Applications of Preclinical MRI/MRS in the Evaluation of Drug Efficacy and Safety

Abstract

The drug discovery process is a series of interrelated, bidirectional steps culminating in the declaration of an investigational new drug. Upon selection of a disease target and initiation of drug screening and chemistry efforts, secondary and tertiary assays to assess the efficacy and safety of potential lead candidates or develop biomarkers to demonstrate a pharmacologic response are initiated. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are well suited to assess drug mechanism of action, efficacy, and safety; to correlate PK/PD measures; and to provide clinically translatable biomarkers of drug action. While MRI is a sensitive measure of tissue structure, functional MRI (fMRI) approaches can be used to assess tissue composition, blood volume and flow, water diffusion, tissue biochemistry, and the consequence of drug intervention. MRI, fMRI, and pharmacological MRI (phMRI) have been used to monitor a broad range of structural and physiological changes in the body associated with disease, including neural network connectivity and neuronal activation/deactivation, atherosclerotic plaque size and composition, tumor vascularity and necrosis, joint cartilage degradation, synovitis, bone edema, and lung alveolar size and function. MRS has been used to assess global neurotransmitter changes, glucose and lipid metabolism associated with diabetes, and the energetic state and pH in muscle and tumors. MRI and MRS have been used in drug intervention studies across all therapeutic areas; however, there is scant utilization of MRI in the evaluation of drug safety despite its potential utility in measuring endpoints dynamically and assessing their reversibility. In summary, MRI and MRS have specific advantages; in that, anatomic changes can be monitored with high spatial resolution over the course of a disease and/or drug intervention. Furthermore, functional measures of a pharmacodynamic effect can be established to demonstrate that target engagement results in a pharmacologic response associated with drug efficacy. Keywords: in vivo imaging; MRI; MRS; drug efficacy; drug safety; preclinical