Using imaging with gadoxetate to non-invasively assess liver function in clinical trials
Chronic liver diseases are characterised by decreased hepatic function resulting from inflammation, cholestasis and/or fibrosis. In many chronic liver diseases, diagnosis, staging of severity and assessment of treatment responses is done via liver biopsy. Liver biopsies are invasive, costly and pose a risk of complications for patients, and due to heterogeneity in the liver, they are also susceptible to sampling bias. It is also widely known that there is a significant risk of inter-observer variability in histopathological assessments. For all these reasons, liver biopsies are not well suited for repeated longitudinal assessments.
Research activity in chronic liver disease is high, and there are many clinical trials in this space, so there is an unmet need for non-invasive biomarkers to replace or limit the need for liver biopsy. There is also a need for biomarkers that enable assessment of liver function, the way that ejection fraction and creatinine are used in the heart and kidney, respectively. Currently available plasma biomarkers and the various proposed composite scores which combine them with clinical parameters, are not sensitive/specific enough and are possibly confounded by a wide range of extrahepatic disorders [1]. In drug development it is often necessary to detect and quantify changes in a small number of patients and over short time periods, and gadoxetate imaging offers a potential solution to non-invasively assess liver function.
Gadoxetate - a liver-specific MR contrast agent
Gadoxetic acid is a magnetic resonance (MR) contrast agent (Gd-EOB-DTPA, sold as Primovist® in the EU and Eovist® in the US) approved for detecting and differentially diagnosing focal liver lesions. In addition to this, it has been used off-label as a non-investigational medicinal product to quantify changes in hepatocellular function and liver perfusions in drug development for chronic liver diseases. At Antaros Medical we use gadoxetate-MRI endpoints to measure liver function, in addition to structural or morphological changes. Functional changes can provide insights in shorter trials earlier than it can take for structural changes to occur. Gadoxetate is actively taken up by the hepatocytes and excreted via the biliary system.
What we can see with imaging
The uptake and excretion of gadoxetate is regulated by various transmembrane transporters on the hepatocytes. The uptake and excretion of gadoxetate is influenced by the relative expression and activity of these transmembrane transporters, and also by the total number of hepatocytes [1,3]. In chronic liver disease, this is typically lower when compared to a healthy liver, due to either decreased expression of OATP1B1/OATP1B3, or reduced function of the transporters, or as the presence of fibrosis and cirrhosis can result in the loss of hepatocytes.
Gadoxetate-enhanced MRI is measuring the effect that gadoxetate is having on the relaxation of the water signal in the image, and this can be done using both static and dynamic imaging protocols. Depending on the protocol, a variety of parameters can be calculated depending on the research question of interest and the indication.
Figure 2: Baseline MRI (left) and 20 minutes after injection of gadoxetate (hepatobiliary phase) (right) showing liver enhancement and appearance of gadoxetate in the bile ducts.
To give some examples, the relative enhancement of the liver seen after injection of gadoxetate can suggest improved hepatocyte function. Parameters such as relative enhancement can also be used to differentiate between stages of fibrosis. Or a parameter like time to arrival in the bile duct, when decreased, could suggest improved bile flow. Several parameters for transporter activity can be derived from compartmental modelling, where the signal intensity in different regions of interest (ROIs) are then used to calculate things like liver perfusion.
- Some of the parameters that can be calculated from gadoxetate-MRI are:
- Relative Enhancement (RE): balance between rate of uptake and the rate of excretion. Has been associated linearly with fibrosis.
- Time to appearance (TTA): looking at the time for GA to appear in a specific location such as the bile duct, gallbladder, at the junction between the left and right bile or hepatic ducts, or at the junction with the duodenum.
- Compartmental modelling: uses complex mathematics and takes signals from blood flow and the liver to calculate liver perfusion, extracellular space, rate of uptake, and rate of excretion
Implementing gadoxetate-enhanced MRI in clinical trials
Gadoxetate-enhanced MRI is a valuable tool for assessing liver function in clinical trials, a currently unmet need in chronic liver disease. At Antaros Medical we are working with gadoxetate across several projects. We have also previously conducted our own internal method development study using gadoxetate-MRI. We are also collaborating as part of the Translational Imaging in Drug Safety Assessment project (TRISTAN) consortium to better understand changes in liver transporter flux.
References
[1] Quantification of liver function using gadoxetic acid-enhanced MRI. Poetter-Lang et al. Abdominal Radiology. 2020
[2] Primovist, Eovist: What to expect? Van Beers et al. J Hepatology. 2012.
[3] Hepatic Gadoxetic Acid Uptake as a Measure of Diffuse Liver Disease: Where Are We?. Ba-Ssalamah et al. J Magnetic Resonance Imaging. 2016.