The poor water solubility of orally administered drugs leads to low dissolution in the GI tract, resulting to low oral bioavailability. Traditionally, in vitro dissolution testing using the compendial dissolution apparatuses I and II has been the gold-standard method for evaluating drug dissolution and assuring drug quality. However, these methods don't accurately represent the complex physiologies of the GI tract, making it difficult to predict in vivo behavior of these drugs. In this study, the in vivo predictive method, gastrointestinal simulator alpha (GIS-α), was used to study the dissolution profiles of commercially available BCS Class II drugs, danazol, fenofibrate, celecoxib, and ritonavir. This biorelevant transfer method utilizes multiple compartments alongside peristaltic pumps, to effectively model the transfer of material in the GI tract. In all cases, the GIS-α with biorelevant buffers gave superior dissolution profiles. In silico modeling using GastroPlus yielded better prediction when utilizing the results from the GIS-α as input compared to the dissolution profiles obtained from the USP II apparatus. This gives the GIS-α an edge over compendial methods in generating drug dissolution profiles and is especially useful in the early stages of drug and formulation development. This information gives insight into the dissolution behavior and potential absorption patterns of these drugs which can be crucial for formulation development, as it allows for the optimization of drug delivery systems to enhance solubility, dissolution, and ultimately, bioavailability.