Gadolinium-based contrast agents: What does “single-dose” mean anymore?

Abstract

The introduction of gadolinium-based contrast agents (GBCAs) 25 years ago ushered in a new era of diagnostic capabilities for magnetic resonance imaging (MRI). GBCAs dramatically accelerate the rate of spin-lattice relaxation, ie, shorten T1 recovery of tissue water that is in close proximity to the gadolinium molecule. This leads to bright signal on T1-weighted images in regions of the tissue that the agent has reached. Clinical use of GBCAs includes a myriad of applications ranging from the depiction of normal anatomy to angiography, as well as the detection and characterization of tumors, infection, myocardial scar, and numerous other important applications. Indeed, contrast-enhanced MRI using GBCAs has become a central core of diagnostic imaging. Further, the increased relaxivity of transverse magnetization has led to important applications for dynamic susceptibility contrast imaging, particularly for cerebral perfusion. The first approved GBCA was gadopentetate dimeglumine (Magnevist, Bayer Healthcare, Berlin, Germany), approved in the United States in 1988. Several other agents rapidly followed including gadoteridol (ProHance, Bracco Diagnostics, Princeton, NJ), gadodiamide (Omniscan, GE Healthcare, London, UK), gadoversetamide (OptiMARK, Mallinckrodt Pharmaceuticals, St. Louis, MO), and more recently gadoterate meglumine (Dotarem, Guerbet, Villepinte, France) (Table 1). Often termed “extracellular fluid” (ECF) agents, these GBCAs have similar pharmacokinetics to iodinated contrast agents commonly used in CT applications, and all have similar relaxivity to each other 1, 2. Gadobenate dimeglumine (Multihance, Bracco Diagnostics, Wayne, NJ) is a high relaxivity agent with weak albumin binding and hepatobiliary excretion, approved for use in the U.S. in 2004. Although the pharmacokinetics and relaxivity are different than the ECF agents, gadobenate dimeglumine has the same approved dosing (0.1 mmol/kg) and concentration (0.5M). For the purposes of this editorial, I will refer to these agents as “traditional formulation agents.” A detailed comparison of the pharmacokinetics and relaxivity of the different GBCAs is beyond the purpose and scope of this editorial. As these traditional formulation agents all have the same approved dose and the same concentration, simplified terminology for dosing came into common parlance during the 1990s. Specifically, it became commonplace to use the terms “single-dose” when referring to 0.1 mmol/kg, “half-dose” referring to 0.05 mmol/kg, and “double-dose” referring to 0.2 mmol/kg, etc. 1, 2. Given the high safety profile of GBCAs, and the emergence of new applications such as MR angiography, many publications document the use of “double-dose” and even “triple-dose” administration of traditional formulation agents 3, 4. More recently, three nontraditional formulation GBCAs have been approved and are commercially available for clinical use. These agents include gadoxetic acid (Eovist/Primovist, Bayer Healthcare), gadofosveset trisodium (Ablavar/Vasovist, Lantheus Medical Imaging, North Billerica, MA), and gadobutrol (Gadavist/Gadovist, Bayer Healthcare). Approved in the U.S. in 2008, gadoxetic acid is an agent used primarily for hepatobiliary imaging. It has pharmacokinetics similar to ECF agents immediately after bolus injection, followed by rapid uptake into hepatocytes and subsequent excretion into bile. As listed in Table 1, the concentration of gadoxetic acid is lower than traditional formulation agents at 0.25 M, and the approved package insert dose is 0.025 mmol/kg, one-quarter that of traditional formulation agents. This dose was determined from the minimum effective dose for delayed hepatobiliary phase imaging for the detection and characterization of liver lesions, without regard to the enhancement characteristics of the dynamic phase. However, there is mounting evidence that demonstrates that 0.025 mmol/kg may be an insufficient dose for dynamic-phase imaging 5-7. For this reason, and for cost considerations, there is high variability of gadoxetic acid dosing among institutions ranging from 0.025–0.05 mmol/kg weight-based dosing, to straight volumetric dosing of 10 mL or 20 mL 6-9. The question then arises: does 0.025 mmol/kg of gadoxetic acid represent a “single-dose” or is this a “quarter-dose”? Is 0.05 mmol/kg a “half-dose” or a “double-dose”? Gadofosveset trisodium is another recently approved agent now available on the market. It is an intravascular contrast agent with indications for MR angiography in patients with known or suspected aorto-iliac disease, and has been approved in both Europe and the U.S. The approved package insert dose for gadofosveset is 0.03 mmol/kg and its concentration, like gadoxetic acid, is half that of traditional formulation agents, ie, 0.25 M. To complicate matters, early phase 1 and phase 2 studies reported results using gadofosveset at a dose of 0.05 mmol/kg 10, 11. Finally, in 2011 gadobutrol (Gadavist/Gadovist, Bayer Healthcare) was approved in the U.S. for imaging of the central nervous system. Gadobutrol is a high relaxivity ECF agent with an approved weight-based dosing of 0.1 mmol/kg, but unlike other agents, gadobutrol has a concentration twice that of traditional formulation agents, ie, 1.0 M, requiring a lower injection volume for the same gadolinium dose. Given the differences in concentrations, injection volumes, differences in recommended doses, and variability in dosing between different institutions and specialty applications, terminology becomes critically important. What does a “single-dose” mean anymore? For example, should we say that 0.05 mmol/kg of one agent (eg, traditional formulation agent) is a “half dose,” while the same number of gadolinium molecules of gadoxetic acid is a “double dose”? What is this dose for 0.05 mmol/kg of gadofosveset − 1.67× dose? Using the “single-dose” terminology leads to tremendous confusion. Further, this raises important safety issues because imprecise dosing terminology could lead to serious medical mistakes. One can easily envision how a request for “double-dose” gadoxetic acid could inadvertently translate into a dose of 0.2 mmol/kg, eight times its package insert dose. Differences in concentration between agents could also lead to confusion and possible incorrect dosing when switching between different GBCAs. Potential overexposure of a GBCA not only has diagnostic and cost implications but also raises very serious safety concerns, particularly in patients with renal failure who may be at increased risk for nephrogenic systemic fibrosis (NSF). I have heard several clinicians suggest the term of “standard dose” as a way to avoid confusion. For example, “double standard dose” for gadoxetic acid would refer to 0.05 mmol/kg. I would argue this still leaves room for ambiguity since the standard dose may vary between institution or application. Hence “standard dose” may not be sufficiently precise. Historically, imaging clinicians such as radiologists have prescribed GBCAs using the nominal “single dose,” etc. terminology, and are often not aware of the particular agent that they might be using. When the only available agents were the conventional ECF agents, all with the same dosing and similar relaxation parameters, this was of little consequence. With the introduction of gadobenate dimeglumine, the terminology did not change since the formulation of this agent is the same as conventional ECF agents. However, given the availability of specialty agents with different relaxivity and different dosing, it is now mandatory that the responsible physician understands the formulations of the different GBCAs available to them on formulary. Contrast agents are drugs, and the responsible physician must understand drug dosing, just as any other physician who prescribes antihypertensive agents, antibiotics, anticoagulants, or chemotherapeutic agents, etc. For these reasons, I believe strongly that in the interest of accuracy, safety, and overall good communication, that the terminology “single-dose,” etc., should be abandoned, and no longer used in clinical practice, publications, or in lectures. Such terminology is confusing and could lead to nondiagnostic scans in the best case through underdosing, and significant medical errors in the worst case through overdosing. Rather, when dosing a GBCA, it is essential to specify 1) the name of the agent, and 2) a weight-based dose (mmol/kg or mL/kg) or a volume-based dose (mL). If this information is not provided, the technologist should request clarification to ensure that the correct agent and correct dose is administered to the patient. As practitioners of MRI we are fortunate to have a broad and increasingly diverse choice of GBCAs to aid us is in the diagnosis and staging of many important diseases. The variability in the formulation and dosing of newer agents, however, now requires closer attention, including a universal understanding of GBCA dosing. Only in this way can we ensure a safe and effective administration of these important diagnostic drugs. Scott B. Reeder, MD, PhD Departments of Radiology, Medical Physics, Medical Biomedical Engineering, and MedicineUniversity of WisconsinMadison, WI