Chemical formula: C₃₃H₃₈GdN₃Na₃O₁₄P Molecular mass: 1,003.85 g/mol PubChem compound: 73049652
Gadofosveset is a formulation of a stable gadolinium diethylenetriaminepentaacetic acid (GdDTPA) chelate substituted with a diphenylcyclohexylphosphate group (gadofosveset trisodium), for use in magnetic resonance imaging (MRI).
Gadofosveset binds reversibly to human serum albumin. Protein binding enhances T1 relaxivity of gadofosveset up to 10 fold compared to non-protein bound gadolinium chelates.
The plasma concentration-time profile of intravenously administered gadofosveset conforms to a twocompartment open model. After intravenous administration of 0.03 mmol/kg dose the mean half-life of the distribution phase (t1/2α) was 0.48 ± 0.11 hours and the volume of distribution at steady state was 148 ± 16 ml/kg, roughly equivalent to that of extracellular fluid. Plasma protein binding was in a range 80% to 87% for up to the first 4 hours after injection.
The results from various evaluations of plasma and urine samples indicated that gadofosveset does not undergo measurable metabolism.
In healthy volunteers, gadofosveset was predominantly eliminated in the urine with 84% (range 79–94%) of the injected dose (0.03 mmol/kg) excreted in the urine in 14 days. Ninety-four percent (94%) of the urinary excretion occurred in the first 72 hours. A small portion of gadofosveset dose was recovered in the faeces (4.7%, range 1.1–9.3%), indicating a minor role of biliary excretion in the disposition of gadofosveset. After intravenous administration of 0.03 mmol/kg dose renal clearance (5.51 ± 0.85 ml/h/kg) and total clearance (6.57 ± 0.97 ml/h/kg) were similar, and mean terminal elimination half-life was 18.5 ± 3.0 hours.
In patients with moderate to severe renal impairment the half-life is markedly prolonged and the AUC increased by 2-3fold.
Gadofosveset can be removed from the body by hemodialysis. After bolus intravenous administration of 0.05 mmol/kg dose in patients requiring three times a week haemodialysis using high-flux filter, at the end of third dialysis session, the plasma concentration had declined to less than 15% of the Cmax. During the dialysis sessions the mean half-life of plasma concentration decline was in the range 5-6 hours. The mean dialysis clearance was between the range of 16-32 ml/h/kg. The high-flux dialysis filter was more efficient compared to the low-flux filter, therefore, use of a high-flux dialysis filter is recommended.
Plasma pharmacokinetics and protein binding of gadofosveset were not significantly influenced by moderate hepatic impairment (Child Pugh B). A slight decrease in faecal elimination of gadofosveset was seen for the hepatic impaired subjects (2.7%) compared to normal subjects (4.8%). In one subject with moderate hepatic impairment and abnormally low serum albumin, total clearance and half-life of gadofosveset was indicative of faster clearance compared to subjects with moderate hepatic impairment and normal serum albumin levels.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute toxicity, local tolerance, contact-sensitising potential, and genotoxicity.
No carcinogenicity studies were performed.
Repeated-dose toxicity studies revealed vacuolation of the tubular cells of the kidneys, with strong evidence for reversibility of the effect. No functional impairment was observed and electron microscopic investigations of the rat kidneys indicated that the observed vacuolation was primarily a storage phenomenon. Effects were of higher severity in rats than in monkeys, probably because of the higher renal clearance in rats. In monkeys, no renal effects were observed after single use even at a dose 100-times higher than the clinical dose.
In rabbits, an increased number of early resorptions and a slight but significant increase in the number of foetal anomalies (in particular hydrocephalus and malrotated limbs) were observed at doses at which no or slight maternal toxicity was observed (exposure was 2 and 5 times the expected human exposure, respectively). In an animal study, it was shown that less than 1% of the dose of gadofosveset administered enters breast milk.
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