Vasovist

Vasovist

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

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.

Pharmacokinetics

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. 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%).

Special Populations

Renal Insufficiency: Administration of gadolinium-based contrast agents, including VASOVIST (gadofosveset trisodium injection for intravenous use) 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]. Prior to use of VASOVIST (gadofosveset trisodium injection for intravenous use) 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 VASOVIST (gadofosveset trisodium injection for intravenous use) at a dose of 0.01 mmol/kg to 0.02 mmol/kg. Consider follow-up renal function assessments following VASOVIST (gadofosveset trisodium injection for intravenous use) 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: Studies of gadofosveset in pediatric patients have not been performed.

Clinical Studies

Safety and efficacy of VASOVIST (gadofosveset trisodium injection for intravenous use) were assessed in two multi-center, open-label, Phase 3 clinical trials. In both trials, patients with known or suspected peripheral vascular disease underwent MRA with and without VASOVIST (gadofosveset trisodium injection for intravenous use) as well as catheter-based X-ray arteriography. Diagnostic efficacy was based upon comparisons of sensitivity and specificity between MRA with and without VASOVIST (gadofosveset trisodium injection for intravenous use) , with X-ray arteriography as the reference standard.

Out of 493 patients enrolled in these two trials, 424 were included in the comparison of the diagnostic efficacy of VASOVIST (gadofosveset trisodium injection for intravenous use) -MRA to that of non-contrast MRA in detection/exclusion of occlusive vascular disease ( ≥ 50% stenosis) in 7 vessel-segments in the aortoiliac region. The interpretation of MRA images from both trials was conducted by three independent radiologist readers who were blinded to clinical data, including the results of X-ray arteriography. In these 424 patients, the median age was 67 years with a range of 29 to 87 years; 58% of the patients were over 65 years of age; 83% were white and 68% were male.

The primary efficacy analyses were designed to demonstrate superiority in sensitivity and non-inferiority in specificity of VASOVIST (gadofosveset trisodium injection for intravenous use) -MRA as compared to non-contrast MRA at the vessel-segment level. The uninterpretable images were assigned an outcome of “wrong diagnosis”. Additionally, success was also based upon acceptable performance characteristics for the uninterpretable non-contrast MRA vessel segments that became interpretable following VASOVIST (gadofosveset trisodium injection for intravenous use) administration. Specifically, the sensitivity and specificity for these VASOVIST (gadofosveset trisodium injection for intravenous use) images were required to exceed 50%. These pre-specified success criteria were to be achieved by at least the same two readers for all primary analyses.

Superiority in sensitivity and non-inferiority in specificity was demonstrated for VASOVIST (gadofosveset trisodium injection for intravenous use) -MRA by all three blinded readers. On average, 316 vessel segments were assessed for sensitivity and 2230 for specificity, by each reader. Table 4 summarizes the efficacy results, by reader.

Table 4: Performance Characteristics of VASOVIST (gadofosveset trisodium injection for intravenous use) -MRA and Non-contrast MRA

Reader SENSITIVITY SPECIFICITY
VASOVIST-
MRA [A]
Non-contrast
MRA [B]
[A] – [B]
(95% CI)*
VASOVIST
MRA [A]
Non-contrast
MRA [B]
[A] – [B]
(95% CI)*
1 89% 69% 20% 72% 71% 1%
(15%, 25%) (-3%, 5%)
2 82% 70% 12% 81% 73% 8%
(7%, 17%) (4%, 12%)
3 79% 64% 15% 85% 85% 0%
(9%, 21%) (-2%, 2%)
* (Based on cluster-corrected McNemar Test)

Among the three readers, 5 to 12% of the vessel-segments were deemed uninterpretable by non-contrast MRA. For these vessel segments, sensitivity of VASOVIST (gadofosveset trisodium injection for intravenous use) -MRA ranged from 72% [95% CI (54%, 90%)] to 97% [95% CI (93%, 100%)] and specificity ranged from 72% [95% CI (67%,76%)] to 84% [95% CI (81%, 88%)].

Last reviewed on RxList: 10/5/2009
This monograph has been modified to include the generic and brand name in many instances.

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