A Comprehensive Monograph on Gadobutrol (Gadavist®/Gadovist®): Chemical Properties, Pharmacology, Clinical Efficacy, and Safety Profile

Executive Summary

Gadobutrol is a second-generation, gadolinium-based contrast agent (GBCA) that holds a prominent position in the field of diagnostic magnetic resonance imaging (MRI). Structurally, it is classified as a non-ionic, macrocyclic chelate, a design that confers exceptional stability and is central to its distinguished safety profile. The gadolinium ion (Gd3+), the paramagnetic component responsible for contrast enhancement, is securely encapsulated within a rigid macrocyclic ligand framework, dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrol). This structure significantly minimizes the in vivo release of toxic free gadolinium, placing Gadobutrol in the lowest-risk category for the rare but severe condition known as nephrogenic systemic fibrosis (NSF).

A key distinguishing feature of Gadobutrol is its unique formulation at a concentration of 1.0 mmol/mL, which is double that of most other GBCAs. This high concentration, combined with its intrinsically high T1 relaxivity, allows for the administration of a smaller injection volume to achieve robust contrast enhancement. This property is particularly advantageous in advanced imaging applications such as dynamic contrast-enhanced MRA and perfusion MRI, where a tight, concentrated bolus of the contrast agent is critical for optimal diagnostic image quality.

The pharmacological profile of Gadobutrol is characterized by its simplicity and predictability. Following intravenous administration, it distributes rapidly within the extracellular fluid space, exhibits negligible protein binding, is not metabolized, and is eliminated unchanged almost exclusively via renal glomerular filtration. This straightforward pharmacokinetic profile is consistent across a wide range of patient populations, including pediatric patients from term neonates to adolescents, allowing for a standardized, weight-based dosing regimen (0.1 mmol/kg) without the need for age-specific adjustments.

Gadobutrol has a broad spectrum of regulatory approvals worldwide. In the United States, under the brand name Gadavist®, it is indicated for MRI of the central nervous system (CNS), breast, and for magnetic resonance angiography (MRA), as well as being the first and only agent approved for cardiac MRI to assess myocardial perfusion and late gadolinium enhancement. In the European Union and other regions, as Gadovist®, it holds similarly broad approvals for whole-body imaging. Its efficacy has been consistently demonstrated in numerous clinical trials, where it provides superior diagnostic performance compared to unenhanced imaging and is non-inferior to other macrocyclic agents.

The safety profile of Gadobutrol is well-established, with the most common adverse effects being mild and transient, such as headache and nausea. While all GBCAs carry a class-wide boxed warning for NSF and concerns exist regarding long-term gadolinium retention in tissues, the evidence overwhelmingly supports the superior safety of macrocyclic agents like Gadobutrol over older, linear agents. It has become a benchmark agent against which new, higher-relaxivity GBCAs are compared, solidifying its role as a cornerstone of modern contrast-enhanced MRI.

Identification and Physicochemical Properties

This section establishes the fundamental identity and chemical characteristics of Gadobutrol, which are foundational to understanding its behavior in vivo and its performance as a magnetic resonance contrast agent.

Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, regulatory documents, and clinical practice, Gadobutrol is designated by a comprehensive set of names, brand names, and database identifiers.

• Generic Name: Gadobutrol [1]
• IUPAC Name: 2−−1,4,7,10−tetrazacyclododec−1−yl]acetate;gadolinium(3+) [3]
• Synonyms and Codes: Common synonyms and development codes include Gd-DO3A-butrol, Gadograf, Protovist, BAY86-4875, and ZK-135079.[1]
• Brand Names: Gadobutrol is marketed globally under several brand names, most notably Gadavist® by Bayer HealthCare Pharmaceuticals in the United States, Gadovist® by Bayer AG in Europe and other regions, and PixxoScan® by GE HealthCare. In India, it is also available as Viv-butrol from Vivere Imaging.[2]
• Database Identifiers: Key identifiers for cross-referencing in major chemical and drug databases are cataloged in Table 1.[1]

Chemical Structure and Formulation

The molecular structure and formulation of Gadobutrol are the direct determinants of its stability, efficacy, and unique clinical characteristics.

• Molecular Composition: The molecular formula for Gadobutrol is C18​H31​GdN4​O9​.[8] Its corresponding molecular weight is approximately 604.7 g/mol (or 604.72 mg/mmol).[3] A monohydrate form, with the formula C18​H31​GdN4​O9​⋅H2​O, has a molecular weight of 622.73 g/mol.[12]
• Structural Class: Gadobutrol is a neutral (non-ionic), paramagnetic complex. It consists of a central, trivalent gadolinium ion (Gd3+) tightly chelated by a macrocyclic ligand known as dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrol).[3] The ligand contains two chiral carbons, resulting in the final product being a racemic mixture of the (13R, 14S) and (13S, 14R) stereoisomers.[5] The gadolinium ion has a coordination number of 9 within the complex.[5]
• Formulation: A defining feature of Gadobutrol is its formulation as a sterile, clear, colorless-to-pale yellow aqueous solution at a concentration of 1.0 mmol/mL (equivalent to 604.72 mg/mL).[2] This concentration is double that of most other commercially available GBCAs, which are typically formulated at 0.5 mmol/mL. This higher concentration allows for a smaller volume of administration for a given molar dose.[2]

Physicochemical Characteristics

The physical and chemical properties of the Gadobutrol solution directly influence its handling, administration, and behavior within the biological system.

• Solubility and Partition Coefficient: Gadobutrol is a highly hydrophilic (water-soluble) compound. This is quantified by its very low n-butanol/water partition coefficient of approximately 0.006 and a log P (n-octanol/water) of -5.4, indicating extremely poor lipid solubility. This property confines the agent primarily to the extracellular fluid space after injection.[5]
• Viscosity, Osmolality, and pH: The 1.0 mmol/mL solution exhibits specific physical properties at body temperature (37 °C). The viscosity is 4.96 mPa·s, and the osmolality is high at 1603 mOsm/kg water (osmolarity of 1117 mOsm/L solution). The pH of the solution ranges from 6.6 to 8.0.[3] These factors can influence the sensation upon injection and underscore the need for secure venous access.
• Molecular Stability: The macrocyclic ligand forms an exceptionally stable complex with the Gd3+ ion. This is reflected in its high thermodynamic stability constant, with a reported log K value of 21-22.[19] This high stability is the fundamental chemical reason for its excellent safety profile, as it strongly resists dechelation and the release of toxic free gadolinium ions in the body.

The molecular architecture of Gadobutrol is a prime example of purposeful chemical engineering aimed at optimizing both safety and efficacy. The structure can be understood as having two key functional components. First, the macrocyclic tetraazacyclododecane (cyclen) core acts as a rigid, pre-organized "cage" for the gadolinium ion.[5] This cage provides exceptionally high kinetic and thermodynamic stability, physically preventing the toxic

Gd3+ ion from escaping into the biological system. This structural feature is the primary reason for its classification as a low-risk agent for both NSF and long-term gadolinium retention when compared to the more flexible and less stable linear GBCAs.[3] Second, the hydrophilic "butrol" side chain, a trihydroxybutyl group rich in hydroxyl (-OH) moieties, was deliberately incorporated to ensure high water solubility.[5] This high hydrophilicity dictates the agent's pharmacokinetic behavior, ensuring it remains confined to the extracellular space, exhibits negligible binding to plasma proteins, and is well-tolerated biologically before being rapidly excreted by the kidneys.[5] Thus, the molecule represents an elegant dual-solution design: the macrocycle solves the safety problem of gadolinium toxicity, while the butrol side chain solves the pharmacokinetic problem, ensuring predictable and favorable distribution and elimination.

Furthermore, the unique 1.0 mmol/mL formulation is not merely a manufacturing choice but a feature that works in synergy with the molecule's intrinsic properties to enhance its clinical utility. Gadobutrol possesses a high T1 relaxivity, meaning it is very efficient at enhancing the MRI signal on a per-molecule basis.[3] This high efficiency means that a standard diagnostic dose can be delivered in a smaller volume of fluid. The 1.0 mmol/mL concentration leverages this efficiency, allowing for the standard 0.1 mmol/kg dose to be administered in a volume half that of conventional 0.5M GBCAs.[2] This smaller, more concentrated injection can be delivered as a more compact and rapid bolus. A tight bolus shape is a critical requirement for high-quality imaging in dynamic, first-pass techniques such as contrast-enhanced MRA and myocardial perfusion MRI, where capturing the initial arrival and transit of the contrast agent is essential for accurate diagnosis.[22] Therefore, the high concentration and high relaxivity are symbiotic features that create a distinct clinical advantage in advanced imaging applications.

Table 1: Key Identifiers and Physicochemical Properties of Gadobutrol

Parameter	Value	Source(s)
Generic Name	Gadobutrol	1
IUPAC Name	2−−1,4,7,10−tetrazacyclododec−1−yl]acetate;gadolinium(3+)	3
Brand Names	Gadavist®, Gadovist®, PixxoScan®, Viv-butrol	2
DrugBank ID	DB06703	1
CAS Number	770691-21-9	3
UNII	1BJ477IO2L	3
Molecular Formula	C18​H31​GdN4​O9​	8
Molecular Weight	604.72 g/mol	3
Structural Class	Macrocyclic, Non-ionic	3
Solubility	Highly water-soluble (hydrophilic)	5
pH (1.0M Solution)	6.6 - 8.0	3
Viscosity (at 37 °C)	4.96 mPa·s	3
Osmolality (at 37 °C)	1603 mOsm/kg water	3
T1 Relaxivity (r1) in plasma	5.2 - 5.6 L⋅mmol−1⋅s−1 (at 1.5 T, 37-40 °C)	3
T2 Relaxivity (r2) in plasma	6.1 L⋅mmol−1⋅s−1 (at 1.5 T, 37 °C)	3

Clinical Pharmacology

This section details the dynamic and kinetic interactions of Gadobutrol within the human body, explaining the fundamental principles of its contrast-enhancing mechanism and its predictable journey from administration to elimination.

Mechanism of Action

Gadobutrol functions as a paramagnetic contrast agent, a substance that alters the magnetic properties of nearby water molecules to enhance the visibility of tissues in MRI.[2] The core of this function lies within the chelated gadolinium (

Gd3+) ion. The Gd3+ ion is a lanthanide metal characterized by seven unpaired electrons in its outer shell, which gives it a very large magnetic moment.[5]

When a patient is placed within the strong, static magnetic field of an MRI scanner, the large magnetic moment of the Gadobutrol molecule creates a fluctuating local magnetic field. This field interacts with the protons of adjacent water molecules in tissues where the agent has accumulated. This interaction provides an efficient energy-exchange pathway, dramatically accelerating the rate at which these water protons return to their equilibrium state after being excited by radiofrequency pulses. This acceleration manifests as a shortening of two key tissue-specific relaxation times: the spin-lattice (or longitudinal) relaxation time, T1, and the spin-spin (or transverse) relaxation time, T2.[1]

In the vast majority of clinical applications, contrast-enhanced MRI relies on T1-weighted imaging sequences. In these sequences, tissues with shorter T1 relaxation times produce a stronger signal and appear brighter on the final image. By profoundly shortening the T1 of tissues where it is present, Gadobutrol causes a significant increase in signal intensity. This effect enhances the contrast between pathological tissues (which may accumulate the agent due to abnormal vascularity or a disrupted blood-brain barrier) and surrounding normal tissues, thereby improving the detection, visualization, and characterization of lesions.[2]

Conversely, at high local concentrations, such as during the initial arterial passage of a bolus injection, the T2-shortening effect can become dominant. In certain imaging sequences, like T2*-weighted gradient echo, this can lead to a decrease in signal intensity due to the creation of local magnetic field inhomogeneities.[19]

Pharmacodynamics

The pharmacodynamic effect of a GBCA is quantitatively measured by its relaxivity, which is the change in the relaxation rate (1/T1 or 1/T2) of water protons per millimolar concentration of the agent. A higher relaxivity indicates greater efficiency in producing contrast enhancement.

Gadobutrol is characterized by its high relaxivity, which contributes to its strong performance as a contrast agent. At a magnetic field strength of 1.5 Tesla (T), a temperature of 37 °C, and physiological pH, the T1 relaxivity (r1) of Gadobutrol in human plasma is approximately 5.2 to 5.6 L⋅mmol−1⋅s−1.[3] Its T2 relaxivity (r2) under similar conditions is approximately 6.1

L⋅mmol−1⋅s−1.[3] These relaxivity values exhibit only a slight dependence on the strength of the magnetic field, ensuring consistent and predictable enhancement across different MRI scanner platforms (e.g., 1.5 T and 3.0 T).[3]

The high r1 relaxivity of Gadobutrol is a key performance metric. It is notably higher than that of several other macrocyclic GBCAs, such as gadoterate meglumine (Dotarem®) and gadoteridol (ProHance®).[17] This means that, on a mole-for-mole basis, Gadobutrol produces a more pronounced T1-shortening effect, which can translate to greater contrast enhancement or allow for equivalent enhancement at a reduced gadolinium dose compared to agents with lower relaxivity.

Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of Gadobutrol is characterized by its simplicity, predictability, and rapid elimination in patients with normal renal function. It behaves as a classic extracellular fluid marker, similar to biologically inert compounds like inulin.[19]

• Administration: Gadobutrol is approved for intravenous administration only, typically as a rapid bolus injection.[2]
• Distribution: Following intravenous injection, Gadobutrol is rapidly and widely distributed throughout the body's extracellular space. This is a direct consequence of its high hydrophilicity and negligible protein binding.[1] Plasma concentrations peak within minutes; for a standard 0.1 mmol/kg dose, an average plasma level of 0.59 mmol/L is measured just 2 minutes after injection, which declines to 0.3 mmol/L by 60 minutes post-injection.[1] In its intended use, it does not cross the intact blood-brain barrier.[19] However, following administration, trace amounts of gadolinium are retained for months or years in various organs, including the brain, bone, and skin.[1]
• Protein Binding: Gadobutrol displays negligible binding to plasma proteins.[1] This lack of binding prevents it from being retained in the vasculature or interacting with biological macromolecules, contributing to its rapid distribution and clearance.
• Metabolism: Gadobutrol is biologically inert and is not metabolized in the body.[1]
• Excretion: The agent is eliminated from the body in its unchanged form almost exclusively by the kidneys via glomerular filtration.[1] The elimination is rapid and efficient in individuals with normal renal function. More than 50% of the administered dose is excreted in the urine within two hours, and over 90% is excreted within 12 hours.[1] Extra-renal (e.g., fecal) elimination is negligible.
• Half-Life and Clearance: In adult subjects with normal renal function, the terminal elimination half-life of Gadobutrol is consistently reported to be in the range of 1.5 to 2.0 hours, with a mean of 1.81 hours.[1] Its renal clearance rate of 1.1 to 1.7 mL/min/kg is comparable to that of inulin, providing strong evidence that its elimination is governed by glomerular filtration.[1]

The pharmacokinetic profile of Gadobutrol is remarkably consistent and predictable, a characteristic that serves as a significant clinical asset. Extensive studies have shown that its behavior in the body is similar across diverse patient populations when dosing is adjusted for body weight. For example, pharmacokinetic analyses in pediatric patients, from term neonates to adolescents, reveal that key parameters like clearance and volume of distribution, when normalized for body weight, are comparable to those in adults.[17] This consistency is the basis for the standardized 0.1 mmol/kg dosing recommendation across all approved age groups, simplifying clinical protocols and reducing the potential for dosing errors.[27] Likewise, while clearance is slightly reduced in geriatric patients due to age-related physiological changes in renal function, the effect is not considered clinically relevant enough to warrant a dose adjustment.[17] The agent's lack of metabolism and negligible protein binding further contribute to this predictability.[1] This means that its disposition in the body is almost entirely governed by a single, well-understood physiological process: renal glomerular filtration. This simplicity minimizes concerns about drug-drug interactions via metabolic pathways and provides clinicians with a high degree of confidence in its performance from patient to patient, provided renal function is not severely compromised.

Table 2: Pharmacokinetic Parameters of Gadobutrol in Key Populations

Population	Terminal Half-Life (t1/2​) (hours)	Systemic Exposure (AUC) (μmol⋅h/L or mmol⋅h/L)	Renal Clearance (CL) (mL/min/kg or L/h/kg)	Source(s)
Adults (Normal Renal Function)	1.80 (Range: 1.20 - 6.55)	1072 (Median); 1.1 (Mean)	1.1 - 1.7 mL/min/kg	1
Pediatrics (0 to <2 years)	2.91 (Range: 1.60 - 12.4)	781 (Median)	0.128 L/h/kg (Median)	1
Pediatrics (2 to 6 years)	1.91 (Range: 1.04 - 2.70)	846 (Median)	0.119 L/h/kg (Median)	1
Pediatrics (7 to 11 years)	1.66 (Range: 0.91 - 2.71)	1025 (Median)	Not specified	1
Pediatrics (12 to <18 years)	1.68 (Range: 1.31 - 2.48)	1237 (Median)	Not specified	1
Geriatrics (>65 years)	Increased by ~33-58% vs. younger adults	Slightly higher vs. younger adults	Slightly lower vs. younger adults	17
Mild/Moderate Renal Impairment	5.8 (Mean)	4.0 mmol⋅h/L (Mean)	0.49 mL/min/kg (Mean)	19
Severe Renal Impairment (not on dialysis)	17.6 (Mean)	11.5 mmol⋅h/L (Mean)	0.16 mL/min/kg (Mean)	19

Clinical Indications, Efficacy, and Administration

This section translates the fundamental pharmacology of Gadobutrol into its practical application in the clinical setting, detailing its approved diagnostic uses, evidence of its efficacy, and established protocols for administration.

Approved Indications by Regulatory Agency

Gadobutrol has secured a broad range of indications from major regulatory bodies worldwide, reflecting its versatility and robust evidence base. There are, however, some differences in the scope and wording of approvals between agencies like the U.S. FDA and the EMA.

U.S. Food and Drug Administration (FDA)

In the United States, Gadobutrol is marketed as Gadavist® and is indicated for intravenous use with MRI for several specific applications:

• Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS): Approved to detect and visualize areas with a disrupted blood-brain barrier (BBB) and/or abnormal vascularity of the CNS. This indication applies to adult and pediatric patients, including term neonates.[1]
• MRI of the Breast: Approved to assess the presence and extent of malignant breast disease in adult patients.[1]
• Magnetic Resonance Angiography (MRA): Approved to evaluate known or suspected supra-aortic or renal artery disease. This indication also applies to adult and pediatric patients, including term neonates.[1]
• Cardiac MRI (CMRI): Uniquely, Gadavist® is the first and only GBCA approved by the FDA for cardiac MRI. This indication is for assessing myocardial perfusion under both stress and rest conditions, as well as for evaluating late gadolinium enhancement (LGE) in adult patients with known or suspected coronary artery disease (CAD).[1]

European Medicines Agency (EMA) and Other Regions

In the European Union, where it is marketed as Gadovist®, and in other regions like Australia (TGA) and Switzerland (Swissmedic), Gadobutrol often has broader, more encompassing approvals that cover all ages, including term neonates:

• Cranial and Spinal MRI: For contrast enhancement of the brain and spine.[18]
• Liver and Kidney MRI: For contrast-enhanced MRI of the liver or kidneys in patients with suspected or known focal lesions, to help classify these lesions as benign or malignant.[18]
• Contrast-Enhanced MRA (CE-MRA): For contrast enhancement in magnetic resonance angiography.[18]
• Whole Body Imaging: A general indication for use in MRI of pathologies throughout the whole body to facilitate the visualization of abnormal structures or lesions and to help differentiate between healthy and pathological tissue.[18]

The chronological expansion of these indications, particularly by the FDA, reflects a growing body of evidence and increasing regulatory confidence in the agent's safety and efficacy. The journey began in 2011 with the foundational CNS approval.[38] A significant milestone was the 2015 approval for use in infants under two years of age, which required a high degree of confidence in its safety within this vulnerable population.[38] The subsequent 2016 approval for MRA capitalized on the agent's unique formulation advantages for dynamic imaging.[38] The pinnacle of this regulatory trajectory was the 2019 approval as the first and only agent for the technically demanding application of cardiac MRI.[34] This progression from a general indication to highly specialized uses illustrates a clear path of clinical and regulatory validation, demonstrating that the agent's inherent properties were successfully proven to meet increasingly stringent diagnostic needs.

Table 3: Summary of Approved Indications by Regulatory Agency (FDA vs. EMA)

Indication Area	U.S. FDA (Gadavist®)	European Medicines Agency (EMA) (Gadovist®)
Central Nervous System	Yes (Adults & Pediatrics, incl. term neonates) 32	Yes (Adults & Pediatrics, incl. term neonates) 18
Breast	Yes (Adults only) 32	Covered under "Whole Body" indication 18
Magnetic Resonance Angiography	Yes (Supra-aortic & renal arteries; Adults & Pediatrics, incl. term neonates) 32	Yes (General CE-MRA; Adults & Pediatrics, incl. term neonates) 18
Liver/Kidney	Not a specific indication, but used off-label	Yes (To classify focal lesions; Adults & Pediatrics, incl. term neonates) 18
Cardiac MRI	Yes (Perfusion & LGE in adults with suspected CAD) 32	Covered under "Whole Body" indication 18
Whole Body Pathologies	No single overarching indication	Yes (General indication for whole-body pathologies; Adults & Pediatrics, incl. term neonates) 18

Clinical Efficacy and Performance

The clinical utility of Gadobutrol is supported by extensive trial data demonstrating its ability to improve diagnostic accuracy and image quality.

• CNS Imaging Efficacy: Pivotal clinical trials have consistently shown that the combination of unenhanced MRI plus gadobutrol-enhanced MRI is diagnostically superior to unenhanced MRI alone. This superiority is evident across key visualization metrics, including the degree of lesion contrast enhancement, the clarity of lesion border delineation, and the visualization of internal lesion morphology.[2]
• Comparative Efficacy:
• In head-to-head trials for CNS imaging, Gadobutrol was proven to be non-inferior to another macrocyclic agent, gadoteridol (ProHance®), for most visualization parameters and for the number of lesions detected. Notably, in some analyses, blinded readers consistently favored the gadobutrol-enhanced images, and Gadobutrol demonstrated a higher sensitivity for determining whether a lesion was malignant.[2]
• When compared to gadoterate meglumine (Dotarem®) for visualizing primary brain tumors, Gadobutrol was found to be non-inferior, providing similar qualitative image quality despite producing quantitatively higher lesion enhancement, a direct result of its higher relaxivity.[39]
• The LEADER-75 trial provided compelling evidence of Gadobutrol's high efficiency, showing that a 25% reduced dose of Gadobutrol (0.075 mmol/kg) provided non-inferior diagnostic performance for brain MRI compared to a standard 0.1 mmol/kg dose of gadoterate.[23] This finding directly links its superior physicochemical property (higher relaxivity) to a tangible clinical benefit (potential for dose reduction).
• Overall Image Quality: In large-scale, real-world observational studies like the GARDIAN study (which included nearly 24,000 patients), treating physicians rated the contrast quality of gadobutrol-enhanced images as "good" or "excellent" in 97-98% of all cases. This high level of performance was consistent across diverse patient groups, including pediatric patients, and across all investigated indications.[21]

Dosage and Administration

Proper administration is crucial for achieving optimal efficacy and ensuring patient safety.

• Standard Dosage: For the vast majority of approved indications in both adult and pediatric populations (including term neonates), the recommended dose of Gadobutrol is 0.1 mL/kg of body weight. This corresponds to a molar dose of 0.1 mmol/kg.[2]
• Administration Technique: Gadobutrol must be administered as an intravenous bolus injection. For CNS imaging, a typical injection rate is approximately 2 mL/second, while for MRA, a slightly faster rate of around 1.5 mL/second may be used.[24] It is standard practice to follow the contrast injection with a flush of sterile normal saline (e.g., 20-30 mL) to ensure the full dose is delivered from the IV line into the circulation.[24]
• Preparation and Handling: As with all parenteral drugs, sterile technique must be strictly observed during preparation and administration. The solution should be drawn into the syringe immediately before use. Before administration, the solution must be visually inspected for any particulate matter, discoloration, or damage to the container; if any are present, the solution must be discarded. Gadobutrol should not be mixed with other medications in the same syringe or intravenous line.[2]

Comprehensive Safety Profile and Risk Management

The safety profile of Gadobutrol is well-characterized and is a cornerstone of its clinical value. While generally very well tolerated, its use is associated with known risks, including rare but serious adverse events that necessitate careful patient screening and risk management strategies.

Adverse Reactions

Adverse reactions to Gadobutrol are infrequent and are typically mild to moderate in severity.

• Common Adverse Reactions: Based on extensive clinical trial data, the most frequently reported adverse reactions (occurring in ≥0.5% of patients) are generally mild and transient. These include headache (with an incidence of approximately 1.5-1.7%), nausea (1.2%), and dizziness (0.5%).[2]
• Uncommon and Rare Reactions: Less common side effects include dysgeusia (an abnormal or unpleasant taste in the mouth), a sensation of heat, various injection site reactions (such as pain, warmth, or a cold feeling), vomiting, rash, pruritus (itching), and dyspnea (difficulty breathing).[2]
• Serious Adverse Reactions: Although rare, severe and potentially life-threatening reactions can occur. The most significant of these are acute hypersensitivity or anaphylactoid reactions, which can manifest with cardiovascular symptoms (e.g., hypotension, circulatory collapse, cardiac arrest), respiratory distress (e.g., bronchospasm, laryngeal edema, respiratory arrest), and/or severe cutaneous reactions. Such events require immediate medical intervention.[10] Acute Respiratory Distress Syndrome (ARDS) has also been reported post-administration.[15]

Table 4: Summary of Adverse Reactions by System Organ Class and Frequency

System Organ Class	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Not Known (Postmarketing)
Immune system disorders		Hypersensitivity / anaphylactoid reactions (e.g., hypotension, urticaria, face edema)	Loss of consciousness, Convulsion	Anaphylactic shock, Circulatory collapse, Respiratory arrest, Cardiac arrest
Nervous system disorders	Headache	Dizziness, Dysgeusia, Paresthesia	Parosmia (altered sense of smell)
Cardiac disorders			Tachycardia, Palpitations
Respiratory, thoracic and mediastinal disorders		Dyspnea		Pulmonary edema
Gastrointestinal disorders	Nausea	Vomiting	Dry mouth
Skin and subcutaneous tissue disorders		Erythema, Pruritus, Rash		Nephrogenic Systemic Fibrosis (NSF)
General disorders and administration site conditions		Injection site reaction, Feeling hot	Malaise, Feeling cold
Source: Adapted from 15

Boxed Warnings and Major Risks

Regulatory agencies have mandated class-wide warnings for all GBCAs to highlight the most severe potential risks.

Nephrogenic Systemic Fibrosis (NSF)

NSF is a rare, debilitating, and sometimes fatal fibrosing disorder that affects the skin, muscles, and internal organs.

• The Risk and Warning: All GBCAs carry a prominent boxed warning regarding the risk of NSF.[10] This risk is now understood to be almost exclusively associated with the administration of GBCAs to patients with impaired drug elimination.
• High-Risk Populations: The patient groups at the highest risk for developing NSF are those with acute kidney injury (AKI) of any severity, or those with chronic, severe kidney disease, typically defined as having a glomerular filtration rate (GFR) less than 30 mL/min/1.73m².[2]
• Gadobutrol's Safety Profile in Relation to NSF: A critical distinction exists between the class warning and the agent-specific risk. Initially, NSF was a concern for all GBCAs. However, extensive research and post-marketing surveillance have revealed that the risk is heavily dependent on the chemical stability of the GBCA molecule. Less stable, linear GBCAs have been associated with the vast majority of NSF cases. In contrast, high-stability macrocyclic agents like Gadobutrol have a much lower propensity to release free gadolinium ions, the presumed trigger for NSF. Consequently, regulatory bodies and professional societies now classify Gadobutrol and other macrocyclic agents in the lowest-risk group for NSF.[3] Large-scale prospective and retrospective studies involving thousands of patients, including those with severe renal impairment, have reported a near-zero incidence of unconfounded NSF cases linked to Gadobutrol.[20] This has led to a nuanced clinical understanding where, despite the mandatory class warning, the actual evidence-based risk of NSF with Gadobutrol is considered negligible.

Gadolinium Retention

• The Phenomenon: It is now unequivocally established that following the administration of any GBCA, trace amounts of gadolinium can be retained for months or even years in various body tissues, including the brain, bones, skin, liver, and spleen.[1] This retention occurs even in patients with normal renal function.
• Agent-Dependent Retention: The magnitude of this retention is highly dependent on the agent's chemical structure. The less stable linear GBCAs are associated with significantly higher levels of retained gadolinium compared to the more stable macrocyclic agents like Gadobutrol.[24]
• Clinical Significance and Evolving Perspective: With the risk of NSF largely mitigated by the widespread shift to macrocyclic agents, gadolinium retention has emerged as the new central safety concern in the field. The clinical consequences of gadolinium deposition in the brain of patients with normal renal function have not been established, and no adverse health effects have been definitively linked to it.[15] However, the presence of a foreign heavy metal in the brain, coupled with the unknown long-term effects, has prompted a strong precautionary approach in clinical practice. This concern was the primary driver for the EMA's 2017 review that resulted in the suspension of several linear agents.[47] It has solidified the market dominance of lower-retention macrocyclic agents and is now fueling the development of a new generation of GBCAs designed to provide equivalent diagnostic information with an even lower gadolinium dose.

Risk Associated with Intrathecal Use

Gadobutrol carries a specific boxed warning against intrathecal administration (injection into the spinal canal). This route of administration is not approved and can cause severe, life-threatening adverse reactions, including death, coma, encephalopathy, and seizures.[15]

Contraindications, Warnings, and Precautions

• Contraindication: The only absolute contraindication to the use of Gadobutrol is a history of a severe hypersensitivity reaction to the drug or any of its components.[15]
• Hypersensitivity Reactions: Patients with a history of bronchial asthma, other allergic disorders, or a prior reaction to any contrast medium are at an increased risk for a hypersensitivity reaction. Therefore, a careful risk-benefit assessment is required for these patients, and medical facilities must be equipped with trained personnel and therapies to promptly manage severe reactions.[10]
• Acute Kidney Injury (AKI): In patients who already have chronic renal impairment, the administration of GBCAs has been associated with the development of AKI, which in some cases has required dialysis. The risk may increase with higher-than-recommended doses, reinforcing the importance of adhering to the approved dosage.[15]
• Extravasation: Care must be taken to ensure the patency of the intravenous catheter before and during injection. Extravasation, or the leakage of the contrast medium into the surrounding soft tissues, may result in local irritation, pain, and swelling.[1]

Use in Specific Populations

The use of Gadobutrol in certain patient populations requires special consideration due to physiological differences or a lack of extensive data. This section addresses the nuances of its use in pediatric patients, individuals with renal impairment, pregnant and lactating women, and the elderly.

Pediatric Population

Gadobutrol has been extensively studied and approved for use in children, demonstrating a favorable profile for both safety and efficacy.

• Regulatory Approval: Gadobutrol is approved for use in all pediatric age groups, including term neonates, for its primary indications of CNS MRI and MRA in both the U.S. and Europe.[1] This broad approval reflects a high level of regulatory confidence. The safety and effectiveness in preterm neonates, however, have not been established.[32]
• Efficacy and Safety: Large-scale post-marketing studies, such as the GARDIAN study which included over 1,000 children, have confirmed that Gadobutrol is very well tolerated in the pediatric population.[40] The safety profile is consistent with that observed in adults, with a low overall rate of adverse drug reactions (ADRs) of approximately 0.5%. The reactions that do occur are typically mild and transient, such as vomiting or nausea.[40] Importantly, no cases of NSF have been identified in pediatric patients aged 6 years and younger following administration of any GBCA, and no skin reactions suggestive of NSF were reported in the pediatric cohort of the GARDIAN study.[32]
• Pharmacokinetics and Dosing: Pharmacokinetic studies have been a cornerstone of pediatric approval. These studies demonstrated that when dosed according to body weight (0.1 mmol/kg), the systemic exposure (AUC) and clearance of Gadobutrol in children, including infants under 2 years of age, are similar to those in adults.[17] This pharmacokinetic similarity supports the use of the standard weight-based dose across all pediatric age groups without the need for age-specific adjustments.[30]
• Special Considerations for Neonates and Infants: While approved for use, caution is advised when administering Gadobutrol to neonates and infants up to 1 year of age. This is due to their physiologically immature renal function; a term neonate's GFR is significantly lower than an adult's, though it matures rapidly within the first year of life.[32] For this reason, regulatory bodies recommend that the agent should only be used in this age group after careful consideration, the standard dose should not be exceeded, and repeat injections should be avoided unless clinically essential.[37]

Patients with Renal Impairment

This patient population requires the most stringent risk management due to the central role of the kidneys in eliminating the drug and the associated risk of NSF.

• Pharmacokinetics: In patients with impaired renal function, the elimination of Gadobutrol is significantly prolonged. The terminal half-life, which is approximately 1.8 hours in individuals with normal renal function, increases to a mean of 5.8 hours in patients with mild-to-moderate impairment (CrCl 30-80 mL/min) and is further prolonged to a mean of 17.6 hours in patients with severe impairment (CrCl <30 mL/min).[19] This delay in clearance leads to a dramatic increase in total systemic exposure (AUC) to the agent, which is approximately tenfold higher in patients with severe renal impairment compared to those with normal function.[27]
• Risk Management and Recommendations:
• Screening: It is mandatory to screen all patients for renal dysfunction prior to administration by obtaining a patient history and/or performing laboratory tests to estimate GFR.[10]
• Avoidance in High-Risk Patients: For patients at the highest risk of NSF—those with acute kidney injury or chronic, severe kidney disease (GFR <30 mL/min/1.73m²)—Gadobutrol should be avoided unless the diagnostic information is deemed essential and cannot be obtained with unenhanced MRI or other imaging modalities.[10]
• Dosing: No specific dosage adjustment is recommended for patients with renal impairment. However, it is crucial that the standard recommended dose (0.1 mmol/kg) is not exceeded. Repeat administrations should be avoided unless necessary, and if a repeat scan is required, a sufficient period of time (e.g., at least 7 days) should be allowed for the drug to be eliminated from the body.[16]
• Hemodialysis: Gadobutrol is effectively removed from the body by hemodialysis. Approximately 98% of the administered dose is eliminated after three dialysis sessions.[19] For patients on hemodialysis, prompt initiation of a dialysis session following the MRI can be considered to enhance the clearance of the contrast agent, although its effectiveness in preventing NSF has not been definitively proven.[16]

Pregnancy and Lactation

The use of GBCAs during pregnancy and lactation involves balancing the diagnostic need of the mother against potential risks to the fetus or infant.

• Pregnancy:
• Risk Summary: It is known that GBCAs, including Gadobutrol, cross the placental barrier, leading to fetal exposure.[1] Animal studies have shown that this exposure results in long-term retention of gadolinium in the tissues of the offspring.[16] While animal studies did not show teratogenic effects, embryolethality was observed in multiple species at high, repeated intravenous doses (8 times or more than the standard human dose) administered during organogenesis.[2] Human data on the association between GBCA exposure and adverse fetal outcomes are limited and have not provided conclusive evidence of harm.[16]
• Recommendation: Due to the potential risks of gadolinium exposure to the fetus and the inconclusive nature of human data, the prevailing recommendation is that Gadobutrol should be used during pregnancy only if the diagnostic imaging is essential for the mother's health and cannot be postponed until after delivery.[1] Gadobutrol has an Australian TGA pregnancy category of B3 and is not assigned a category by the U.S. FDA under the new labeling rules.[51]
• Lactation:
• Excretion into Breast Milk: While specific data for Gadobutrol are not available, studies of other GBCAs consistently show that an extremely small fraction of the maternally administered dose—typically less than 0.04%—is excreted into the breast milk.[51]
• Infant Absorption: Furthermore, the gastrointestinal absorption of GBCAs by the nursing infant is known to be very poor (less than 5% of the ingested amount).[51] The combination of minimal excretion into milk and poor absorption from the infant's gut means the systemic dose received by the infant is negligible.
• Recommendation: Based on this evidence, major professional organizations, including the American College of Radiology (ACR) and the European Society of Urogenital Radiology (ESUR), have issued guidelines stating that it is safe for a mother to continue breastfeeding without interruption after receiving a standard dose of a GBCA.[52] The theoretical risk to the infant is considered extremely low.

Geriatric Population

• Pharmacokinetics: Elderly subjects (aged 65 years and older) have been shown to have a slightly higher systemic exposure (AUC) and a slightly lower clearance of Gadobutrol compared to younger adults. This is attributed to the natural, age-related decline in renal function.[17] The terminal half-life may be increased by approximately 33-58%.[19]
• Recommendation: Despite these pharmacokinetic changes, no specific dose adjustment is required for the geriatric population. However, because of the higher prevalence of reduced renal function in this group, caution should be exercised, and it is particularly important to screen elderly patients for renal impairment before administering the agent.[24]

Comparative Analysis and Regulatory Context

This final section situates Gadobutrol within the broader landscape of gadolinium-based contrast agents, analyzing its key differentiators and summarizing its regulatory journey, which has shaped its current role as a standard-of-care agent in diagnostic imaging.

Comparison with Other Gadolinium-Based Contrast Agents (GBCAs)

The properties and clinical profile of a GBCA are largely determined by its chemical structure. Gadobutrol's classification as a macrocyclic, non-ionic agent places it in a distinct category with specific advantages in stability, performance, and safety.

• Structural Classification and Stability:
• Macrocyclic vs. Linear: The most critical distinction among GBCAs is between macrocyclic and linear structures. Macrocyclic agents, such as Gadobutrol, gadoterate, and gadoteridol, feature a pre-organized, cage-like ligand that rigidly encapsulates the Gd3+ ion. This structure confers very high kinetic and thermodynamic stability.[19] In contrast, linear agents (e.g., gadopentetate, gadodiamide) have a more flexible, open-chain ligand that binds the gadolinium ion less tightly. This lower stability makes linear agents more prone to dechelation, the in vivo release of toxic free Gd3+. This fundamental difference in stability is the direct cause of the vastly superior safety profile of macrocyclic agents with respect to both NSF risk and long-term gadolinium retention.[3]
• Non-ionic vs. Ionic: Gadobutrol is a non-ionic (electrically neutral) molecule. Non-ionic agents generally have a lower osmolality than their ionic counterparts at equivalent concentrations, which can contribute to better patient tolerance and comfort during injection.
• Performance and Efficacy Comparison:
• vs. Gadoterate meglumine (Dotarem®): Both are widely used macrocyclic agents. However, Gadobutrol possesses a significantly higher T1 relaxivity, approximately 25-40% greater than that of gadoterate.[23] This superior molecular efficiency means it can produce a stronger contrast effect per mole of gadolinium. This has been demonstrated clinically in the LEADER-75 trial, which showed that a 25% reduced dose of Gadobutrol was non-inferior to a standard dose of gadoterate for brain MRI.[23] Additionally, Gadobutrol's unique 1.0M formulation, double the concentration of gadoterate's 0.5M, provides a more compact bolus beneficial for dynamic imaging techniques.[39]
• vs. Gadopiclenol (Elucirem™/Vueway™): Gadopiclenol represents the next generation of high-relaxivity macrocyclic agents. Its relaxivity is approximately double that of Gadobutrol.[44] This has led to a new paradigm of "dose-sparing," where clinical trials have shown that gadopiclenol administered at half the standard gadolinium dose (0.05 mmol/kg) provides non-inferior, and in some metrics superior, contrast enhancement compared to Gadobutrol at its full standard dose (0.1 mmol/kg).[56]
• Safety Comparison: The primary market shift in the last decade has been away from the high-risk linear agents, many of which were suspended by the EMA, toward the exclusive use of macrocyclic agents for most indications.[47] Within the macrocyclic class, Gadobutrol is firmly established in the lowest-risk category for NSF, a status it shares with other macrocyclics.

The comparative data reveals a clear evolutionary hierarchy in the GBCA market. The first-generation linear agents have been largely superseded on safety grounds. The second-generation macrocyclic agents, like gadoterate, became the new standard due to their superior stability. Gadobutrol can be seen as an enhanced "2.5 generation" agent, offering performance advantages (higher relaxivity, higher concentration) on top of the established macrocyclic safety platform. The emergence of next-generation agents like gadopiclenol, focused on dose-sparing through even higher relaxivity, marks the next step in this evolution. In this context, Gadobutrol stands as the high-performance incumbent and the established benchmark against which new innovations are designed, tested, and measured.

Table 5: Comparative Profile of Gadobutrol vs. Selected GBCAs

Feature	Gadopentetate Dimeglumine (Magnevist®)	Gadoterate Meglumine (Dotarem®)	Gadobutrol (Gadavist®/Gadovist®)	Gadopiclenol (Elucirem™/Vueway™)
Structural Class	Linear, Ionic	Macrocyclic, Ionic	Macrocyclic, Non-ionic	Macrocyclic, Non-ionic
Kinetic Stability	Low	High	High	High
T1 Relaxivity in Plasma (at 1.5 T)	~4.1 L⋅mmol−1⋅s−1 17	~3.6 L⋅mmol−1⋅s−1 17	~5.2 L⋅mmol−1⋅s−1 17	~11.6 mM−1⋅s−1 (in biologic medium) 44
Standard Dose	0.1 mmol/kg	0.1 mmol/kg	0.1 mmol/kg	0.05 mmol/kg
Formulation Concentration	0.5 mmol/mL	0.5 mmol/mL	1.0 mmol/mL 39	0.5 mmol/mL
NSF Risk Category	High (Group I) 59	Low (Group II) 44	Low (Group II) 44	Low (Group II) 44
Gadolinium Retention	High	Low	Low	Expected to be very low (due to half-dose)

Regulatory History and Perspective

The regulatory history of Gadobutrol charts its path from initial development to its current status as a globally recognized standard of care, successfully navigating major class-wide safety reviews.

• Early Approvals: Gadobutrol was first approved in Switzerland in 1998, followed by Germany in 2000. Its indications were progressively expanded in Europe over the following decade.[2]
• U.S. FDA Approval Timeline: The U.S. approvals for Gadavist® were granted incrementally, reflecting a stepwise validation of its use in different clinical settings (see Table 6).[2]
• European Medicines Agency (EMA) Landmark Review: The most significant regulatory event for the entire GBCA class was the EMA's 2017 Article 31 referral, initiated due to concerns about gadolinium deposition in the brain.[47] This comprehensive review concluded that while gadolinium retention was real, the benefit-risk profile for macrocyclic agents remained positive. The EMA's final decision was to suspend the marketing authorizations for several intravenous linear agents but to maintain the authorizations for all macrocyclic agents, including Gadobutrol (Gadovist®). The recommendation was to continue their use at the lowest effective dose only when unenhanced scans are unsuitable.[47] This decision effectively reshaped the European market and cemented the position of stable macrocyclic agents as the standard of care.

Table 6: Key Milestones in the Regulatory History of Gadobutrol

Date	Regulatory Body	Action / Decision	Significance
1998	Swissmedic	Initial Marketing Approval	First global approval of Gadobutrol.
2000	BfArM (Germany)	EU Marketing Approval	Approval for CNS imaging in the EU, with subsequent expansions. 49
Mar 14, 2011	U.S. FDA	Initial Approval (Gadavist®)	Approved for MRI of the Central Nervous System in the U.S. 38
Jan 5, 2015	U.S. FDA	Indication Expansion	Approved as the first GBCA for use in pediatric patients <2 years of age. 38
Jul 14, 2015	EMA	Indication Expansion	Label extended in the EU for use in pediatric patients <2 years of age. 49
Apr 29, 2016	U.S. FDA	Indication Expansion	Approved for use in MRA of supra-aortic arteries. 38
Jul 20, 2017	EMA	Article 31 Referral Outcome	Confirmed that Gadobutrol's marketing authorization should be maintained, while suspending several linear agents due to retention concerns. 47
Jul 15, 2019	U.S. FDA	Indication Expansion	Approved as the first and only GBCA for use in Cardiac MRI. 38
Aug 14, 2020	U.S. FDA	Formulation Approval	Approved the Imaging Bulk Package for multi-patient dosing. 61

Conclusion

Gadobutrol has firmly established itself as a cornerstone of modern contrast-enhanced magnetic resonance imaging. Its development represents a successful application of rational drug design, where the combination of a highly stable macrocyclic chelate and a hydrophilic side chain resulted in a molecule with an exceptional balance of safety and efficacy. The macrocyclic structure provides high kinetic stability, which is the fundamental basis for its classification as a low-risk agent for nephrogenic systemic fibrosis and for its lower potential for long-term gadolinium retention compared to older linear agents.

The unique 1.0 mmol/mL formulation, coupled with its high T1 relaxivity, provides tangible clinical advantages, particularly in dynamic imaging applications that benefit from a compact, high-concentration contrast bolus. This has contributed to its broad range of approved indications across CNS, breast, vascular, and cardiac imaging, including its landmark approval as the first GBCA for cardiac MRI in the United States.

The pharmacokinetic profile of Gadobutrol is notable for its simplicity and predictability. Its behavior as a biologically inert, extracellular agent that is eliminated unchanged via glomerular filtration allows for consistent, weight-based dosing across diverse patient populations, from term neonates to the elderly, simplifying clinical practice.

In the evolving landscape of GBCAs, where safety concerns have shifted from NSF to the unknown long-term consequences of gadolinium retention, Gadobutrol's high-stability macrocyclic structure has solidified its position as a standard of care. It now serves as the incumbent benchmark against which the next generation of even higher-relaxivity, dose-sparing agents are being developed and evaluated. In conclusion, the comprehensive body of evidence from chemical analysis, pharmacological studies, extensive clinical trials, and decades of post-marketing surveillance confirms that Gadobutrol is a highly effective, versatile, and safe diagnostic tool, indispensable to modern radiology.

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