The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.

Oral administration is the most common route of drug delivery. The absorption of a drug from the gut into the bloodstream involves disintegration of the solid dosage form, dissolution of the active pharmaceutical ingredient and its transport across the gut wall. The efficiency of these processes is determined by highly complex and dynamic interplay between the gastrointestinal tract, the dosage form and the API. The European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) aims to improve our understanding of intestinal drug absorption by creating a multidisciplinary Network of researchers from academia and industry engaging in scientific discussions. As part of the basis for the UNGAP project, this review aims to summarize the current knowledge on anatomy and physiology of the human gastrointestinal tract with emphasis on human studies for the evaluation of the regional drug absorption and the prediction of oral dosage form performance. A range of factors and methods will be considered, including imaging methods, intraluminal sampling and, models for predicting segmental/regional absorption. In addition, in vitro and in silico methods to evaluate regional drug absorption will be discussed. This will provide the basis for further work on improving predictions for the in vivo behavior of drug products in the gastrointestinal tract.