Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants

Abstract

Objective: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method.

Material and methods: Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later.

Results: Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence.

Conclusion: Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes.

Clinical trial: This trial was registered at ClinicalTrials.gov as NCT03191045.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: the author AM is the CEO of Motilent Limited.

Figures

Fig 1. Study diagram.

Schematic diagram of the study day timeline.

Fig 2. Image analysis.

Example of MRI data analysis. The stomach wall boundaries and the axis of the stomach are shown in green. The yellow lines represent the lumen diameter perpendicular to the stomach axis. AC, ascending colon; TC, transverse colon; GB, gall bladder.

Fig 3. MRI and manometry plots.

Examples of MRI gastric antral motility plots (in red) and corresponding perfused manometry traces (in blue) from different participants, during antral contractions (A and B) and quiescence (C).

Fig 4. Comparison of MRI and manometry mean area under the curves.

Mean (± SEM) values of manometry AUC for each participant plotted against the corresponding mean MRI AUC (n = 15) during one of the visits (Pearson’s correlation coefficient, r = 0.860).

Fig 5. Comparison of MRI and manometry individual area under the curves.

Scatter plot of individual values of MRI antral motility for each 3.5 min imaging block AUC and the corresponding 3.5 min perfused manometry motility AUC for all participants, thereby providing n = 421 data points (Pearson’s correlation coefficient, r = 0.843).

Fig 6. Time courses of gastric antral motility.

Time courses of the area under the curve of gastric antral contractile activity observed with MRI (solid line) and water-perfused manometry (dotted line) aggregated for all subjects at consecutive intervals (mean ± SD).