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In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug together with food can result in highly variable drug plasma concentrations, which may affect the efficacy and safety of the pharmacotherapy. In this work, the pharmacokinetic (PK) data obtained from two fed-state bioequivalence studies with the immediate release (IR) drug products Viagra (sildenafil) and Adenuric (febuxostat) have been analyzed. This evaluation revealed that basically three characteristic types of onset behaviors of drug plasma concentration can be distinguished. It was hypothesized that the different types of onset behaviors were mainly caused by the interplay between gastric drug dissolution and gastric emptying. To study this interplay in vitro, a biopredictive dissolution toolGastroDuowas developed and used for both drug products. Therefore, three different test programs have been applied to simulate certain aspects of the postprandial human stomach, which included dynamic pH changes, gastric peristalsis, and the kinetics of gastric emptying. Specifically, the behavior of noncaloric fluids by the so-called "Magenstrasse" was taken into deeper consideration. The experiments revealed that the dissolution and emptying behavior of the two drug products were affected in different ways by the three test programs. The in vitro data nicely explained the tendencies of the drug products for certain types of onset behaviors observed in the PK data. While Viagra was strongly affected by simulated peristalsis, Adenuric was more sensitive to the simulated emptying kinetics. This work clearly demonstrated the important role of gastric fluid emptying for the onset of drug plasma concentration after oral administration of IR formulations in the fed state. Moreover, this was the first study in which GastroDuo was applied as a biopredictive in vitro model which is able to simulate crucial parameters of the human stomach (e.g., pH profiles and gastric emptying) in a realistic manner.

Drug absorption following oral administration is determined by complex and dynamic interactions between gastrointestinal (GI) physiology, the drug, and its formulation. Since many of these interactions are not fully understood, the COST action on “Understanding Gastrointestinal Absorption-related Processes (UNGAP)” was initiated in 2017, with the aim to improve the current comprehension of intestinal drug absorption and foster future developments in this field. In this regard, in vivo techniques used for the characterization of human GI physiology and the intraluminal behavior of orally administered dosage forms in the GI tract are fundamental to gaining deeper mechanistic understanding of the interplay between human GI physiology and drug product performance. In this review, the potential applications, advantages, and limitations of the most important in vivo techniques relevant to oral biopharmaceutics are presented from the perspectives of different research fields.

The fasted state administration of immediate release (IR) dosage forms is often regarded as uncritical since physiological aspects seem to play a minor role for disintegration and drug release. However, recent in vivo studies in humans have highlighted that fasted state conditions are in fact highly dynamic. It was therefore the aim of this study to investigate the disintegration and drug release behavior of four different IR formulations of the probe drug caffeine under physiologically relevant conditions with the aid of the GastroDuo. One film-coated tablet and three different capsule formulations based on capsule shells either made from hard gelatin or hydroxypropylmethyl cellulose (HPMC) were tested in six different test programs. To evaluate the relevance of the data generated, the four IR formulations were also studied in a four-way cross-over study in 14 healthy volunteers by using the salivary tracer technique (STT). It could be shown that the IR formulations behaved differently in the in vitro test programs. Thereby, the simulated parameters affected the disintegration and dissolution behavior of the four IR formulations in different ways. Whereas drug release from the tablet started early and was barely affected by temperature, pH or motility, the different capsule formulations showed a longer lag time and were sensitive to specific parameters. However, once drug release was initiated, it typically progressed with a higher rate for the capsules compared to the tablet. Interestingly, the results obtained with the STT were not always in line with the in vitro data. This observation was due to the fact that the probability of the different test programs was not equal and that certain scenarios were rather unlikely to occur under the controlled and standardized conditions of clinical studies. Nonetheless, the in vitro data are still valuable as they allowed to discriminate between different formulations.

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