Contribution of the Dynamic Intestinal Absorption Model (Diamod) to the Development of a Patient-Centric Drug Formulation.

Compound X is a weak basic drug targeting the early stages of Parkinson's disease, for which a theoretical risk assessment has indicated that elevated gastric pH conditions could potentially result in reduced plasma concentrations. Different in vitro dissolution methodologies varying in level of complexity and a physiologically based pharmacokinetic (PBPK) absorption model demonstrated that the dissolution, solubility, and intestinal absorption of compound X was indeed reduced under elevated gastric pH conditions. These observations were confirmed in a crossover pharmacokinetic study in Beagle dogs. As a result, the development of a formulation resulting in robust performance that is not sensitive to the exposed gastric pH levels is of crucial importance. The dynamic intestinal absorption MODel (Diamod), an advanced in vitro gastrointestinal transfer tool that allows to study the gastrointestinal dissolution and interconnected permeation of drugs, was selected as an in vitro tool for the formulation optimization activities given its promising predictive capacity and its capability to generate insights into the mechanisms driving formulation performance. Different pH-modifiers were screened for their potential to mitigate the pH-effect by decreasing the microenvironmental pH at the dissolution surface. Finally, an optimized formulation containing a clinically relevant dose of the drug and a functional amount of the selected pH-modifier was evaluated for its performance in the Diamod. This monolayer tablet formulation resulted in rapid gastric dissolution and supersaturation, inducing adequate intestinal supersaturation and permeation of compound X, irrespective of the gastric acidity level in the stomach. In conclusion, this study describes the holistic biopharmaceutics approach driving the development of a patient-centric formulation of compound X.

Candida species-specific colonization in the healthy and impaired human gastrointestinal tract as simulated using the Mucosal Ileum-SHIME® model.

Candida species primarily exist as harmless commensals in the gastrointestinal tract of warm-blooded animals. However, they can also cause life-threatening infections, which are often associated with gut microbial dysbiosis. Identifying the microbial actors that restrict Candida to commensalism remains a significant challenge. In vitro models could enable a mechanistic study of the interactions between Candida and simulated colon microbiomes. Therefore, this study aimed to elucidate the spatial and temporal colonization kinetics of specific Candida, including C. albicans, C. tropicalis, and C. parapsilosis, and their relative Nakaseomyces glabratus, by using an adapted SHIME® model, simulating the ileum, and proximal and distal colons. We monitored fungal and bacterial colonization kinetics under conditions of eubiosis (commensal lifestyle) and antibiotic-induced dysbiosis (pathogenic lifestyle). Our findings highlighted the variability in the colonization potential of Candida species across different intestinal regions. The ileum compartment proved to be the most favourable environment for C. albicans and C. parapsilosis under conditions of eubiosis. Antibiotic-induced dysbiosis resulted in resurgence of opportunistic Candida species, especially C. tropicalis and C. albicans. Future research should focus on identifying specific bacterial species influencing Candida colonization resistance and explore the long-term effects of antibiotics on the mycobiome and bacteriome.

The Dynamic Intestinal Absorption Model (Diamod®), an in vitro tool to study the interconnected kinetics of gastrointestinal solubility, supersaturation, precipitation, and intestinal permeation processes of oral drugs.

This study aimed at developing the Diamod® as a dynamic gastrointestinal transfer model with physically interconnected permeation. The Diamod® was validated by studying the impact of the intraluminal dilution of a cyclodextrin-based itraconazole solution and the negative food effect for indinavir sulfate for which clinical data are available demonstrating that the systemic exposure was strongly mediated by interconnected solubility, precipitation, and permeation processes. The Diamod® accurately simulated the impact of water intake on the gastrointestinal behavior of a Sporanox® solution. Water intake significantly decreased the duodenal solute concentrations of itraconazole as compared to no intake of water. Despite this duodenal behavior the amount of permeated itraconazole was not affected by water intake as observed in vivo. Next to this, the Diamod® accurately simulated the negative food effect for indinavir sulfate. Different fasted and fed state experiments demonstrated that this negative food effect was mediated by an increased stomach pH, entrapment of indinavir in colloidal structures and the slower gastric emptying of indinavir under fed state conditions. Therefore, it can be concluded that the Diamod® is a useful in vitro model to mechanistically study the gastrointestinal performance of drugs.

Human Milk Oligosaccharides and Lactose Differentially Affect Infant Gut Microbiota and Intestinal Barrier In Vitro.

BACKGROUND: The infant gut microbiota establishes during a critical window of opportunity when metabolic and immune functions are highly susceptible to environmental changes, such as diet. Human milk oligosaccharides (HMOs) for instance are suggested to be beneficial for infant health and gut microbiota. Infant formulas supplemented with the HMOs 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT) reduce infant morbidity and medication use and promote beneficial bacteria in the infant gut ecosystem. To further improve infant formula and achieve closer proximity to human milk composition, more complex HMO mixtures could be added. However, we currently lack knowledge about their effects on infants' gut ecosystems. METHOD: We assessed the effect of lactose, 2'-FL, 2'-FL + LNnT, and a mixture of six HMOs (HMO6: consisting of 2'-FL, LNnT, difucosyllactose, lacto-N-tetraose, 3'- and 6'-sialyllactose) on infant gut microbiota and intestinal barrier integrity using a combination of in vitro models to mimic the microbial ecosystem (baby M-SHIME®) and the intestinal epithelium (Caco-2/HT29-MTX co-culture). RESULTS: All the tested products had bifidogenic potential and increased SCFA levels; however, only the HMOs' fermented media protected against inflammatory intestinal barrier disruption. 2'-FL/LNnT and HMO6 promoted the highest diversification of OTUs within the Bifidobactericeae family, whereas beneficial butyrate-producers were specifically enriched by HMO6. CONCLUSION: These results suggest that increased complexity in HMO mixture composition may benefit the infant gut ecosystem, promoting different bifidobacterial communities and protecting the gut barrier against pro-inflammatory imbalances.