast and “paired pre- and post-contrast”) were interpreted by three independent off-site readers blinded to clinical information. The primary efficacy analysis compared three patient-level visualization scores (paired images) to baseline MRI (pre-contrast images) for adults who received DOTAREM. The three primary visualization components were: contrast enhancement, border delineation and internal morphology. For each of these components there was a pre-defined scoring scale. Lesion counting (up to five per patient) was also reflected within each component's patient-level visualization score.
Among the adult patients, 245 received DOTAREM and their data comprised the primary efficacy population. There were 114 (47%) men and 131 (53%) women with a mean age of 53 years (range 18 to 85 years), the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other.
Table 6 displays a comparison of paired images (pre-and post-contrast) to pre-contrast images with respect to the proportion of patients who had paired image scores that were greater “better”, or same/worse “not better” than the pre-contrast scores and with respect to the difference in the mean patient level visualization score. Across the three readers 56% to 94% of patients had improved lesion visualization for paired images compared to pre-contrast images. DOTAREM provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images.
Table 6: Study A. Improvement in Patient-level Lesion
Visualization Scores, Paired versus Pre-contrast Imagesa
|Lesion Scores||Reader 1
n = 231
n = 232
n = 237
|Better||195 (84%)||215 (93%)||132 (56%)|
|Not Better||28 (12%)||7 (3%)||88 (37%)|
|Missing||8 (4%)||10 (4%)||17 (7%)|
|Difference in Mean Scoreb||2.26*||2.89*||1.17*|
|Better||218 (94%)||214 (93%)||187 (79%)|
|Not Better||5 (2%)||8 (3%)||33 (14%)|
|Missing||8 (4%)||10 (4%)||17 (7%)|
|Difference in Mean Scoreb||2.74*||2.75*||1.54*|
|Better||208 (90%)||216 (93%)||208 (88%)|
|Not Better||15 (6%)||6 (3%)||12 (5%)|
|Missing||8 (4%)||10 (4%)||17 (7%)|
|Difference in Mean Scoreb||3.09*||3.69*||2.92*|
|a Better: number of patients with paired
(pre-and post-contrast) score greater than the pre-contrast score Not better:
number of patients with paired score same as or worse than the pre-contrast
score Missing: number of patients with missing score
b Difference = paired mean score minus pre-contrast mean score
*Statistically significant improvement by paired t-test
In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. DOTAREM lesion visualization scores were similar to those for gadopentetate dimeglumine. DOTAREM imaging results in the pediatric patients were also similar to those seen in adults.
In a second clinical trial (Study B), MR images were reread from 150 adult patients with known CNS lesions who had participated in previously conducted clinical trial. DOTAREM administration and image interpretation was performed in the same manner as in Study A. Similar to Study A, this trial also demonstrated improved lesion visualization with DOTAREM.
Last reviewed on RxList: 4/5/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Dotarem 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.