The aim of the current study was (1) to develop an automation-based protocol for in vitro assessment of enzymatic drug stability at fasted- and fed-state intestinal conditions, (2) to characterize the inter-individual variability of drug degradation in fasted- and fed-state human intestinal fluids, and (3) to compare the obtained in vitro results to drug degradation in human intestinal fluids by taking variability into account. In human intestinal fluids, drug degradation displayed large inter-individual variability, with coefficients of variance generally ranging between 30 and 70 %. The effect of food on the inter-individual variability was highly dependent on the type of drug. The increase of pH in the range between 5.0 and 7.0 significantly accelerated the degradation rate of the studied drugs both in the in vitro and ex vivo experiments. In contrast, the increase of bile salt and phospholipid concentrations in the in vitro screen decreased strongly the degradation rate of the hydrophobic drugs. The developed automated in vitro screen mimicked relatively well the ex vivo degradation of all drugs in the fasted state, whereas in the fed state the degradation of only one of the drugs was adequately reproduced.

Previous research revealed marked differences in the composition of intestinal fluids between infants and adults. To explore the impact on the solubilization of orally administered drugs, the present study assessed the solubility of five poorly water-soluble, lipophilic drugs in intestinal fluid pools from 19 infant enterostomy patients (infant HIF). For some but not all drugs, the average solubilizing capacity of infant HIF was similar to that of HIF obtained from adults (adult HIF) in fed conditions. Commonly used fed state simulated intestinal fluids (FeSSIF(-V2)) predicted fairly well drug solubility in the aqueous fraction of infant HIF, but did not account for the substantial solubilization by the lipid phase of infant HIF. Despite similarities in the average solubilities of some drugs in infant HIF and adult HIF or SIF, the underlying solubilization mechanisms likely differ, considering important compositional differences (e.g., low bile salt levels). Finally, the huge variability in composition of infant HIF pools resulted in a highly variable solubilizing capacity, potentially causing variations in drug bioavailability. The current study warrants future research focusing on (i) understanding the mechanisms underlying drug solubilization in infant HIF and (ii) evaluating the sensitivity of oral drug products to interpatient variations in drug solubilization.

Food-drug interactions frequently hamper oral drug development due to various physicochemical, physiological and formulation-dependent mechanisms. This has stimulated the development of a range of promising biopharmaceutical assessment tools which, however, lack standardized settings and protocols. Hence, this manuscript aims to provide an overview of the general approach and the methodology used in food effect assessment and prediction. For in vitro dissolution-based predictions, the expected food effect mechanism should be carefully considered when selecting the level of complexity of the model, together with its drawbacks and advantages. Typically, in vitro dissolution profiles are then incorporated into physiologically based pharmacokinetic models, which can estimate the impact of food-drug interactions on bioavailability within 2-fold prediction error, at least. Positive food effects related to drug solubilization in the GI tract are easier to predict than negative food effects. Preclinical animal models also provide a good level of food effect prediction, with beagle dogs remaining the gold standard. When solubility-related food-drug interactions have large clinical impact, advanced formulation approaches can be used to improve fasted state pharmacokinetics, hence decreasing the fasted/fed difference in oral bioavailability. Finally, the knowledge from all studies should be combined to secure regulatory approval of the labelling instructions.

High plasma concentrations of cholesterol are associated with cardio-vascular disease complications and high risk of myocardial infarction. The absorption of dietary cholesterol depends on its bioaccessibility, which is in turn influenced by phytosterols, saponins and lipid digestion products. Therefore, we explored the interplay between phytosterols, Quillaja Dry saponin extract (QD), their combinations and lipid digestion on cholesterol bioaccessibility via an in vitro.