Gadobutrol

證據等級: L5

預測適應症: 10 個

Gadobutrol: From CNS MRI Contrast Enhancement to Peripheral Arterial Disease Diagnosis

One-Sentence Summary

Gadobutrol (Gadovist) is a high-concentration (1.0 mol/L) macrocyclic gadolinium-based contrast agent (GBCA) primarily used for MRI enhancement of the central nervous system and whole-body imaging. The TxGNN model's highest-evidence prediction suggests it may serve a diagnostic role in Peripheral Arterial Disease (PAD), with 4 clinical trials and 20 publications currently supporting this direction. It is important to note that this represents a diagnostic, rather than therapeutic, repurposing — Gadobutrol's role in PAD is as a contrast medium for CE-MRA (contrast-enhanced MR angiography), not as a treatment agent.

Quick Overview

Item	Content
Original Indication	CNS MRI enhancement (brain and spine); whole-body MR angiography
Predicted New Indication	Peripheral Arterial Disease (PAD)
TxGNN Prediction Score	76.72% (rank #2 by evidence quality; rank #1 BPH has no supporting evidence)
Evidence Level	L1 (2 completed Phase 4 RCTs directly comparing Gadobutrol in PAD)
Singapore Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Note on TxGNN Rank Interpretation: The model's rank 1 prediction (Benign Prostatic Hyperplasia, score 83.2%) has zero clinical trial or literature support and is mechanistically implausible. This report focuses on PAD (rank 2, score 76.7%), which carries the strongest evidence and a coherent mechanistic rationale.

Why is This Prediction Reasonable?

Gadobutrol is a macrocyclic, extracellular gadolinium chelate formulated at a uniquely high concentration of 1.0 mol/L — twice that of conventional 0.5 mol/L GBCAs. This high molarity shortens T1 relaxation time more efficiently, producing superior vessel-to-background contrast even at lower injection volumes. The physical mechanism is straightforward: high [Gd]→ enhanced MRI signal → superior vascular delineation.

In the context of peripheral arterial disease, contrast-enhanced MR angiography (CE-MRA) is the established non-invasive reference standard for assessing stenosis severity, lesion extent, and guiding revascularisation decisions. Gadobutrol's concentration advantage is particularly valuable in multi-station CE-MRA protocols covering the entire runoff vasculature from the aorta to the foot — a technically demanding study where bolus timing and signal-to-noise ratio are critical. The high relaxivity of Gadobutrol allows lower gadolinium doses (0.1 mmol/kg) while maintaining diagnostic image quality, which also carries safety benefits in patients with comorbid renal dysfunction.

The TxGNN knowledge graph likely identifies this connection through the shared pathway: Gadobutrol ↔ MR angiography ↔ vascular disease diagnosis, reflecting real-world clinical practice rather than a novel therapeutic mechanism. While this does not constitute pharmacological drug repurposing in the conventional sense, it does represent an expansion of the diagnostic indication for Gadobutrol into peripheral vascular imaging — an application already well-supported by high-quality clinical evidence but potentially not yet formally registered in all markets.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01026389	Phase 4	Completed	189	Head-to-head RCT comparing Gadovist® (Gadobutrol) vs Dotarem® (gadoterate) CE-MRA in abdominal and lower limb arterial disease — the largest PAD diagnostic comparison trial
NCT00955617	Phase 4	Completed	20	Intra-individual crossover comparison of Gadobutrol vs gadoterate in CE-MRA for clinically significant abdominal/lower limb arterial disease
NCT02917213	N/A	Completed	92	Prospective observational study assessing quantitative cardiac and vascular MRI (including Gadobutrol) for predicting thromboembolic complications including peripheral arterial embolism post-MI
NCT05685160	N/A	Enrolling by Invitation	75	Imaging comparison of intermetatarsal bursitis vs Morton's neuroma using MRI with contrast — limited direct relevance to PAD diagnosis

Literature Evidence

PMID	Year	Type	Journal	Key Findings
26001243	2015	RCT	AJR Am J Roentgenol	Large-scale randomised prospective study demonstrating non-inferiority of gadoterate vs Gadobutrol at 3T MRA in peripheral arterial occlusive disease, using DSA as reference — establishes Gadobutrol as diagnostic benchmark
12928960	2003	Prospective Cohort	Eur Radiol	Multi-centre blinded study (n=203) comparing Gadobutrol CE-MRA vs intra-arterial DSA in peripheral vascular disease — demonstrated high diagnostic accuracy for pelvic and peripheral arteries
22848033	2012	Prospective RCT	J Magn Reson Imaging	Single-centre randomised crossover double-blind study comparing 0.5M gadoterate vs 1.0M Gadobutrol in peripheral MRA at 3T for abdominal/lower limb arterial disease
20959539	2010	Prospective Cohort	Radiology	Evaluated a 3T MRA protocol combining continuous table movement with time-resolved TWIST-MRA using single-dose Gadobutrol (0.1 mmol/kg) in peripheral arterial occlusive disease
23188773	2013	Prospective Comparative	J Magn Reson Imaging	Compared CE-MRA vs DSA in lower extremity arterial disease, confirming high diagnostic accuracy for stenosis grading in symptomatic peripheral arterial occlusive disease
15149986	2004	Prospective Cohort	AJR Am J Roentgenol	Whole-body 3D CE-MRA with Gadobutrol in 51 patients with PAD; demonstrated feasibility of single-injection whole-body vascular coverage compared to DSA
19652610	2009	Prospective Cohort	Invest Radiol	Proof-of-concept for peripheral CTM MRA combined with time-resolved TWIST-MRA using single low dose of Gadobutrol (0.1 mmol/kg) at 3.0T
12677513	2003	Prospective Cohort	RoFo	Early clinical results for 1.0M Gadobutrol CE-MRA vs intra-arterial DSA in peripheral arterial occlusive disease — established early evidence base
24893292	2014	Prospective Comparative	PLoS One	Compared enhancement characteristics and image quality of Gadobutrol vs gadoterate in low-dose time-resolved 3T MRA at calf station — relevant for distal PAD assessment
21031523	2010	Prospective Comparative	J Magn Reson Imaging	Inter-individual prospective comparison of gadobenate dimeglumine vs Gadobutrol in CE run-off MRA of the lower extremities for diagnostic accuracy and image quality

Singapore Market Information

Gadobutrol is currently not registered with the Health Sciences Authority (HSA) of Singapore. No product authorisations are on file.

Gadobutrol (marketed as Gadovist® by Bayer and as Gadavist® in North America) holds regulatory approval in multiple major markets including the European Union, United States, Japan, and Australia for MRI enhancement of CNS and body imaging. A formal registration application to HSA would be required before clinical use in Singapore.

Safety Considerations

No HSA-specific package insert warnings or contraindications data were available for this review. No drug-drug interaction data were identified in the query log.

Please refer to the originator's package insert (Gadovist®, Bayer) for complete safety information. Key class-related considerations for gadolinium-based contrast agents include:

Nephrogenic Systemic Fibrosis (NSF): Risk in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). Gadobutrol is a macrocyclic GBCA with a more stable chelate structure than linear agents, associated with lower NSF risk.
Gadolinium Retention: Long-term gadolinium deposition in the brain and other tissues has been reported for all GBCAs; macrocyclic agents including Gadobutrol show lower retention than linear agents.
Hypersensitivity Reactions: As with all contrast media, anaphylactoid reactions are possible; resuscitation facilities should be available.
Renal Function Monitoring: Screen for renal impairment before administration; dose adjustment or avoidance may be required in renally compromised patients.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: The evidence base for Gadobutrol in peripheral arterial disease diagnosis is substantial and of high quality — two completed Phase 4 RCTs and multiple prospective cohort studies consistently demonstrate diagnostic non-inferiority or equivalence to the reference standard (DSA), with a clear and well-understood mechanistic basis. This is not a speculative pharmacological repurposing but an evidence-grounded diagnostic indication expansion backed by L1-level evidence.

To proceed, the following is needed:

HSA Registration: Gadobutrol is not currently registered in Singapore. A regulatory submission to HSA is required. The existing EU and US approval dossiers (Gadovist® / Gadavist®) provide a strong foundation for a submission.
Formal Safety Data for Singapore Label: Obtain and translate the complete package insert (warnings, contraindications, NSF risk communication) to fulfil HSA label requirements.
Renal Safety Protocol: Establish a local institutional protocol for pre-administration eGFR screening, consistent with international radiology society guidelines (ACR, ESUR) for macrocyclic GBCA use.
MOA Documentation: Formal documentation of the gadolinium chelate mechanism for regulatory dossier completeness.
Post-Market Surveillance Plan: Given gadolinium retention signals across the class, a pharmacovigilance plan aligned with MHC/HSA requirements should be prepared.

Research Disclaimer: This report is for research reference only and does not constitute medical advice. All drug repurposing candidates require clinical validation before application.

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.