The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group.

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.

Combined Application of MRI and the Salivary Tracer Technique to Determine the in Vivo Disintegration Time of Immediate Release Formulation Administered to Healthy, Fasted Subjects.

The process of disintegration is a crucial step in oral drug delivery with immediate release dosage forms. In this work, the salivary tracer technique was applied as a simple and inexpensive method for the investigation of the in vivo disintegration time of hard gelatin capsules filled with caffeine. The disintegration times observed with the salivary tracer technique were verified by magnetic resonance imaging (MRI). After an overnight fast of at least 10 h and caffeine abstinence of minimum 72 h, conventional hard gelatin capsules containing 50 mg caffeine and 5 mg iron oxide were administered to 8 healthy volunteers. For the period of 1 h after capsule intake, subjects were placed in supine position in the MRI scanner, and scans were performed in short time intervals. Each MRI measurement was directly followed by saliva sampling by drooling. Salivary caffeine concentrations were determined by high performance liquid chromatography followed by mass spectrometric detection (LC/MS-MS). The time point of capsule disintegration was determined by visual inspection of the MR images as well as by an increase in the salivary caffeine concentration. The results indicated that the difference in mean disintegration times of the capsules as determined by the two in vivo methods was around 4 min (8.8 min for MRI vs 12.5 min for saliva). All disintegration times determined by the salivary tracer technique were slightly higher. This delay could be explained by the fact that the appearance of caffeine in saliva required drug absorption in the small intestine. Because capsule disintegration happened mainly in the stomach, the exact site of disintegration as well as the processes of gastric mixing and gastric emptying contributed to the delay between the two methods. This work demonstrated the feasibility of the salivary tracer technique to investigate the in vivo disintegration of immediate release dosage forms in a simple and reliable manner.

In vitro models for the prediction of in vivo performance of oral dosage forms: Recent progress from partnership through the IMI OrBiTo collaboration.

The availability of in vitro tools that are constructed on the basis of a detailed knowledge of key aspects of gastrointestinal (GI) physiology and their impact on formulation performance and subsequent drug release behaviour is fundamental to the success and efficiency of oral drug product development. Over the last six years, the development and optimization of improved, biorelevant in vitro tools has been a cornerstone of the IMI OrBiTo (Oral Biopharmaceutics Tools) project. By bringing together key industry and academic partners, and by linking tool development and optimization to human studies to understand behaviour at the formulation/GI tract interface, the collaboration has enabled innovation, optimization and implementation of the requisite biorelevant in vitro tools. In this paper, we present an overview of the in vitro tools investigated during the collaboration and offer a perspective on their future use in enhancing the development of new oral drug products.

Low dose caffeine as a salivary tracer for the determination of gastric water emptying in fed and fasted state: A MRI validation study.

Improving our knowledge about human gastrointestinal physiology and its impact on oral drug delivery is crucial for the development of new therapies and effective drug delivery systems. The aim of this study was to develop an in vivo tool to determine gastric emptying of water by administration of a caffeine as a tracer substance followed by subsequent saliva caffeine analysis. For this purpose, 35 mg of caffeine were given to six healthy volunteers after a 10 h overnight together with 240 mL of tap water either on a fasted stomach or 30 min after the high-caloric, high-fat breakfast recommended for bioavailability/bioequivalence (BA/BE) studies. Caffeine was administered in form of an ice capsule in order to omit the contamination of the oral cavity with caffeine. Parallel to saliva sampling, magnetic resonance imaging (MRI) was applied in order to validate this novel approach. After administration of the ice capsule, MRI measurements were performed every 2 min for the first 20 min followed by further measurements after 25, 30, 35, 40, 50 and 60 min. Saliva samples were collected always 1 min after the MRI measurement in supine position in the MRI scanner and continued for further 240 min. The caffeine concentration in saliva was quantified after liquid-liquid extraction by a validated HPLC/MS-MS method. The obtained MRI data revealed a fast emptying of the co-administered water within 10 to 50 min in the fasted state and likewise in the fed state. Salivary caffeine kinetics showed a Cmax from 150 to 400 ng/mL with a tmax from 20 to 90 min. MRI data were normalized by setting the maximum emptied volume to 100% and the salivary caffeine kinetics were normalized by setting Cmax to 100%. In order to compare the results obtained by the MRI and the saliva method, the normalized data for each volunteer was correlated based on a linear regression. In the fasted state the mean slope for six comparisons was 0.9114 ±â€¯0.1500 and the mean correlation coefficient was 0.912 ±â€¯0.055. In the fed state, a mean slope of 0.8326 ±â€¯0.1630 and a mean correlation coefficient of 0.887 ±â€¯0.047 were obtained. Based on these results, we could show that salivary caffeine concentrations are suitable to describe the emptying of water as a non-caloric liquid from the fasted and the fed stomach. The presented technique provides a straight-forward, inexpensive and noninvasive method to assess gastric emptying of hydrophilic liquids, which can be broadly used in oral biopharmaceutics. Possible applications are the characterization of real-life conditions, specific populations (e.g. elderly people) and the better understanding of the contribution of gastric emptying to pharmacokinetic profiles of orally administered drugs.

Effect of Coadministered Water on the In Vivo Performance of Oral Formulations Containing N-Acetylcysteine: An In Vitro Approach Using the Dynamic Open Flow-Through Test Apparatus.

The drug plasma profile after oral administration of immediate release dosage forms can be affected by the human gastrointestinal physiology, the formulation, and the drug itself. In this work, we investigated the in vivo and in vitro performance of two formulations (granules vs. tablet) containing the highly soluble drug N-Acetylcysteine (BCS class I). Thereby, special attention was paid to the effect of the dosage form and the coadministration of water on drug release. Interestingly, the in vivo results from a pharmacokinetic study with 11 healthy volunteers indicated that the drug plasma concentrations were comparable for the tablet given with water as well as for the granules given with and without water. In order to mechanistically understand this outcome, we used a biorelevant dissolution test device, the dynamic open flow-through test apparatus. With the aid of this test apparatus, we were able to simulate biorelevant parameters, such as gastric emptying, hydrodynamic flow as well as physical stress. By this, it was possible to mimic the intake conditions of the clinical trial (i.e., drug intake with and without water). Whereas the experiments in the USP paddle apparatus revealed differences between the two formulations, we could not observe significant differences in the release profiles of the two formulations by using the dynamic open flow-through test apparatus. Even by considering the different intake conditions, drug release was slow and amounted to around 30% until simulated gastric emptying. These results suggest that dissolution was irrespective of coadministered water and the formulation. Despite the high aqueous solubility of N-Acetylcysteine, the limiting factor for drug release was the slow dissolution rate in relation to the gastric emptying rate under simulated gastric conditions. Thus, in case of administration together with water, large amounts of the drug are still present in the stomach even after complete gastric emptying of the water. Consequently, the absorption of the drug is largely controlled by the nature of gastric emptying of the remaining drug. The data of this study indicated that the water emptying kinetics are only determining drug absorption if drug release is rapid enough. If this is not the case, physiological mechanisms, such as the migrating motor complex, play an important role for oral drug delivery.

Navigating the human gastrointestinal tract for oral drug delivery: Uncharted waters and new frontiers.

Many concepts of oral drug delivery are based on our comprehension of human gastrointestinal physiology. Unfortunately, we tend to oversimplify the complex interplay between the various physiological factors in the human gut and, in particular, the dynamics of these transit conditions to which oral dosage forms are exposed. Recent advances in spatial and temporal resolution of medical instrumentation as well as improved access to these technologies have facilitated clinical trials to characterize the dynamic processes within the human gastrointestinal tract. These studies have shown that highly relevant parameters such as fluid volumes, dosage form movement, and pH values in the lumen of the upper GI tract are very dynamic. As a result of these new insights into the human gastrointestinal environment, some common concepts and ideas of oral drug delivery are no longer valid and have to be reviewed in order to ensure efficacy and safety of oral drug therapy.