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

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 DOI 10.1002/jmri.24352 View this article online at wileyonlinelibrary.com. JOURNAL OF MAGNETIC RESONANCE IMAGING 39:1343–1345 (2014)