Jens Van Den Abeele

Gastrointestinal Behavior of Weakly Acidic BCS Class II Drugs in Man--Case Study of Diclofenac Potassium.

This study aimed to investigate the gastrointestinal supersaturation and precipitation behavior of a weakly acidic Biopharmaceutics Classification System (BCS) Class II drug in healthy volunteers. For this purpose, a tablet containing 50 mg diclofenac potassium (Cataflam(®)) was predissolved in 240 mL of water and this solution was subsequently orally administered to five healthy volunteers under fasted and fed state conditions with or without concomitant use of a proton-pump inhibitor (PPI) (40 mg esomeprazole, Nexiam(®)). Subsequently, total diclofenac content and dissolved intraluminal drug concentrations as well as drug thermodynamic solubility were determined in gastrointestinal aspirates. In all volunteers, gastric supersaturation resulted in precipitation of diclofenac in the stomach. The extent of precipitation correlated well with gastric pH (r = - 0.78). pH dependency of precipitation was corroborated by the absence of precipitate in the stomach after coadministration of a meal and/or a PPI. Diclofenac was found to be fully dissolved in the duodenum in all test conditions. It can be concluded that substantial pH-dependent gastric precipitation of a weakly acidic BCS Class II drug administered as a solution occurs in humans. With regard to its implications for intestinal absorption, results suggest the instantaneous redissolution of gastric drug precipitate upon transfer to the duodenum.

The dynamic gastric environment and its impact on drug and formulation behaviour

Before being absorbed in the small intestine and/or colon, orally administered drugs inevitably need to pass through the stomach. Hence, it seems reasonable that the residence of a dosage form in the gastric environment, however brief it may be, may influence drug disposition further down the gastrointestinal tract and may potentially impact systemic exposure to a drug of interest. However, research efforts in the past mainly focused on drug disposition at the level of the intestine, i.e. the main site of absorption, hereby disregarding or oversimplifying the stomachs contribution to gastrointestinal drug disposition. In the first part of this review, the complexity of the stomach with regard to anatomy, physiology and gastric fluid composition is emphasized. Between-population differences in gastric functioning and physicochemical characteristics of gastric fluids are discussed. The second part of this review focuses on several of the processes to which a dosage form can be exposed during its passage through the stomach and the implications for gastrointestinal drug behaviour and systemic drug disposition. Finally, the influence of real-life dosing conditions on drug disposition is discussed in the context of the stomach.

Exploring the link between gastric motility and intragastric drug distribution in man

Graphical abstract Figure. No caption available. Abstract In drug development, the stomach is often considered to be a simple, one‐compartmental organ, a waiting room for transfer of an orally administered dosage form to the duodenum. However, factors such as gastric acidity and hydrodynamics in the gastric environment may influence drug disposition. Although a link between gastrointestinal drug behaviour and gastric motility has often been hypothesized, they have not been simultaneously investigated in humans yet. In this proof‐of‐concept study, the combination of a well‐established intraluminal sampling technique with high‐resolution manometric measurements in the gastrointestinal tract was evaluated. This new combination of in vivo techniques proved to be feasible from a practical point of view and yielded valuable additional information regarding intraluminal drug behaviour. As a first application, the link between fasted state gastric motility and (in)homogeneous distribution of an orally administered drug in the stomach was investigated in healthy subjects. To this end, drug concentrations were measured in different regions of the stomach after oral administration of a commercially available drug product (Gabbroral®, 250 mg paromomycin) during a specific period of gastric contractile activity. A clear trend towards better mixing of an orally administered drug with gastric contents was observed when dosed in the presence of gastric contractions, resulting in a more homogeneous distribution of the drug throughout the stomach compared to dosing in the absence of gastric contractions.

Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools

This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated.

Gastric fluid composition in a paediatric population: Age-dependent changes relevant for gastrointestinal drug disposition

ABSTRACT This work aimed to (i) expand the dataset on gastric fluid composition in the paediatric population (0–18 years old) and (ii) improve our understanding of age‐dependent changes in gastric fluid characteristics involved in gastrointestinal drug disposition. For this purpose, gastric fluids from preterm neonates, term neonates, infants, children and adolescents were collected during routine medical procedures. Gastric fluid constituents relevant for gastrointestinal drug disposition were characterized i.e., pH, osmolality and bile salts (concentration + composition). Differences in gastric fluid composition compared to adults were most prominent in neonates. In this context, the fact that neonates are rarely fasted due to frequent feedings should be taken into account during paediatric drug product development. It remains to be explored to what extent the observed variability and differences in gastric fluid characteristics within and between age groups translates to variability and/or differences in oral drug disposition. Graphical abstract Figure. No Caption available.