Clinical Trial Issues Prokinetic Agents

Many technologies have been developed to enable the study of GI motility in the clinical setting, suitable for use in both healthy volunteers and patients. The 'gold standard' approach to the measurement of gastric emptying has involved the use of radioisotopes such as indium and technetium to label liquid and solid meal components followed by their detection using gamma scintigraphy. An alternative to this has been developed which negates the need for expensive gamma cameras and radioactivity. This uses 13C-labeled octanoate or acetate which is given orally, with the rate of gastric emptying being determined through the emergence of expired 13CO2. Strategies have been pursued to develop further nonnuclear techniques with which to determine gastric emptying. This has been driven by a desire to reduce the exposure of subjects to radiation and so facilitate repeated measurement of gastric emptying in the same individuals, so reducing variability. Such techniques have employed ultrasound4 and magnetic resonance imaging (MRI)5 and while these have been used to demonstrate the prokinetic effects of experimental compounds, these technologies have not yet been adopted widely.

However, MRI in particular offers the opportunity to study the regional distribution of test meals within the stomach and also the stimulation of regional motility by experimental drugs, for example in the gastric antrum. The measurement of intestinal motility in the clinic is more problematic. Rather than measuring motility directly, technologies have been developed to study the effects of drugs on the movement of material along the intestines, the so-called intestinal transit. Once again, the gold standard technique is to use a combination of radionuclides and scintigraphic recording and this can be applied to both the small and large bowel. Nonisotopic markers have been used much in the same way as in the stomach, with measurements of breath hydrogen following ingestion of a nonabsorbable carbohydrate, such as lactulose, being a useful index of orocecal transit time. The between- and within-subject variability of these techniques, together with the effects of gut function of the transit markers, needs to be fully understood. The continued reliance of radiographic measurements limits the number of investigations that can be carried out in an individual and so impacts the design of clinical trials of potential new prokinetics. Antiemetic Agents

The study of potential novel antiemetic agents in the clinic presents particular challenges. While the major utility of such agents in clinical medicine is to treat emesis resulting from treatment with chemo- and radiotherapy, for ethical reasons such emetogens are not suitable for studying in healthy volunteer populations. Consequently, models of emesis have been developed in healthy volunteers that use ipecacuanha or motion as the emetic stimulus. These strategies have been highly successful in identifying novel agents and clinically effective doses, as illustrated during the development of the 5HT3 receptor antagonists. Once NCEs progress to patients, then further considerations apply. Given that effective therapies exist, it is inappropriate to withhold treatment and so the opportunity to determine the efficacy of a novel antiemetic as a stand-alone treatment may be limited, if for example in early patient studies the level of control of emesis appears lower than that of current standard of care. Under these circumstances, experimental agents may need to be given in combination with established agents.

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