First established as a standard practice in clinics, in vivo imaging also benefits translational or preclinical research. For the past 25 years, many studies have relied on in vivo imaging as a method to quantify treatment response and gain early insights on efficacy. Now, as the technology advances, researchers can expect to benefit from greater spatial resolution and software advancements that allow faster, cost-effective translation of study results.
"Imaging often gives you unique information that can't be obtained any other way. The phenomena that you would observe preclinically may be the same disease state in the clinical trial," says Michael Cockman, Senior Scientist and Manager of the Imaging Center at Covance. "It's common to hear from a client who wants to test a type of imaging, called a modality, in a particular disease state to find out if it is appropriate for clinical development later."
Assessing the therapeutic efficacy or safety of compounds during and after treatment is an ideal application for in vivo imaging for many reasons. Noninvasive imaging techniques allow repetitive measurements in live animal models over the course of treatment. With high spatial resolution and inherent 3D techniques, in vivo imaging can characterize soft-tissue, measure bone density, or quantify perfusion.
Multiple modalities can be complementary. "Each imaging modality has its own strengths and weaknesses," says Cockman. "Depending on the disease of interest, we might use one or more." For example, in progressive osteoarthritis, the cartilage begins to degrade. As a result of the osteoarthritis, the surrounding bone density can increase, a condition called subchondral sclerosis.
Explains Cockman, "One might want to view and measure both the cartilage degeneration and sclerosis phenomenon. Magnetic resonance imaging (MRI) is an excellent soft tissue modality that visualizes the cartilage very well. With x-ray computed tomography (CT) the cartilage is difficult to see but one can look at underlying bone density. You really need both modalities to fully characterize the disease."
When clients call Covance about using a modality to answer a drug discovery or development question, Cockman's team can provide advice on several options with a leader for each imaging technology: MRI, CT, ultrasound, fluorescence, and dual-energy x-ray absorptiometry (DEXA).
In some cases, two completely different modalities might be appropriate. Cockman mentions a study examining renal insufficiency. To determine the effectiveness of a treatment, imaging can measure kidney perfusion to see how the blood distributes in addition to analyzing its flow. First, Doppler ultrasound can measure the velocity to see the rate of blood moving through arteries. Then, to analyze the subsequent distribution, fluorescence is employed. Tissues don't show much native fluorescence, so the animal receives an injection of a fluorescent probe. These coupled modalities can provide powerful study data.
"Today there is an amazing breadth of fluorescent probes for examining different functional and molecular processes." says Cockman. "If a client is interested in a particular enzyme within a tumor, it is likely that a fluorescent probe already exists. It can be injected and will fluoresce in the presence of the enzyme. This is true molecular imaging."
At Covance, the in vivo imaging services are well integrated into the overall study design to streamline the process and accelerate candidate selection. Cockman describes how studies can use imaging to triage or enroll animals in studies.
"Imaging is especially powerful in brain tumor studies. You'll need an imaging technique because tumors don't grow uniformly in animals. Say that 16 animals each received the same numbers of tumor cells. We will examine them with MRI five days later, but might see only 3 responders-the rest are not growing. We can exclude the non-responders from the study, which conserves test material and improves study statistics."
A faster turnaround time between exploration to discovery is also aided by data analysis. "We all know it's not good enough to collect the images," says Cockman. "We have to convert these into useful metrics."
Segmentation is the first step where the team identifies the region or pathology of interest. Now, with the growth of computing capabilities, automated image processing has sped up the analyses and provided greater quantitative information, such as how much a particular tumor shrank or the size of a bone fracture and its subsequent healing post therapy.
"Imaging doesn't stand alone," remarks Cockman. "It's a service that is integrated into overall study design." Other services include a formulation group to produce the test article, animal husbandry experts and veterinarians to oversee the models, a pathology group for evaluation of tissues, along with a pharmacology group that understands the appropriate animal models and therapeutic approaches. Coupled with specialized teams for biomarker discovery and genomics analysis, these integrated capabilities help identify candidates and enable rapid decisions.