Chemical formula: C₂₀H₃₄GdN₅O₁₀ Molecular mass: 661.76 g/mol PubChem compound: 444013
Gadoversetamide is a chelate containing gadolinium – which has paramagnetic properties and is responsible for the contrast enhancement effect in MRI – and the ligand versetamide.
The purpose of an MRI contrast agent is to induce signal intensity changes within the lesion thereby facilitating its recognition from the surrounding normal structures. The use of a contrast agent may therefore reduce the threshold for lesion detection and visualization. Gadolinium containing MRI contrast agents (gadolinium-based chelates) are designed to act indirectly on the local magnetic environment by altering proton T1 (spin-lattice) and T2 (spin-spin) relaxation times and at the usual concentration of 100 micromol/kg, the T1 shortening predominates, and the T2 shortening is not significant using T1-weighted sequences.
Gadoversetamide, an extracellular gadolinium chelate, after intravenous administration, equilibrates rapidly within the extracellular fluid/space and is eliminated primarily by glomerular filtration.
The pharmacokinetics of gadoversetamide conforms to a two compartment open-model. At the 100 micromol/kg dose, the mean distribution half life in normal subjects calculated by the method of residuals in 12 normal volunteers is 13.3 ± 6.8 min. Mean volume of distribution at the 100 micromol/kg dose in non-renally impaired patients (including both normal subjects and patients with CNS or liver pathology) was 158.7 ± 29.0 to 214.3 (range 116.4 to 295.0) ml/kg. This volume of distribution (approximately 10-15 l for a body weight of 70 kg) is consistent with a medicinal product which distributes into the extracellular fluid. Dose level has no consistent effect on the volume of distribution in any of the studies. Gadoversetamide does not undergo protein binding in vitro.
The elimination half life at the 100 micromol/kg dose ranges from 1.49 ± 0.15 h in healthy volunteers to 2.11 ± 0.62 h in non-renally impaired patients (including normal subjects and patients with CNS or liver pathology).
The mean plasma clearance of gadoversetamide in healthy subjects (111.0 ± 14.1 ml/min/1.73m² BSA) is not significantly different from the mean renal clearance. Similar results are obtained in normal subjects and patients with various combinations of liver, CNS and renal dysfunctions with renal clearance of gadoversetamide being approximately 95% of the total plasma clearance. Such results (ratio renal clearance/total plasma clearance close to 1) indicate that gadoversetamide is essentially cleared through the kidneys.
There was no systematic difference in any of the kinetic parameters as a function of dose level (100 to 700 micromol/kg). Therefore, within this dose range, the kinetics of gadoversetamide appear to be linear.
The high accountability for the dose as intact complex in urine suggests that no significant metabolism of gadoversetamide occurs in humans.
Adult male and female subjects were enrolled in two pharmacokinetic studies. No significant differences in pharmacokinetics based on gender were identified.
When corrected for body weight, the total body clearance of gadoversetamide is greater in the 2 to 11 year age group (143 ± 27.9 ml/h/kg) than that observed in the 12 to 18 year age group (117 ± 26.1 ml/h/kg) and the two adult populations (82.1 ± 16.8 and 56.5 ± 9.7 ml/h/kg in the 19 to 64 and ≥65 year of age groups, respectively).
The elimination half life in the 2 to 11 and 12 to 18 year age groups (1.4 ± 0.3 and 1.6 ± 0.3 h-1, respectively) is shorter than that observed in the two adult populations (1.9 ± 0.5 and 2.5 ± 0.5 h-1 in the 19 to 64 and ≥65 year of age groups, respectively). The number of elderly patients in whom the pharmacokinetics were determined was limited (over 65 years, N=3).
Gadoversetamide plasma levels increase linearly with decreasing renal function; in patients with severe renal impairment (CrCl<30 ml/min) this even leads to a six-fold decreased gadoversetamide clearance and a corresponding six-fold increased extent of exposure AUC and t½. Since gadoversetamide is only administered as a single dose this will lead to a longer and higher exposure for a limited duration. Still, after 72 hours even in patients with severe renal impairment nearly the whole dose is recovered in the urine and in healthy populations up to 500 micromol/kg doses were administered without safety issues. Nevertheless, because of reported cases of NSF that may be associated with renal impairment for other gadolinium containing contrast agents and for gadoversetamide, it should not be used in these patients.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute toxicity, reproductive toxicity, local tolerance, antigenicity, and genotoxicity. No carcinogenicity studies were performed.
Repeated-dose toxicity studies in rats and dogs revealed vacuolation of the tubular cells of the kidneys, with strong evidence for reversibility of the effect. No functional impairment was observed.
The elimination of gadoversetamide in dogs younger than 3 months of age was significantly delayed because of immature renal function and resulted in a high systemic exposure to gadoversetamide. Weekly repeated dosing of two to twenty times the clinical dose from one week of age through maturation resulted in extensive mineralization of tissues, which produced localized effects, such as ulcerative dermatitis, compromised circulation and hepatic dysfunction.
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