Magazine Article | October 1, 2009

Imaging Methods In Drug Development

Source: Life Science Leader

By Dr. Mehdi Adineh

Medical imaging is utilized in all phases of drug development. Imaging results can help determine disease diagnosis, treatment, prognosis, progression, and outcomes. In an early phase trial, imaging can evaluate a drug’s mechanism of action and activity against the target pathology. In a late phase trial, imaging results can serve as primary or secondary endpoints.

Traditional (i.e. anatomic or structural) imaging methods, including radiography, computed tomography (CT), and magnetic resonance imaging (MRI), have long been used in clinical trials. Novel imaging techniques, such as positron emission tomography (PET), dynamic contrast enhanced MRI (DCE-MRI), and magnetic resonance spectroscopy (MRS), have recently emerged as useful modalities.

Traditional Imaging In Clinical Trials
Radiography (X-ray) produces 2-D images highlighting bone and joint conditions. X-rays serve as biomarkers in some orthopedic and rheumatologic studies. Comprised of multiple cross-sectional views, CT best evaluates muscle, bone, tumors, cancer, heart disease, infections, and blood clots. Displaying detailed cross-sectional anatomical images, MRI showcases abnormalities of the spine, bone and joints, abdomen, brain, and blood vessels.

Despite providing excellent anatomical information, these techniques are limited as biomarkers. As an indicator of antitumor drug efficacy, anatomic measurements are highly variable and have an uncertain correlation with clinical outcomes. Novel imaging methods provide information about drug effects in vivo. These mechanistic (i.e. functional or molecular) techniques offer insight into drug activity and efficacy for better decision making in clinical trials.

Functional Imaging In Clinical Trials
While traditional imaging obtains anatomical pictures, functional imaging assesses physiological, cellular, or molecular processes. It has improved our ability to detect and stage tumors, select and monitor treatment, gauge prognosis, and measure outcomes. Functional imaging techniques have emerged as attractive biomarkers.

PET imaging has the potential to overcome many of the shortcomings mentioned previously regarding anatomical imaging. PET uses diagnostic radiotracers to measure the metabolic rates of normal and abnormal tissues. More recently, combined PET/CT scanners have been introduced and have become the imaging modality of choice for molecular imaging. PET/CT scanners acquire simultaneous mechanistic and structural images for precise correlation between physiology and anatomy. Widely utilized in oncology, PET also has proven or potential applications in neurology, neuropsychology, psychiatry, and cardiology.

PET allows repeated investigation of the same subjects in preclinical trials, which improves statistical data quality. Pharmacokinetic PET studies investigate drug uptake, binding, receptor affinity, tissue concentration, and elimination. PET can determine how well a drug reaches its target and inhibits target activity. Other clinical trial applications include assessment of tumor blood flow, hypoxia, DNA synthesis, and apoptosis.

Oncology studies typically feature PET with 18F-fluorodeoxyglucose (FDG) because most malignant tumors exhibit increased glucose metabolism. Cancer staging via FDG-PET is often conducted to ensure accurate patient registration. An early biomarker of effective treatment, decreased FDG uptake with anti-tumor therapy precedes measurable tumor shrinkage. FDG-PET can demonstrate drug activity across a spectrum of tumors and help determine maximum tolerated dose. FDG-PET results can support trial discontinuation based upon poor treatment response.

Perfusion-based DCE-MRI tracks the entrance of diffusible contrast agents into tissue. Because tumors elicit angiogenic factors to spur blood vessel growth, vascular destructive agents can be effective anti-tumor therapies. DCE-MRI estimates tumor blood flow by the rate of contrast accumulation. During trials for vascular-targeted therapy, DCE-MRI measures vascular response to the drug and the longevity of anti-tumor effect. Demonstrating vascular changes before anatomical imaging shows tumor shrinkage: DCE-MRI allows earlier assessment of drug efficacy.

Analyzing the magnetic properties of chemical compounds, MRS assigns a unique biochemical signature to each tissue type. Whereas MRI identifies tumor location, MRS defines a tumor’s biochemical profile. MRS has proven useful for the evaluation of brain and liver abnormalities, including cancer, metabolic disorders, epilepsy, Parkinson’s disease, and Huntington’s chorea. MRS is gaining ground in its utility in various stages of drug discovery.

Determining efficacy early in the drug development process, medical imaging saves time and money. While traditional imaging has a role in clinical trials, functional imaging methods are proving themselves as reliable biomarkers in medical studies. Mechanistic imaging reveals drug efficacy before anatomical changes become measurable. It is noninvasive and more practical than serial biopsy. With the potential to investigate countless physiological processes, functional imaging has a promising future in drug development.

Dr. Mehdi Adineh is the scientific director of the core laboratory of the American College of Radiology (ACR). The core laboratory is key to both the National Cancer Institute-sponsored clinical trials conducted by the ACR Imaging Network (ACRIN), as well as ACR Image Metrix, which conducts multicenter clinical trials for pharma and biomedical industries.