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Ablavar (Gadofosveset Trisodium) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Ablavar (gadofosveset trisodium) Injection is a sterile, nonpyrogenic, formulation of a stable gadolinium diethylenetriaminepentaacetic acid (GdDTPA) chelate derivative with a diphenylcyclohexylphosphate group. Each mL of Ablavar Injection contains 244 mg of gadofosveset trisodium (0.25 mmol), 0.268 mg of fosveset, and water for injection.

It contains no preservative and the solution pH ranges between 6.5 and 8.0.

Gadofosveset trisodium is chemically trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl]-diethylenetriaminepentaacetato)(aquo) gadolinium(III),with a molecular weight of 975.88 g/mol, and an empirical formula of C33H40GdN3Na3O15P. It has a structural formula:

Pertinent physiochemical data of Ablavar Injection are provided below:

Table 3. Physiochemical Characteristics
Parameter Condition Value
Osmolality (mOsmol/kg water) @ 37C 825
Viscosity (cP) @ 20C 3.0
Density (g/mL) @ 25C 1.1224

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, 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%).

Special Populations

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.

NONCLINICAL TOXICOLOGY

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) ].

CLINICAL STUDIES

Safety and efficacy of Ablavar 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 Ablavar as well as catheter-based X-ray arteriography. Diagnostic efficacy was based upon comparisons of sensitivity and specificity between MRA with and without Ablavar, 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 Ablavar-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 Ablavar-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 Ablavar administration. Specifically, the sensitivity and specificity for these Ablavar 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 Ablavar-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 Ablavar-MRA and Non-contrast MRA
*(Based on cluster-corrected McNemar Test)
Reader SENSITIVITY SPECIFICITY
Ablavar- Non-contrast [A] – [B] Ablavar Non-contrast [A] – [B]
MRA [A] MRA [B] (95% CI)* MRA [A] MRA [B] (95% CI)*
1 89% 69% 20%
(15%, 25%)
72% 71% 1%
(-3%, 5%)
2 82% 70% 12%
(7%, 17%)
81% 73% 8%
(4%, 12%)
3 79% 64% 15%
(9%, 21%)
85% 85% 0%
(-2%, 2%)

Among the three readers, 5 to 12% of the vessel-segments were deemed uninterpretable by non-contrast MRA. For these vessel segments, sensitivity of Ablavar-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%)].

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