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.     

Comparison of mathematical methods for calculating colonic compliance in humans: power exponential, computer-based and manual linear interpolation models

Abstract  Measuring compliance allows differentiation of sensory changes from changes in thresholds because of altered compliance. As compliance of the colorectum is sigmoidal, a power exponential analysis was recommended. We aimed to develop and validate simpler measurements of compliance. Forty subjects (23 female, 17 male) underwent colonic barostat procedures comparing dronabinol vs placebo. Results of the effects on compliance were reported elsewhere. Compliance was determined as volume response to pressures ranging from 0 to 36 mmHg. Pressures corresponding to 10%, 50% and 90% (Pr10, Pr50 and Pr90) of maximum volume at 36 mmHg were estimated using a power exponential model, computer-based and manual linear interpolation. Data were compared and concordance evaluated. Pr50 and Pr90 were not significantly different by all methods for baseline and post-treatment. Respectively, concordance correlation coefficients were: pretreatment, 0.879, 0.464 and post-treatment, 0.879, 0.623. There is larger variation in Pr10 comparing all methods and manual calculations allow for the closest fit to the data. Concordance correlation coefficients were pretreatment = 0.189 and post-treatment = 0.322. There were no gender differences in compliance measurements. Results of compliance are highly concordant amongst all models. However, computer-based or manual interpolations appear superior to power exponential models for estimating Pr10.     

Brain activation responses to subliminal or supraliminal rectal stimuli and to auditory stimuli in irritable bowel syndrome

Visceral hypersensitivity in irritable bowel syndrome (IBS) has been associated with altered cerebral activations in response to visceral stimuli. It is unclear whether these processing alterations are specific for visceral sensation. In this study we aimed to determine by functional magnetic resonance imaging (fMRI) whether cerebral processing of supraliminal and subliminal rectal stimuli and of auditory stimuli is altered in IBS. In eight IBS patients and eight healthy controls, fMRI activations were recorded during auditory and rectal stimulation. Intensities of rectal balloon distension were adapted to the individual threshold of first perception (IPT): subliminal (IPT -10 mmHg), liminal (IPT), or supraliminal (IPT +10 mmHg). IBS patients relative to controls responded with lower activations of the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) to both subliminal and supraliminal stimulation and with higher activation of the hippocampus (HC) to supraliminal stimulation. In IBS patients, not in controls, ACC and HC were also activated by auditory stimulation. In IBS patients, decreased ACC and PFC activation with subliminal and supraliminal rectal stimuli and increased HC activation with supraliminal stimuli suggest disturbances of the associative and emotional processing of visceral sensation. Hyperreactivity to auditory stimuli suggests that altered sensory processing in IBS may not be restricted to visceral sensation.     

Influence of clinical parameters on the results of 13C-octanoic acid breath tests: examination of different mathematical models in a large patient cohort

Abstract It is assumed, although not proven, that ¹³CO₂‐excretion following ingestion of ¹³C‐octanoic acid (¹³C‐OA) does not only depend on gastric emptying (GE) but also on absorption and metabolism of ¹³C‐OA and endogenous CO₂‐production. Our aims were (i) to test the effects of patient characteristics and of diseases that may impair ¹³C‐OA‐metabolism on GE parameters. (ii) To compare different GE endpoints. Therefore, we investigated effects of age, gender, BMI and diseases with potential impact on ¹³C‐OA‐metabolism (including pancreatic, liver and lung disease, diabetes, IBD) on cumulative 4h‐¹³CO₂‐excretion (4h‐CUM) and T½ calculated by non‐linear regression model (NL, determined by shape of breath test curve) and generalized linear regression model (GLR, reflects absolute ¹³CO₂‐excretion) in 1279 patients and 19 healthy controls who underwent a standardized ¹³C‐OA‐breath test. Digestive and metabolic disturbances hardly influenced 4h‐CUM or T½ calculated by NL or GLR models. In the multivariate linear regression models, 4h‐CUM was significantly predicted by diabetes adjusted for age, gender and IBD but influence of these parameters was small (R² = 0.028, P < 0.0001). T½_NL and 4h‐CUM were weakly correlated, even after exclusion of tests with unrealistically high estimates for T½_NL (n = 1095, R² = 0.029, P < 0.0001). Conversely, 4h‐CUM was closely associated with T½_GLR (exponential correlation, R² = 0.774, P < 0.00001, n = 1279). We conclude that influences of digestive and metabolic disturbances on ¹³CO₂‐excretion following ¹³C‐OA‐application are generally low. Thus, our findings resolve an important criticism of methods using absolute ¹³CO₂‐excretion for evaluation of ¹³C‐OA‐breath tests and suggest that such models may correctly identify T½ in a mixed patient population.     

Challenges in drug development for functional gastrointestinal disorders. Part II: Visceral pain

There is a need to have predictive biomarkers to test novel experimental medicines in functional gastrointestinal disorders. The human pharmacodynamic models and biomarkers pertaining to two important conditions are reviewed in a two-part article: functional dyspepsia (part I) and visceral pain (part II). With visceral pain models, the large coefficient of variation in sensation end points in human studies precludes definitive conclusions such as go/no go decisions or dose selection for phase IIb or III studies, unless very large numbers of patients are evaluated in phase IIA pharmacodynamic studies. This renders such pharmacological studies ambitious, or unachievable in a timely fashion. Moreover, the results of tests and clinical trials should be interpreted with greater knowledge of the drug pharmacokinetics, including the influence of CYP metabolism and potential drug interactions. Thus, it is important to identify valid biomarkers of visceral pain for the assessment of treatment response in pharmacodynamic studies. In this second part of a two-part article, we shall discuss the special challenges in developing medications for visceral pain and the general importance of including pharmacokinetic and pharmacogenomic studies in drug development programmes.