The physiological conditions of the gastrointestinal (GI) tract can largely affect the in vivo performance of orally administered dosage forms during bioavailability and bioequivalence studies. Various parameters within the GI tract such as pH value, pressure activity, temperature, transit times as well as composition of intraluminal contents can influence the liberation and extent of absorption of drug substances.
Work package 3 within the OrBiTo consortium sets as its goal to facilitate model development by providing approaches and data to better understand the in vivo systems and systems biology impacting drug formulation behavior and drug absorption. Thus new and established in vivo tools for better in vivo prediction of the in vivo dosage form behavior can be assessed.
Even today the effects of food on the dosage form in vivo are not well understood. It is obvious that this effect of food on the dosage form can be the result of changed GI conditions. Such effects by co-ingested food can be caused by various reasons such as the delay of gastric emptying, the enhancement of solubility, the binding to food components, or the change of GI pH values and can contribute to the (unwanted) intra- and inter-individual variability of response to drug therapy.
In the present study*, temperature, pH and pressure profiles of nine healthy human volunteers were investigated after ingestion of the SmartPill® under clinical fasting conditions and compared to the same subjects who received the SmartPill® under fed conditions as recommended by the Food and Drug Administration (FDA). Since large non-digestible objects are mainly emptied during phase III of the interdigestive migrating motor complex, the gastric residence time of the SmartPill® was found to be clearly shorter under fasting conditions. Intragastric pH values during the initial 5 min were comparable with mean values of pH 4.2 under fasting and pH 4.6 under fed conditions. Interestingly, the lowest observed intragastric pH values in fasted state were about one pH unit higher than under fed conditions. Highest pressure activity was observed within the stomach, in relation to gastric emptying. In the fasted state, pressure values upon gastric emptying varied strongly between 30 mbar and 304 mbar, whereas in the fed state, values of at least 240 mbar could always be observed. The data showed highly variable gastrointestinal parameters even under clinical fasting conditions which must be considered when evaluating clinical studies and developing biorelevant in vitro test methods.
Figure: Pressure, pH and temperature profile of a subject obtained after fasted state (left) and fed state (right) ingestion of the SmartPill®. GE – gastric emptying, CA – colon arrival.
*Felix Schneider, Michael Grimm, Mirko Koziolek, Christiane Modeß, Anne Dokter, Tarek Roustom, Werner Siegmund and Werner Weitschies: Resolving the physiological conditions in bioavailability and bioequivalence studies: comparison of fasted and fed state. Submitted for publication