Proton pump inhibitors are potent gastric acid-suppressing agents and belong to the most widely sold drugs in the world. However, even though these antisecretory agents are regarded as safe, they can show several interactions with co-administered drugs. Due to the suppression of gastric acid secretion, the can significantly alter the intragastric pH-conditions and are thus likely to affect the bioavailability of co-administered drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Among these drugs, itraconazole, a poorly soluble triazole-type antifungal compound can be found. Based on observations reported in the literature, gastric pH-alterations due to the co-administration of PPIs or acidic beverages can significantly decrease (PPI) or increase (e.g. Coca-Cola®) the bioavailability of this compound. In the present work we tried to estimate the fraction of itraconazole that can be absorbed (fabs) from Sporanox® capsules or an itraconazole-HBenBCD complex formulation after oral admistration with and without co-administration of a PPI or an acidic (carbonated) beverage. For this purpose, the sensitivity of the two formulations towards the impact of various gastric variations (pH, volume and emptying rate) as they can result from such administration conditions was studied using solubility and dissolution experiments and a physiologically based absorption model. Simulating co-administration of the two formulations with a PPI resulted in a significant (~10 fold) decrease in itraconazole fabs, indicating the pH to be essential for in-vivo dissolution and subsequent absorption. Itraconazole’s fabs after co-administered acidic beverage (Coca-Cola®) that was far lower than the fabs obtained for itraconazole alone, did not support the observations reported in the literature. These results clearly indicate that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, co-administered Coca-Cola® is likely to alter a range of gastrointestinal parameters relevant to in-vivo dissolution rather than solely affecting the intragastric pH.