Magnetic Resonance Imaging in Pharmaceutical Safety Assessment
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Introduction. . . . . . . . . . . . . . . . . . . . Liver Volume Measurement . . . . Cardiac Hypertrophy . . . . . . . . . . Hepatic Steatosis . . . . . . . . . . . . . . .
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I.Q.1 Introduction ICI (now AstraZeneca) and Sandoz (now Novartis) introduced the first Magnetic Resonance Imaging (MRI) scanners into the pharmaceutical industry over twenty years ago. Most major pharmaceutical companies have since invested in in-house MRI for the evaluation of preclinical drug efficacy and most are now using MRI in clinical trials at extramural centres. MRI has been successful in the pharmaceutical industry for the same reasons that it is popular in clinical practice; it is a non-invasive imaging technique with superb soft tissue contrast capable of delivering quantitative 3D information on organ anatomy and function (Beckmann et al. 2004; Maronpot et al. 2004). Because it is non-invasive aside from the need to anaesthetise animals to immobilise them during image acquisition, animals can be imaged on multiple occasions and studies can be designed so that each animal serves as its own control increasing the statistical power of experiments and allowing group sizes to be reduced. However, despite penetration into preclinical and clinical drug efficacy studies, there are relatively few reports of the use of MRI in drug safety studies. Toxicology accounts for approximately one third of attrition in development and is thus a major cost in the pharmaceutical industry. MRI is a powerful tool that could potentially be used to reduce attrition in the late pipeline where it is most expensive. It is important to understand why MRI has not been more widely used in the drug safety arena before describing in detail a few of the MRI assays appropriate for preclinical safety studies (which includes both toxicity and safety pharmacology studies).
There are three types of safety pharmacology studies conducted in the pharmaceutical industry, 1) single dose core portfolio preclinical safety studies conducted to Good Laboratory Practise (GLP); 2) supplemental studies of compound specific effects after chronic dosing that are conducted when results from the core battery of tests raise concern; and 3) ‘frontloading’ safety studies conducted in the drug discovery function with the aim of designing safety liabilities out of the lead compound series. The first type of study forms part of the legally required activities towards the registration of a pharmaceutical product. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) safety pharmacology guidelines recommend the use of unanaesthetised animals, which is incompatible with the standard MRI experiment in which animals are anaesthetised to prevent motion interfering with image quality. It is certainly feasible to habituate conscious animals to the MRI environment, however in practice the results may not warrant the effort involved. In addition, it is unlikely that MRI assays will repl
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