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%)].