Mechanism of Action
Following intravenous injection, gadofosveset binds reversibly to endogenous serum albumin resulting in longer vascular residence time than non-protein binding contrast agents. The binding to serum albumin also increases the magnetic resonance relaxivity of gadofosveset and decreases the relaxation time (T1) of water protons resulting in an increase in signal intensity (brightness) of blood.
In human studies, gadofosveset substantially shortened blood T1 values for up to 4 hours after intravenous bolus injection. Relaxivity in plasma was measured to be 33.4 to 45.7 mM-1s-1 (0.47 T) over the dose range of up to 0.05 mmol/kg.
The pharmacokinetics of intravenously administered gadofosveset conforms to a two-compartment open model with mean plasma concentrations (reported as mean ±SD) of 0.43 ± 0.04 mmol/L at 3 minutes post-injection, and 0.24 ± 0.03 mmol/L at one hour post-injection. The mean half-life of the distribution phase is 0.48 ± 0.11 hours and the mean half-life of the elimination phase is 16.3 ± 2.6 hours. The mean total clearance of gadofosveset is 6.57 ± 0.97 mL/h/kg following the administration of 0.03 mmol/kg.
Distribution: The mean volume of distribution at steady state for gadofosveset was 148 ± 16 mL/kg, roughly equivalent to that of extracellular fluid. A significant portion of circulating gadofosveset is bound to plasma proteins, predominantly albumin. At 0.05, 0.5, 1 and 4 hours after injection of 0.03 mmol/kg the plasma protein binding of gadofosveset ranges from 79.8 to 87.4%.
Metabolism: Gadofosveset does not undergo measurable metabolism in humans.
Excretion: Gadofosveset is eliminated primarily in the urine with approximately 83.5% of an injected dose excreted in the urine over 14 days. Ninety-four percent (94%) of urinary excretion occurs in the first 72 hours. A small portion of gadofosveset dose is recovered in feces (approximately 4.7%).
Renal Insufficiency: Administration of gadolinium-based contrast agents, including Ablavar to patients with severe renal insufficiency increases the risk for NSF. Administration of these agents to patients with mild to moderate renal insufficiency may increase the risk for worsened renal function [ see Warnings and Precautions (5.1 and 5.3)
]. Prior to use of Ablavar in these patients, ensure that no satisfactory diagnostic alternatives are available. In patients with moderate to severe renal impairment (glomerular filtration rate < 60 mL/kg/m2), administer Ablavar at a dose of 0.01 mmol/kg to 0.02 mmol/kg. Consider follow-up renal function assessments following Ablavar administration to any patients with renal insufficiency.
A clinical study of gadofosveset, at a dose of 0.05 mmol/kg, was conducted in patients with mild, moderate, and severe renal impairment. The clearance decreased substantially as renal function decreased and the systemic exposure (AUC) increased almost 1.75-fold in patients with moderate (creatinine clearance: 30 to 50 mL/min) and 2.25-fold in patients with severe renal impairment (creatinine clearance < 30 mL/min). The elimination half-life increased from 19 hours in normal subjects to 49 hours in patients with moderate and 70 hours in patients with severe renal impairment. The volume of distribution at steady state and plasma protein binding of gadofosveset were not affected by renal impairment. Fecal elimination of gadofosveset increased as a function of increasing renal impairment (6.5% in normal subjects to 13.3% in patients with severe renal impairment).
Hemodialysis: Gadofosveset is removed from the body by hemodialysis using high-flux filters. Elimination of the total administered dose of gadolinium in dialysate over 3 dialysis sessions using high-flux filters averaged 46.8%, 12.9%, and 6.11% for the first, second, and third sessions, respectively.
Hepatic Insufficiency: The pharmacokinetics and plasma protein binding of gadofosveset was not significantly influenced by moderate hepatic impairment. A slight decrease in fecal elimination of gadofosveset was seen for the hepatic impaired subjects (2.7%) compared to normal subjects (4.8%).
Gender: No dosage adjustment is necessary based on gender. Gender had no meaningful effect on the pharmacokinetics of gadofosveset.
Geriatric: No dosage adjustment is necessary based on age. Age had no meaningful effect on the pharmacokinetics of gadofosveset.
Pediatric: of gadofosveset in pediatric patients have not been performed.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadofosveset. Gadofosveset was negative in the in vitro bacterial reverse mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay. Administration of up to 1.5 mmol/kg (8.3 times the human dose) to female rats for 2 weeks and to male rats for 4 weeks did not impair fertility [ see Use in Specific Populations (8.1)