Gadofosveset Trisodium (DB06705): A Comprehensive Monograph on a First-in-Class Blood-Pool MRA Agent

Executive Summary

Gadofosveset trisodium is a gadolinium-based contrast agent (GBCA) developed as a specialized intravascular or "blood-pool" agent for magnetic resonance angiography (MRA).[1] Its key innovation was a unique pharmacological profile, characterized by reversible binding to serum albumin, which conferred a prolonged intravascular residence time. This property enabled high-resolution, steady-state imaging of the vascular system, representing a significant advantage over conventional extracellular GBCAs that rapidly extravasate into the interstitial space.[3] It was the first agent to be approved by the U.S. Food and Drug Administration (FDA) specifically for MRA, with proven efficacy in evaluating aortoiliac occlusive disease (AIOD) where it demonstrated superior diagnostic accuracy compared to unenhanced MRA.[3]

Despite its clinical efficacy, the agent's lifecycle was dominated by two critical safety issues. First, it was subject to the class-wide Black Box Warning for Nephrogenic Systemic Fibrosis (NSF), a rare but debilitating and potentially fatal condition occurring in patients with severe renal impairment. This risk was theoretically amplified for gadofosveset due to its significantly prolonged elimination half-life in this patient population.[7] Second, its use coincided with the emerging concern of long-term gadolinium deposition in the brain and other tissues, a phenomenon particularly associated with its structural class of linear GBCAs.[10]

Developed by EPIX Pharmaceuticals and marketed under the brand names Vasovist and Ablavar, its commercial history was brief.[12] The agent was ultimately withdrawn from the market, with the manufacturer citing "poor sales" as the reason for discontinuation in 2017.[12] This commercial failure, however, was intrinsically linked to the escalating safety concerns and a broader market shift towards safer, macrocyclic GBCAs. Gadofosveset trisodium thus stands as a paradigm of a scientifically innovative but commercially unsuccessful pharmaceutical product. Its history serves as a cautionary tale where a novel mechanism of action was inseparable from the mechanism of its most severe potential toxicities, leading to its obsolescence in an increasingly risk-averse clinical and regulatory environment.

Compound Profile and Physicochemical Characteristics

Chemical Identification and Nomenclature

Gadofosveset trisodium is a small molecule drug classified as a paramagnetic contrast agent.[3] Its identity is established through a comprehensive set of chemical and regulatory identifiers.

• Primary Name: Gadofosveset trisodium.[1]
• Systematic (IUPAC) Name: Trisodium 2-{-3-[(4,4-diphenylcyclohexyl)oxy-oxidophosphoryl]oxypropyl]-[bis(2-oxido-2-oxoethyl)amino]ethyl]amino}acetate.[12] An alternate name provided by PubChem is trisodium;2--3-[(4,4-diphenylcyclohexyl)oxy-oxidophosphoryl]oxypropyl]-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+).[4]
• CAS Number: 193901-90-5 (for the anhydrous form).[4]
• DrugBank ID: DB06705.[3]
• Synonyms and Brand Names: The agent was developed under the code name MS 325 (or MS-325) and has been marketed under the trade names Vasovist and Ablavar. Other synonyms include AngioMARK.[5]
• Other Identifiers: It is also cataloged under the Unique Ingredient Identifier (UNII) XM33Q67UVH, KEGG ID D08005, and the Anatomical Therapeutic Chemical (ATC) code V08CA11.[4]

Molecular Structure and Composition

The chemical architecture of gadofosveset is central to both its function and its risk profile. It is a stable gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) chelate derivative.[4] Structurally, it is classified as a

linear, ionic chelate.[2] This classification is critical, as the open-chain (linear) structure is less kinetically stable compared to the caged (macrocyclic) structure of other GBCAs, a factor with significant implications for gadolinium release.

The molecule's defining feature is a diphenylcyclohexylphosphate group covalently attached to the Gd-DTPA backbone.[4] This lipophilic moiety mediates the drug's unique, non-covalent, and reversible binding to human serum albumin (HSA), which is the cornerstone of its blood-pool mechanism of action.[5] The molecular structure of gadofosveset trisodium is a clear illustration of a structure-function-risk relationship. The diphenylcyclohexylphosphate group is the key to its innovative blood-pool mechanism, but the underlying Gd-DTPA backbone classifies it as a linear chelate. This linear structure is inherently less stable than macrocyclic structures, predisposing it to gadolinium release (transmetallation), which is the putative mechanism for both NSF and gadolinium deposition.[11] The very chemical design that made gadofosveset innovative also placed it in a high-risk category for long-term toxicity.

The chemical formula is reported as C33​H40​GdN3​Na3​O15​P (for the monohydrate form) and C33​H38​GdN3​Na3​O14​P (for the anhydrous form).[12] Correspondingly, the molar mass is 975.88 g/mol for the monohydrate and 957.87 g/mol for the anhydrous form.[8]

Physicochemical Properties

Gadofosveset trisodium was supplied as a sterile, nonpyrogenic, clear aqueous solution for intravenous injection.[8] Each milliliter of the solution contained 244 mg of gadofosveset trisodium, equivalent to 0.25 mmol/mL.[7] The solution, which contains no preservative, has a pH between 6.5 and 8.0.[8] The high degree of plasma protein binding, ranging from 79.8% to 87.4% (predominantly to albumin), is its defining characteristic and separates it from conventional extracellular GBCAs.[8] Other key physicochemical data are summarized in Table 1.

Table 1: Key Identifiers and Physicochemical Properties of Gadofosveset Trisodium

Parameter	Value	Source(s)
DrugBank ID	DB06705	3
CAS Number	193901-90-5 (anhydrous)	12
Molecular Formula	C33​H40​GdN3​Na3​O15​P (monohydrate)	12
Molar Mass	975.88 g/mol (monohydrate)	8
Brand Names	Ablavar, Vasovist	12
ATC Code	V08CA11	4
Molecular Structure Class	Linear, Ionic Chelate	2
Plasma Protein Binding	79.8% - 87.4%	8
Osmolality (@ 37°C)	825 mOsmol/kg water	8
Viscosity (@ 20°C)	3.0 cP	8

Pharmacological Profile: Mechanism and Kinetics of a Blood-Pool Agent

Mechanism of Action

Like all gadolinium-based contrast agents, gadofosveset is a paramagnetic substance.[3] When administered intravenously and subjected to the strong external magnetic field of an MRI scanner, it induces a large local magnetic field in the blood vessels where it circulates.[25] This local magnetic field interacts with nearby water protons, disrupting their random motion and accelerating their realignment with the main magnetic field. This process, known as T1 relaxation, is significantly shortened.[3] On T1-weighted MR images, tissues with shorter T1 relaxation times produce a stronger signal, appearing brighter. Gadofosveset thereby enhances the signal intensity of blood, making blood vessels more conspicuous.[3]

The key differentiator in gadofosveset's mechanism is its strong but reversible binding to endogenous human serum albumin (HSA).[3] This interaction effectively traps the agent within the intravascular space, or "blood pool," significantly limiting its diffusion into the extravascular, extracellular space. This contrasts sharply with conventional extracellular GBCAs, which distribute rapidly throughout the extracellular fluid compartment.[2]

Pharmacodynamics

The pharmacodynamic effects of gadofosveset are a direct consequence of its albumin-binding properties. When bound to the large, slowly tumbling albumin molecule, the rotational motion of the gadolinium complex is dramatically reduced. This slower rotation is the primary factor that increases its magnetic resonance relaxivity—its efficiency at shortening T1.[3] The T1 plasma relaxivity of gadofosveset is increased by a factor of 5 to 10 compared to non-protein-binding agents.[25] At a field strength of 1.5 T, its relaxivity in plasma is 18-20 L·mmol⁻¹s⁻¹, a value significantly higher than that of other GBCAs.[2]

This albumin binding also results in a prolonged intravascular residence time.[3] This creates an extended "steady-state" imaging window that can last for an hour or more after injection. This allows for the acquisition of high-resolution images without the critical need for precise timing of the contrast bolus, a major advantage for complex angiographic studies.[2] The onset of action is approximately 5 to 7 minutes, with a duration of action for the primary imaging effect of about one hour.[25]

Pharmacokinetics

The pharmacokinetic profile of gadofosveset is unique among GBCAs and is central to both its efficacy and its primary safety concerns.

Distribution: The mean volume of distribution at steady state (Vdss​) is 148 ± 16 mL/kg, a volume roughly equivalent to that of the extracellular fluid.[8] The initial half-life of its distribution within the intravascular space is approximately 29 minutes.[5]

Metabolism: Gadofosveset is not metabolized in the body. It is eliminated entirely as the unchanged drug.[3]

Elimination: The primary route of elimination is renal excretion via glomerular filtration.[3] Between 83.5% and 94% of an injected dose is recovered in the urine over 14 days, with a small fraction of approximately 5% eliminated in the feces.[3]

Elimination Half-Life: The elimination half-life of gadofosveset is substantially longer than that of extracellular agents and is critically dependent on renal function.

• In individuals with normal renal function, the mean elimination half-life (t1/2​) is approximately 16.3 to 18.5 hours.[4]
• In patients with impaired renal function, the half-life is dramatically prolonged. It increases to approximately 49 hours in patients with moderate renal impairment and to 70 hours in those with severe renal impairment.[25]

This pharmacokinetic profile is the origin of the agent's heightened NSF risk. The pharmacodynamic advantage of a long imaging window is a direct result of its pharmacokinetic properties (albumin binding and a long half-life). In patients with renal impairment, this same profile becomes a major liability. The extension of the half-life from ~16 hours to 70 hours means the body is exposed to a less-stable linear chelate for a vastly extended period. This dramatically increases the time available for the gadolinium complex to dissociate (transmetallation) and release toxic free Gd³⁺ ions, the process believed to precipitate NSF.[22] The very property that makes the drug effective is thus the same property that makes it exceptionally dangerous in the at-risk population.

Table 2: Summary of Pharmacokinetic Parameters in Patients with Normal and Impaired Renal Function

Parameter	Normal Renal Function	Moderate Renal Impairment (CrCl 30-50 mL/min)	Severe Renal Impairment (CrCl <30 mL/min)	Source(s)
Elimination Half-Life (t1/2​)	16.3 ± 2.6 hours	49 hours	70 hours	25
Plasma Clearance	6.57 ± 0.97 mL/h/kg	Substantially decreased	Substantially decreased	8
Area Under the Curve (AUC)	Baseline	1.75-fold increase	2.25-fold increase	25

Clinical Efficacy and Diagnostic Utility in Magnetic Resonance Angiography

Approved Indications and Dosing Regimen

Gadofosveset trisodium was specifically indicated for use as a contrast agent in magnetic resonance angiography (MRA) to evaluate aortoiliac occlusive disease (AIOD) in adult patients with known or suspected peripheral vascular disease.[3]

The recommended clinical dose was 0.03 mmol/kg of body weight (equivalent to 0.12 mL/kg), which is notably lower than the typical 0.1–0.2 mmol/kg dose used for extracellular GBCAs in MRA applications.[5] The agent was administered as a single intravenous bolus injection over a period of up to 30 seconds, immediately followed by a 25-30 mL flush of normal saline.[7]

The imaging protocol for gadofosveset was unique, involving two essential stages to leverage its distinct pharmacokinetic properties:

1. Dynamic Imaging: This first-pass phase captures the initial arrival of the contrast bolus in the arterial system.
2. Steady-State Imaging: This phase is performed from 5 minutes up to an hour after injection, taking advantage of the agent's prolonged intravascular retention to acquire high-resolution, detailed images of the vasculature.[5]

Summary of Clinical Trial Efficacy

Clinical trials consistently demonstrated that gadofosveset was a highly effective diagnostic agent that provided significant advantages over existing non-invasive methods.

• Superiority to Unenhanced MRA: Multiple Phase 3 trials established that gadofosveset-enhanced MRA was significantly superior to unenhanced MRA. For the diagnosis of significant vascular stenosis, it produced statistically significant improvements in sensitivity, specificity, and overall accuracy.[6] Furthermore, it dramatically reduced the rate of uninterpretable examinations from 30% to less than 2% in one key study.[6]
• Comparability to X-ray Angiography: The performance of gadofosveset-enhanced MRA was shown to be comparable in overall accuracy to catheter-based X-ray angiography, which is the invasive "gold standard" for vascular imaging.[28]
• Efficacy in Specific Vascular Beds:
• Renal Artery Disease: In a multi-center study of 127 patients, gadofosveset-enhanced MRA significantly improved sensitivity (by up to 42%), specificity (by up to 29%), and accuracy (by up to 29%) for detecting renal artery stenosis compared to non-enhanced MRA.[6]
• Pedal Arterial Disease: A study involving 185 patients with known or suspected pedal arterial disease found that gadofosveset-enhanced MRA offered a marked improvement in specificity (21-35% increase) over unenhanced MRA. The study also concluded that the standard 0.03 mmol/kg dose was more effective and safer than a higher 0.05 mmol/kg dose.[29]

The unequivocal evidence from these trials shows that gadofosveset was a clinically superior diagnostic tool that addressed the limitations of unenhanced MRA and offered a less invasive, highly accurate alternative to catheter angiography. This clinical success makes its eventual market failure all the more notable, pointing directly to its safety profile and the prevailing market dynamics as the primary reasons for its discontinuation.

Expanded and Investigational Applications

The unique properties of gadofosveset led to its investigation for a range of other advanced imaging applications beyond its approved indication.

• Comprehensive Vascular Imaging: Its prolonged intravascular residence time made it particularly well-suited for comprehensive evaluations of both arterial and venous systems, as well as for dynamic and functional vascular studies, all with a single, low-dose injection.[5]
• Coronary MRA: Studies at 3T MRI explored its use for non-invasive coronary angiography. These investigations found that a double dose (0.06 mmol/kg) could significantly improve image quality and the visualization of more distal coronary artery segments compared to the standard dose.[31]
• Perfusion and Plaque Imaging: The agent's blood-pool characteristics gave it theoretical potential for quantitative perfusion imaging (e.g., measuring renal blood flow) and for the characterization of atherosclerotic plaques during the steady-state phase.[5]
• Hepatic Imaging: A clinical trial was designed to prospectively compare the diagnostic accuracy of gadofosveset with the standard agent gadobutrol for the detection of liver metastases.[32]

Comprehensive Safety Profile and Risk Mitigation

Black Box Warning: Nephrogenic Systemic Fibrosis (NSF)

Gadofosveset trisodium was subject to the FDA's most stringent safety warning, the Black Box Warning, concerning Nephrogenic Systemic Fibrosis (NSF).[9] This warning applied to all GBCAs but was particularly relevant for gadofosveset due to its chemical structure and pharmacokinetics.

• The Warning: The FDA mandated a boxed warning stating that GBCAs increase the risk of NSF in patients with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m²) and in patients with acute renal insufficiency of any severity, such as those with hepato-renal syndrome.[8]
• Pathophysiology and Symptoms: NSF is a rare but severe and potentially fatal systemic fibrosing disorder that affects the skin, muscles, and internal organs.[7] Clinical manifestations include skin thickening, hardening, and hyperpigmentation, often accompanied by burning and itching, severe joint contractures leading to immobility, deep bone pain, and muscle weakness.[27]
• Mechanism of Risk: The development of NSF is strongly linked to the in vivo dissociation of the gadolinium ion (Gd³⁺) from its chelate ligand, a process known as transmetallation.[22] As a linear GBCA, gadofosveset is inherently less kinetically stable and more prone to releasing toxic free Gd³⁺ than macrocyclic agents.[21] This inherent structural risk is profoundly exacerbated by its dramatically prolonged elimination half-life (up to 70 hours) in patients with severe renal impairment, creating an extended opportunity for the complex to break down and deposit gadolinium in tissues, triggering the fibrotic cascade.[25]
• Risk Mitigation: To mitigate this risk, regulatory agencies and professional bodies mandated that all patients be screened for renal dysfunction through a clinical history and/or laboratory testing prior to administration.[7] The use of gadofosveset was to be avoided in high-risk patients unless the diagnostic information was deemed essential and unobtainable through other means.

Gadolinium Retention and Deposition

Subsequent to the identification of NSF, a new safety concern emerged regarding the long-term retention of gadolinium in body tissues—including the brain (specifically the globus pallidus and dentate nucleus), bone, and skin—even in patients with normal renal function.[10]

• Association with Linear Agents: A growing body of evidence has demonstrated that linear GBCAs, the structural class to which gadofosveset belongs, are associated with significantly higher amounts of retained gadolinium compared to the more stable macrocyclic agents.[10]
• Clinical Significance and Regulatory Response: As of the late 2010s, no definitive adverse health effects had been directly linked to gadolinium deposition in the brain of patients with normal renal function. However, the finding raised substantial safety concerns. In 2017, this led the European Medicines Agency (EMA) to suspend or restrict the marketing of several linear GBCAs.[37] The U.S. FDA, while acknowledging the retention phenomenon, did not restrict the use of linear agents, citing a lack of evidence of harm, but did require updated warnings on all GBCA labels.[36] For gadofosveset, its classification as a linear agent placed it squarely in the high-risk category for retention, which undoubtedly influenced its clinical use and market perception during its final years.

Other Significant Warnings and Precautions

• Hypersensitivity Reactions: Gadofosveset carries a risk of serious, life-threatening anaphylactic or anaphylactoid reactions. In clinical trials, such reactions occurred in two of 1,676 subjects. Close monitoring and the availability of emergency resuscitation equipment were advised.[7]
• Acute Renal Failure: In patients with pre-existing renal insufficiency, the administration of GBCAs, including gadofosveset, could precipitate acute renal failure or a worsening of renal function.[7]
• QTc Prolongation: Clinical trials documented a small, transient increase in the average QTc interval (2.8 msec) at 45 minutes post-injection. While this was not associated with arrhythmias in the trials, caution was recommended for patients with underlying conditions or on concomitant medications that put them at high risk for arrhythmias.[7]

Documented Adverse Reactions

The most common adverse reactions observed in clinical trials were generally mild to moderate in intensity. A relative frequency analysis indicated that the most commonly affected systems were general disorders and administration site conditions (17.31%), skin and subcutaneous tissue disorders (15.38%), and cardiac disorders (13.46%).[16] Many common medications, such as acetaminophen and various NSAIDs, were noted to potentially decrease the excretion rate of gadofosveset, which could lead to higher serum levels and increased risk.[3]

Table 3: Adverse Reactions with Incidence ≥1% in Clinical Trials (0.03 mmol/kg Dose)

Adverse Reaction	Incidence Rate	Source(s)
Pruritus (Itching)	4.4%	5
Nausea	3.8%	5
Vasodilation (Flushing)	2.9%	5
Paresthesia (Tingling/Numbness)	2.6%	5
Headache	≥1%	6
Dysgeusia (Altered Taste)	≥1%	35
Burning Sensation	≥1%	35

Regulatory Trajectory and Market Lifecycle

Development and Global Regulatory Approvals

Gadofosveset trisodium was developed by EPIX Pharmaceuticals, Inc., under the investigational code name MS-325.[5] Its regulatory journey was marked by early success in Europe followed by a prolonged and challenging path to approval in the United States.

• European Approval: The agent first received marketing authorization in the European Union on October 2, 2005, under the brand name Vasovist.[5]
• U.S. Approval: The U.S. FDA approval process was arduous, involving multiple review cycles and a formal appeal by the manufacturer.[13] Ultimately, on December 22, 2008, the FDA approved Vasovist, making it the first contrast agent specifically approved for MRA in the United States.[13]

Commercialization and Brand History

Following its regulatory approvals, the commercial rights and branding of the agent evolved.

• Initial Marketing: Global marketing rights were initially held by Bayer Schering Pharma.[28]
• Acquisition and Rebranding: In April 2009, Lantheus Medical Imaging acquired the U.S., Canadian, and Australian rights from EPIX Pharmaceuticals.[44] Lantheus subsequently rebranded the product in the U.S. market from Vasovist to Ablavar.[5]

Market Withdrawal and Discontinuation

Despite its innovative design and proven efficacy, gadofosveset had an exceptionally short and unsuccessful market life.

• European Withdrawal: In a telling sign of the challenging market environment, the European marketing authorization was voluntarily withdrawn by the marketing authorization holder on October 18, 2011, for "commercial reasons." The agent was never actually marketed in any European country, despite having been approved there for six years.[46]
• U.S. Discontinuation: The manufacturer, Lantheus Medical, officially discontinued production of Ablavar in 2017, citing "poor sales" as the reason.[12] The product's status is listed as "Discontinued" in FDA records and other drug databases.[13]

The commercial failure of gadofosveset was not a sudden event but rather the predictable outcome of its regulatory and market context. The fact that it was never launched in Europe despite a 2005 approval suggests its commercial viability was questioned even before the full scope of the NSF crisis was understood. Its U.S. launch in late 2008 was profoundly ill-timed, coinciding with peak concern over NSF and the beginning of a market-wide "flight to safety" towards macrocyclic agents. The official reason of "poor sales" is the direct result of a multi-year trend where the drug's risk profile, dictated by its chemical class, made it an increasingly undesirable choice for clinicians in a market that was actively shifting away from its entire class of chemistry.

Table 4: Key Milestones in the Regulatory and Commercial Timeline of Gadofosveset Trisodium

Date	Event Description	Key Company/Agency	Source(s)
Oct 2, 2005	First marketing authorization granted in the European Union for Vasovist.	EMA / EPIX	5
Nov 23, 2005	FDA issues first "Approvable Letter" for Vasovist, indicating issues to be resolved.	FDA / EPIX	13
Dec 22, 2008	Vasovist receives final marketing approval in the United States.	FDA / EPIX	13
Apr 7, 2009	Lantheus Medical Imaging acquires U.S., Canadian, and Australian rights from EPIX.	Lantheus / EPIX	44
Oct 8, 2009	Lantheus announces the U.S. brand name will be changed from Vasovist to Ablavar.	Lantheus	45
Oct 18, 2011	European marketing authorization is voluntarily withdrawn for commercial reasons.	EMA / TMC Pharma	46
2017	Lantheus Medical Imaging discontinues production of Ablavar.	Lantheus	12

Concluding Analysis and Perspectives

The history of gadofosveset trisodium presents a compelling paradox of pharmacological innovation and inescapable risk. Its novel blood-pool mechanism, enabled by reversible albumin binding, offered undeniable clinical advantages, creating a new potential for high-resolution, steady-state MRA and filling a specific diagnostic niche.[5] However, this innovative functionality was engineered upon a linear Gd-DTPA chelate backbone, a structural class of molecule that was becoming progressively obsolete due to severe and mounting safety concerns.[22]

Gadofosveset was a victim of exceptionally poor timing and a powerful class effect. Its U.S. launch in late 2008 occurred just as the NSF crisis was cresting, and its entire market life was defined by the subsequent rise of concerns over long-term gadolinium deposition. Consequently, it was judged not merely on its own clinical data but by the well-documented risks and perceived failures of its entire structural class. The market could not sustain a new, premium-priced agent from a high-risk chemical family when safer alternatives—the macrocyclic GBCAs—were readily available.

The official reason for its discontinuation, "poor sales," was a direct reflection of a rational clinical market shifting its preference decisively towards agents with superior long-term safety profiles. For clinicians and healthcare systems, the potential risk of inducing a fatal condition like NSF, or the unknown long-term consequences of gadolinium deposition in the brain, far outweighed the specialized diagnostic benefits offered by a blood-pool agent.

Ultimately, gadofosveset trisodium serves as a critical case study in pharmaceutical development and risk management. It demonstrates with stark clarity that clinical efficacy alone is insufficient for market success. A product's safety profile, its structural class, the prevailing regulatory climate, and the availability of safer alternatives are all powerful, and in this case decisive, determinants of its fate. Gadofosveset represents a technological dead-end—a lesson in how the inherent risks of a drug's core chemistry can render even a clever and effective molecular design untenable in modern medicine.

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