Challenges in drug development for functional gastrointestinal disorders. Part I: functional dyspepsia.

There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders (FGID). The human pharmacodynamic models and biomarkers in functional dyspepsia (part I) and visceral pain (part II) are reviewed, including the general challenges of these two disorders (part I). Part II will also discuss the importance of drug pharmacokinetics and potential of pharmacogenomics, including the influence of CYP metabolism and potential drug interactions. The great heterogeneity of mechanisms potentially responsible for dyspeptic symptoms adds a significant complexity to this FGID. Strategies are needed to identify subgroups most likely to benefit from a specific pharmacological action targeted to one or more mechanisms. Thus, while there are significant challenges in drug development for functional dyspepsia, there is still an important role for pharmacodynamic studies. It remains to be demonstrated that identifying subgroups enhances the response to the pharmacological drug effect. This is feasible as the end points and performance of each test of gastric emptying, accommodation and sensitivity are well characterized. Of these, gastric emptying appears best validated at present, though responsiveness to this biomarker has not yet been translated into positive phase III trials. Eligibility criteria are proposed for selection of patients for functional dyspepsia trials.