Gadopiclenol: A Comprehensive Monograph on a High-Relaxivity, Macrocyclic Gadolinium-Based Contrast Agent

1.0 Introduction: The Evolution of Gadolinium-Based Contrast Agents and the Advent of High-Relaxivity Formulations

1.1 Overview of Gadolinium-Based Contrast Agents (GBCAs) in Magnetic Resonance Imaging (MRI)

Gadolinium-based contrast agents (GBCAs) are indispensable tools in modern diagnostic medicine, serving to enhance the quality and diagnostic yield of magnetic resonance imaging (MRI).[1] MRI is a powerful, non-ionizing imaging modality that utilizes strong magnetic fields and radio waves to generate detailed images of internal body structures.[1] GBCAs, which contain the paramagnetic gadolinium ion (

), are administered intravenously to alter the magnetic properties of nearby water protons. This interaction shortens proton relaxation times, leading to a stronger signal on T1-weighted images and thereby improving the visualization of lesions, organs, and blood vessels.[3] The clinical utility of these agents is underscored by their widespread use; GBCAs are administered in an estimated 45% of all MRI examinations conducted in the United States.[6]

1.2 The Clinical Challenge: Gadolinium Retention, Nephrogenic Systemic Fibrosis (NSF), and the Drive for Dose Reduction

Despite their diagnostic benefits, the history of GBCAs has been shaped by significant safety considerations. In 2006, a clear association was established between the use of certain GBCAs and the development of nephrogenic systemic fibrosis (NSF), a rare but severe and potentially fatal fibrosing disorder that affects the skin, muscles, and internal organs.[6] This condition occurs exclusively in patients with pre-existing renal impairment.[6] Subsequent investigations revealed that the risk of NSF was disproportionately linked to less stable, linear-structured GBCAs, which have a higher propensity to release the toxic free gadolinium ion in vivo.[7] In contrast, macrocyclic GBCAs, which chelate the gadolinium ion more tightly within a cage-like molecular structure, demonstrated a much lower risk.[9] This critical distinction led regulatory bodies, including the European Medicines Agency (EMA), to suspend or severely restrict the marketing authorizations for most linear GBCAs.[9]

This initial safety concern evolved with the discovery of long-term gadolinium retention. It is now well-established that trace amounts of gadolinium can be retained for months or even years in various body tissues—including the brain, bone, and skin—following GBCA administration, even in patients with normal renal function.[11] While the clinical consequences of this retention in patients with normal kidney function have not been definitively established, the finding prompted a class-wide safety warning from the U.S. Food and Drug Administration (FDA) and a global consensus among health authorities to adhere to the principle of using the lowest effective dose of gadolinium possible without compromising diagnostic quality.[12] This regulatory and clinical imperative created a clear unmet need for a new generation of GBCAs that could maintain or improve diagnostic efficacy while fundamentally reducing the patient's total gadolinium exposure.

1.3 Introduction to Gadopiclenol as a Novel, High-Relaxivity Agent

Gadopiclenol emerges as a direct and innovative response to this clinical need. It is a next-generation, macrocyclic, non-ionic GBCA engineered specifically to address the concerns surrounding gadolinium exposure.[4] The core innovation of Gadopiclenol lies in its exceptionally high relaxivity—a measure of its efficiency in enhancing the MRI signal. This high efficiency allows it to provide diagnostic information that is equivalent or superior to that of conventional GBCAs but at half the standard gadolinium dose.[16] By enabling a "half-dose" imaging paradigm, with a recommended dose of 0.05 mmol/kg compared to the conventional 0.1 mmol/kg, Gadopiclenol directly embodies the "lowest effective dose" principle, representing a significant advancement in the safety and efficacy of contrast-enhanced MRI.[16]

2.0 Physicochemical Properties and Molecular Profile

2.1 Chemical Identification

Gadopiclenol is a well-characterized small molecule with a unique set of identifiers that define its chemical identity. These are critical for regulatory, research, and clinical purposes.

Property	Value	Source(s)
Name	Gadopiclenol	11
DrugBank ID	DB17084	3
CAS Number	933983-75-6	3
IUPAC Name	2-[3,9-bis[1-carboxylato-4-(2,3-dihydroxypropylamino)-4-oxobutyl]-3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-yl]-5-(2,3-dihydroxypropylamino)-5-oxopentanoate;gadolinium(3+)	3
Molecular Formula		16
Molar Mass	970.10 g·mol⁻¹	16
Structure Type	Macrocyclic, non-ionic, pyclen-based	4
Water Exchange Sites (q)	2	17
Synonyms	P03277	21
Other Identifiers	UNII: S276568KOY, KEGG: D12435, PubChem CID: 16223405	3

2.2 Molecular Structure, Formula, and Weight

The chemical formula for Gadopiclenol is , with a corresponding molar mass of approximately 970.10 g·mol⁻¹.[16] Its complex structure contains a total of six stereocenters, contributing to its specific three-dimensional conformation.[21]

2.3 The Pyclen-Based Macrocyclic Structure and Its Significance for Stability and Relaxivity

The molecular architecture of Gadopiclenol is central to its function and safety profile. It is a paramagnetic, non-ionic complex built upon a pyclen macrocyclic scaffold that tightly chelates a central gadolinium ion.[3] This macrocyclic design is fundamentally important, as it imparts high kinetic stability to the complex. This stability minimizes the risk of dechelation—the in vivo release of the potentially toxic free

 ion—which is the primary mechanism behind gadolinium-related toxicity and a key feature that distinguishes it from the less stable linear class of GBCAs.[7]

However, Gadopiclenol represents more than just an iteration of existing macrocyclic designs. Its structure was deliberately engineered for superior efficiency. A key structural feature, and an exception among all other clinically approved GBCAs, is the presence of two inner-sphere water molecule exchange sites (a hydration number, q, of 2).[17] In contrast, conventional GBCAs possess only one such site (q=1).[22] Historically, attempts to increase the number of water exchange sites to boost efficiency often came at the cost of reduced molecular stability.[22] The design of Gadopiclenol successfully overcomes this trade-off, doubling the number of sites for interaction with surrounding water protons while maintaining the high stability inherent to the macrocyclic backbone. This unique structural optimization is the direct chemical basis for its exceptionally high relaxivity.

3.0 Comprehensive Pharmacological Profile

3.1 Mechanism of Action: Paramagnetism and Proton Relaxation

Gadopiclenol functions as a paramagnetic contrast agent. When administered and subsequently placed within the strong magnetic field of an MRI scanner, the gadolinium complex develops a large magnetic moment.[3] This creates a powerful local magnetic field that significantly alters the relaxation rates of adjacent water protons within body tissues.[3] Specifically, it shortens both the spin-lattice (T1) and spin-spin (T2) relaxation times of these protons.[4] On T1-weighted MRI sequences, this accelerated relaxation results in a marked increase in signal intensity, causing tissues where the agent has accumulated to appear brighter. This effect enhances the contrast between normal and pathological tissues, particularly those with abnormal vascularity or a disrupted blood-brain barrier, thereby improving lesion detection and characterization.[3]

3.2 Pharmacodynamics: The Principle of High Relaxivity

The pharmacodynamic effect of a GBCA is quantified by its relaxivity (), which is a measure of its potency in shortening the T1 relaxation time of water protons.[4] Gadopiclenol's defining characteristic is its exceptionally high relaxivity, which is the highest among all currently available non-specific GBCAs.[23]

As established, this high efficiency is a direct result of its innovative molecular structure, which incorporates two water exchange sites.[18] This allows each gadolinium ion to interact with and influence twice the number of water molecules compared to conventional agents, effectively doubling its signal-enhancing capability.[25] Quantitatively, Gadopiclenol's

 relaxivity has been measured at 12.8 L·mmol⁻¹·s⁻¹ in human plasma at 1.5 T and 37°C.[9] This value is approximately two to three times higher than that of other widely used macrocyclic GBCAs, such as gadobutrol (

 L·mmol⁻¹·s⁻¹) and gadoterate meglumine ( L·mmol⁻¹·s⁻¹).[9] This superior pharmacodynamic potency is the fundamental reason why Gadopiclenol can achieve robust diagnostic efficacy at half the conventional gadolinium dose.[16]

3.3 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Gadopiclenol is predictable and favorable for an intravenously administered diagnostic agent. It is characterized by linear kinetics, distribution limited to the extracellular space, and rapid, complete elimination without undergoing metabolic alteration. This "clean" ADME profile is a key component of its overall safety, complementing the stability of its macrocyclic structure by ensuring the agent does not linger or transform within the body.

Parameter	Value	Source(s)
(at 0.05 mmol/kg)	525 µg/mL	3
(at 0.05 mmol/kg)	569 µg·h/mL	3
Volume of Distribution ()	13 L (at steady state)	3
Plasma Protein Binding		4
Metabolism	None; eliminated unchanged	4
Route of Elimination	Primarily renal, via glomerular filtration	3
% Excreted in Urine (48h)	~98%	3
Elimination Half-life ()	~1.5 - 2.0 hours	4
Total Body Clearance	100 mL/min	4
Renal Clearance	81 mL/min	4

After intravenous administration, the peak plasma concentration () and total systemic exposure () of Gadopiclenol increase proportionally with the dose, indicating linear pharmacokinetics over a wide range.[3] The agent distributes within the extracellular fluids, consistent with its low volume of distribution and negligible binding to plasma proteins.[3] Crucially, Gadopiclenol is not metabolized in the body.[4] It is eliminated rapidly and almost entirely in its unchanged form through the kidneys via glomerular filtration, with approximately 98% of the dose recovered in the urine within 48 hours.[3] This efficient renal clearance results in a short elimination half-life of approximately 1.5 to 2 hours in patients with normal renal function.[4]

4.0 Clinical Efficacy and Application in Diagnostic Imaging

4.1 Approved Indications and Patient Populations (Adult and Pediatric)

Gadopiclenol is approved for diagnostic use with MRI to detect and visualize lesions characterized by abnormal vascularity.[3] Its indications are broad, encompassing both adult and pediatric patients aged 2 years and older.[3] Safety and efficacy have not been formally established in children younger than 2 years of age, although pharmacokinetic studies in this population are underway.[1] The approved anatomical regions for contrast enhancement are comprehensive and include:

• Central Nervous System (CNS): Brain, spine, and associated tissues.[3]
• Body: A wide range of extra-cranial regions, including the head and neck, thorax, abdomen, pelvis, and the musculoskeletal system.[1]

4.2 Dosage and Administration: The Half-Dose Regimen

A defining feature of Gadopiclenol's clinical use is its half-dose regimen. The recommended dose for all approved indications in both adults and children (2 years and older) is 0.05 mmol/kg of actual body weight.[11] This corresponds to an injection volume of 0.1 mL/kg and is administered as an intravenous bolus at a rate of approximately 2 mL/sec.[11] This dosage is precisely half that of conventional non-specific GBCAs, such as gadobutrol, which are typically administered at 0.1 mmol/kg.[16]

4.3 In-Depth Analysis of Pivotal Phase III Clinical Trials

The global regulatory approvals for Gadopiclenol were principally supported by the robust evidence from two large-scale, prospective, randomized, double-blind, crossover Phase III studies: PICTURE (for CNS imaging) and PROMISE (for body imaging).[18] The choice of a within-patient crossover design for these trials represents a high standard of scientific rigor. In this design, each patient receives both the investigational agent (half-dose Gadopiclenol) and the active comparator (full-dose gadobutrol) at separate imaging sessions. This allows each patient to serve as their own control, effectively minimizing inter-patient variability and providing a direct, powerful comparison of the two agents' performance. This high level of evidence was instrumental in demonstrating the non-inferiority of the half-dose regimen and likely contributed to the agent receiving priority review status from the FDA.

Feature	PICTURE Trial (NCT03996447)	PROMISE Trial (NCT03986138)
Indication	Central Nervous System (CNS) Imaging	Body Imaging (Head/Neck, Thorax, Abdomen, Pelvis, Musculoskeletal)
Patient Population (N)	256 adults with known/suspected CNS lesions	273 adults with suspected enhancing abnormalities in the body
Study Design	Randomized, double-blind, crossover	Randomized, double-blind, crossover
Test Arm	Gadopiclenol 0.05 mmol/kg	Gadopiclenol 0.05 mmol/kg
Comparator Arm	Gadobutrol 0.1 mmol/kg	Gadobutrol 0.1 mmol/kg
Primary Efficacy Endpoint	Non-inferiority of Gadopiclenol vs. Gadobutrol for 3 lesion visualization criteria (border delineation, internal morphology, contrast enhancement)	Non-inferiority of Gadopiclenol vs. Gadobutrol for 3 lesion visualization criteria
Key Secondary Endpoints	Superiority vs. unenhanced MRI; quantitative metrics (contrast enhancement, CNR, LBR); reader preference	Superiority vs. unenhanced MRI; quantitative metrics (contrast enhancement); reader preference
Safety Outcome Summary	Similar incidence and type of adverse events for both agents (4.9% related AEs for Gadopiclenol vs. 6.9% for Gadobutrol)	Similar incidence and type of adverse events for both agents (4.2% AEs for Gadopiclenol vs. 5.5% for Gadobutrol)

4.3.1 The PICTURE Trial (NCT03996447): Efficacy in Central Nervous System (CNS) Imaging

The PICTURE trial evaluated Gadopiclenol in 256 patients with known or suspected CNS lesions.[5] The study successfully met all its primary and secondary endpoints. For the primary endpoint, 0.05 mmol/kg Gadopiclenol was demonstrated to be non-inferior to 0.1 mmol/kg gadobutrol across all three co-primary lesion visualization criteria (border delineation, internal morphology, and contrast enhancement), as assessed by three independent blinded readers (p<0.0001).[8] Furthermore, Gadopiclenol-enhanced MRI was statistically superior to unenhanced MRI.[31] On quantitative secondary measures, Gadopiclenol exhibited a superior percentage of contrast enhancement and a superior lesion-to-background ratio compared to full-dose gadobutrol (p<0.0001).[8] Reflecting this enhanced performance, a statistically significant majority of image evaluations by all three readers showed a preference for the images acquired with half-dose Gadopiclenol.[32]

4.3.2 The PROMISE Trial (NCT03986138): Efficacy in Body Imaging

The PROMISE trial extended this investigation to 273 patients with suspected pathologies in various body regions.[5] The results mirrored those of the PICTURE trial, with all endpoints being met. Gadopiclenol at 0.05 mmol/kg was proven to be non-inferior to gadobutrol at 0.1 mmol/kg for all qualitative visualization parameters across all blinded readers (P<.001).[31] It was also superior to unenhanced imaging.[34] In terms of quantitative metrics, two of the three readers found a higher percentage of lesion enhancement with Gadopiclenol (P<.001), while the lesion-to-background ratio did not differ between the two agents.[24] In this trial, for the majority of cases (75%-83%), readers reported no preference between the images from the two agents, strongly reinforcing the conclusion of non-inferiority at half the dose.[24]

4.4 Clinical Studies in Special Populations, including Pediatrics

The extrapolation of efficacy from adult to pediatric populations was supported by a dedicated study in 80 children aged 2 to 17 years. This study demonstrated that the pharmacokinetic profile of Gadopiclenol in children was comparable to that observed in adults, indicating that no age-based dose adjustments are necessary within this age range.[6] For geriatric patients, no specific age-related problems have been identified, although caution is warranted as elderly patients have a higher prevalence of underlying renal disease.[1]

5.0 Safety, Tolerability, and Risk Management

5.1 Overview of the Clinical Safety Profile and Common Adverse Reactions

The overall safety profile of Gadopiclenol is consistent with that of other macrocyclic GBCAs.[5] Clinical trial data from over 1,000 patients and extensive post-marketing surveillance confirm its favorable tolerability.[23] The most commonly reported adverse reactions are generally mild and transient. These include injection site reactions (such as pain, warmth, or coldness) and headache, each occurring with an incidence of less than 1%.[11] Other less frequent side effects include nausea, dizziness, and localized swelling.[11] Importantly, the pivotal comparative trials showed that the incidence, type, and severity of adverse events were similar between patients receiving half-dose Gadopiclenol and those receiving full-dose gadobutrol.[8] Post-marketing data from the first year of use in the U.S., covering over 882,550 administrations, reported no serious adverse events and a very low rate of non-serious adverse events (approximately 1 case per 27,580 exposures), further reinforcing its positive safety profile in real-world clinical practice.[33]

5.2 Boxed Warning: Nephrogenic Systemic Fibrosis (NSF)

In line with all GBCAs approved for use, Gadopiclenol's prescribing information includes a boxed warning regarding the risk of NSF.[3] This serious condition is known to occur in patients with impaired elimination of gadolinium-containing drugs. The highest-risk populations are patients with chronic, severe kidney disease (defined as an estimated glomerular filtration rate, or eGFR, < 30 mL/min/1.73m²) and those with acute kidney injury (AKI).[11] To mitigate this risk, standard practice requires screening all patients for renal dysfunction prior to administration. This is particularly important for patients at higher risk, such as those over 60 years of age or those with a history of hypertension or diabetes.[15] In at-risk patients, the recommended dose should not be exceeded, and a sufficient time interval should be allowed for drug elimination before any repeat administration.[28]

5.3 Gadolinium Retention: A Class-Wide Consideration

Gadolinium retention is a recognized class effect for all GBCAs, with trace amounts of the metal remaining in the body for months to years post-administration.[12] The magnitude of this retention is highly dependent on the chemical stability of the GBCA. It is well-established that retention is significantly lower for stable macrocyclic agents compared to less stable linear agents.[12]

Preclinical studies were conducted to specifically position Gadopiclenol within this context. A long-term study in healthy rats directly compared brain gadolinium retention over 12 months following repeated administration of Gadopiclenol, gadobutrol (another macrocyclic agent), and gadodiamide (a linear agent).[39] The results were definitive: Gadopiclenol and gadobutrol showed similarly low levels of brain retention and a comparable, efficient washout profile, with approximately 80% of the gadolinium being cleared from the brain over one year. In stark contrast, the linear agent gadodiamide resulted in significantly higher initial retention and a much slower washout, with only 15% clearance over the same period.[39] This evidence confirms that, from a molecular standpoint, Gadopiclenol's retention characteristics are consistent with those of other high-stability macrocyclic GBCAs.

While the long-term clinical consequences of gadolinium retention in the brain of patients with normal renal function remain unknown, the phenomenon underpins the universal recommendation to minimize patient exposure.[11] Gadopiclenol's primary safety advantage is therefore not that it is intrinsically less prone to retention than other safe macrocycles on a molecule-for-molecule basis, but rather that its clinical application inherently achieves this goal. By providing full diagnostic efficacy at half the dose, it reduces a patient's total gadolinium burden for a given diagnostic procedure by 50%, directly addressing the core of the retention concern through pharmacodynamic efficiency.

5.4 Contraindications, Hypersensitivity Reactions, and Other Precautions

The primary contraindication for Gadopiclenol is a history of a severe hypersensitivity reaction to the drug itself.[15] As with all contrast media, there is a risk of hypersensitivity reactions, ranging from mild to severe and life-threatening. Therefore, patients should be assessed for a history of allergies or asthma, and administration should only occur in a setting where trained personnel and emergency therapies are readily available.[23]

Other important precautions include:

• Intrathecal Use: Gadopiclenol is not approved for intrathecal administration. This route of administration is associated with serious adverse reactions, including death, coma, and seizures.[1]
• Acute Kidney Injury (AKI): In patients with pre-existing chronic kidney disease, GBCAs can increase the risk of developing AKI.[36]
• Interference with Non-Contrast MRI: As with any GBCA, Gadopiclenol may obscure or alter the appearance of lesions that are visible on unenhanced MRI scans. Caution should be exercised when interpreting contrast-enhanced scans without a companion non-contrast acquisition.[28]

5.5 Use in Specific Populations: Renal Impairment, Pregnancy, and Lactation

• Renal Impairment: While no specific dose adjustment is recommended, the use of Gadopiclenol should be avoided in patients with severe chronic kidney disease or AKI unless the diagnostic information is deemed essential and cannot be obtained otherwise.[11] The systemic exposure to Gadopiclenol increases as renal function declines.[9] The agent can be effectively removed from the body by hemodialysis.[37]
• Pregnancy: GBCAs are known to cross the human placenta, leading to fetal exposure and gadolinium retention. Therefore, Gadopiclenol should be used during pregnancy only if the imaging is essential and cannot be delayed.[28]
• Lactation: Data on the presence of Gadopiclenol in human milk are not available. While general professional guidelines often state that breastfeeding need not be interrupted after receiving a GBCA, given the lack of specific data for Gadopiclenol, other agents may be preferred when nursing a newborn or preterm infant.[1]

6.0 Comparative Analysis: Gadopiclenol in the Context of Existing GBCAs

Gadopiclenol's introduction represents a significant advancement in the field of contrast media. Its clinical value is best understood through a direct comparison with existing GBCAs across the key domains of chemical structure, functional efficiency, and the resulting safety profile. This comparison reveals a paradigm shift from a reliance on dose quantity to an emphasis on molecular efficiency.

Parameter	Gadopiclenol	Gadobutrol (Macrocyclic)	Gadoterate (Macrocyclic)	Gadodiamide (Linear)
Chemical Structure Class	Macrocyclic (Pyclen-based)	Macrocyclic	Macrocyclic	Linear
Relaxivity () in plasma/serum	~12.8 L·mmol⁻¹·s⁻¹	~5.2 L·mmol⁻¹·s⁻¹	~3.6 L·mmol⁻¹·s⁻¹	N/A (Lower)
Standard Clinical Dose	0.05 mmol/kg	0.1 mmol/kg	0.1 mmol/kg	0.1 mmol/kg
Kinetic Stability	High	High	High	Lower
Relative Gd Retention (Preclinical)	Low (similar to Gadobutrol)	Low	Low	High
Primary Safety Concern(s)	NSF risk (class effect), Gd retention (class effect)	NSF risk (class effect), Gd retention (class effect)	NSF risk (class effect), Gd retention (class effect)	High NSF risk, High Gd retention

6.1 Structural Comparison: Macrocyclic Stability vs. Linear Agents

Gadopiclenol belongs to the macrocyclic class of GBCAs, a structural feature it shares with established agents like gadobutrol and gadoterate.[7] This class is defined by a pre-organized, cage-like ligand that provides high thermodynamic and kinetic stability, securely sequestering the gadolinium ion.[9] This high stability is in stark contrast to linear agents (e.g., gadodiamide), which are more flexible and have a higher propensity for dechelation and subsequent gadolinium release. This structural difference is the primary reason for the markedly better safety profile of macrocyclic agents concerning both NSF and long-term tissue retention.[39]

6.2 Relaxivity and Dosing Efficiency: A Paradigm Shift

The most significant differentiator for Gadopiclenol is its relaxivity. With an  value of approximately 12.8 L·mmol⁻¹·s⁻¹, it is two- to three-fold more efficient at enhancing MRI signal than other macrocyclic agents like gadobutrol (~5.2 L·mmol⁻¹·s⁻¹) and gadoterate (~3.6 L·mmol⁻¹·s⁻¹).[9] This leap in efficiency is not an incremental improvement but a fundamental change in capability. It effectively uncouples diagnostic performance from gadolinium dose. Historically, achieving greater contrast enhancement required administering more of the agent. Gadopiclenol breaks this paradigm by enhancing the intrinsic efficiency of each molecule. This allows clinicians to achieve non-inferior—and in some quantitative measures, superior—image quality with only half the amount of gadolinium (0.05 mmol/kg) compared to the standard full dose (0.1 mmol/kg) of agents like gadobutrol and gadobenate dimeglumine.[19] This represents a shift from a "quantity-based" approach to an "efficiency-based" one.

6.3 Comparative Safety Profiles: Balancing Efficacy and Long-Term Exposure Risks

When administered, the immediate safety profile of Gadopiclenol, in terms of the type and frequency of acute adverse events, is comparable to that of other safe, macrocyclic GBCAs.[8] However, its overall benefit-risk profile is substantially improved by its dosing regimen. The central safety concerns of the entire GBCA class—NSF and long-term gadolinium retention—are dose-dependent phenomena. By halving the required gadolinium dose per procedure, Gadopiclenol directly and significantly reduces a patient's exposure to the metal ion at the heart of these risks. This makes it a particularly advantageous choice for patient populations who are at higher theoretical risk from cumulative exposure, such as pediatric patients, pregnant women, and individuals requiring multiple contrast-enhanced scans over their lifetime.[13]

7.0 Regulatory and Commercial Landscape

7.1 Global Regulatory Approval Pathway: FDA, EMA, and MHRA

Gadopiclenol navigated the global regulatory landscape efficiently, securing approvals from major health authorities in rapid succession, a process aided by the strength of its clinical data and its designation as a priority agent by the FDA.

• U.S. Food and Drug Administration (FDA): The New Drug Application (NDA 216986) was granted Priority Review, a designation reserved for therapies that offer significant improvements in safety or effectiveness over available options.[18] Approval was granted on September 21, 2022.[16]
• European Medicines Agency (EMA): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on October 12, 2023, the European Commission granted full marketing authorization for the European Union on December 7, 2023.[16]
• Medicines and Healthcare products Regulatory Agency (MHRA): Marketing authorization in Great Britain was granted on December 12, 2023.[45]

7.2 Commercialization: The Guerbet (Elucirem) and Bracco (Vueway) Collaboration

The development and commercialization of Gadopiclenol are managed through a unique strategic collaboration between two major competitors in the diagnostic imaging space: Guerbet and Bracco Imaging. Gadopiclenol was initially invented by Guerbet, with subsequent intellectual property contributions from Bracco.[18] In December 2021, the two companies entered into a worldwide collaboration agreement covering manufacturing, research, and development.[42]

Under this agreement, the same active pharmaceutical ingredient is commercialized independently by both companies under distinct brand names:

• Guerbet: Markets the product as Elucirem™.[16]
• Bracco Imaging: Markets the product as VUEWAY™.[16]

Manufacturing is a shared effort, taking place at facilities in both the United States and France.[23] This dual-branding and collaborative model is a noteworthy business strategy. By pooling R&D resources and sharing valuable intellectual property, the two companies were able to de-risk a complex and costly development process. This co-opetition strategy allows both entities to leverage their established global marketing and distribution networks, accelerating market access and aiming to more rapidly establish Gadopiclenol as a new standard of care.

8.0 Conclusion and Future Perspectives

8.1 Synthesis of Gadopiclenol's Benefit-Risk Profile

Gadopiclenol presents a highly favorable benefit-risk profile that marks a significant evolution in the field of gadolinium-based contrast agents. Its primary benefit is its high diagnostic efficacy, which has been rigorously proven in large-scale clinical trials to be non-inferior to full-dose standard agents for a comprehensive range of CNS and body imaging indications. This high level of performance is achieved at half the conventional gadolinium dose, a direct result of its innovative molecular design and superior relaxivity. The risks associated with Gadopiclenol are consistent with the known and manageable risks of the stable macrocyclic GBCA class. However, these risks are substantially mitigated by the 50% reduction in gadolinium exposure per diagnostic procedure. This fundamentally improves the long-term safety equation, directly addressing the paramount clinical and regulatory concerns regarding gadolinium retention.

8.2 Clinical Implications: The Impact of Half-Dose Gadolinium Imaging

The introduction of Gadopiclenol provides a powerful tool for aligning clinical practice with the global mandate to minimize patient exposure to gadolinium. It empowers radiologists to significantly reduce the gadolinium burden for their patients without compromising diagnostic confidence. This is particularly impactful for vulnerable populations, including pediatric patients and those with chronic conditions requiring repeated MRI examinations, where cumulative gadolinium exposure is a primary concern. The availability of a high-efficiency, half-dose agent represents a tangible step forward in enhancing the safety of a vital diagnostic modality.

8.3 Future Research Directions and Unanswered Questions

While the current body of evidence for Gadopiclenol is robust, several avenues for future research remain. Long-term, prospective clinical studies tracking gadolinium retention in patients after Gadopiclenol administration will be valuable for confirming the favorable preclinical findings in a real-world setting. Further pharmacokinetic and safety studies are needed for the pediatric population under 2 years of age to expand its approved indications.[27] Additionally, future research could explore the potential of high-relaxivity agents like Gadopiclenol in advanced MRI applications, such as perfusion imaging or molecular imaging. Finally, the combination of high-efficiency contrast agents with emerging technologies like artificial intelligence and deep learning reconstruction could open pathways for even further dose reduction, pushing the boundaries of safe and effective contrast-enhanced imaging.

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