Evaluating the Impact of Intestinal Bile Salts on Drug Absorption Using PBPK Modeling: Case Studies With Efavirenz, Cinnarizine, and Posaconazole

A high number of poorly soluble compounds are being developed; thus, understanding the factors that influence their absorption is critical. Intestinal bile salts, which facilitate micelle-mediated solubilization, are particularly important for drugs with low solubility and are reported to be highly variable. The aim of this study was to evaluate the effect of luminal bile salt concentrations on the absorption of poorly soluble compounds, using efavirenz, cinnarizine, and posaconazole as examples. Physiologically-based pharmacokinetic (PBPK) models were developed and validated using the Simcyp Simulator. Sensitivity analyzes were performed to assess the impact of bile salts and other gastrointestinal parameters on drug absorption. Simulations revealed that drug absorption in the fasted state was most sensitive to bile salt concentrations compared to other gastrointestinal parameters such as luminal pH, fluid volumes, and gastric emptying. The findings indicate that efavirenz, cinnarizine, and posaconazole exhibit high micelle-mediated solubility, with bile salts playing a critical role in their absorption, particularly in the fasted state. These results highlight the importance of considering bile salt concentrations in PBPK modeling of poorly soluble compounds.