Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility. The intrinsic solubility was obtained by deconvoluting the model against the observed active metabolite PK profiles with various fractions of base in healthy subjects with or without PPI. The developed PBPK absorption model accurately predicted the average active metabolite PK profiles in healthy subjects without PPI for the product containing 100% salt. A model based on assumptions of the fraction of a dose absorbed remaining unchanged for formulations containing different fractions of base over predicted the reduction of bioavailability upon conversion to the base. Therefore, this represented the conservative estimate with respect to the impact of free base in a product on BE evaluation. Virtual BE trial simulation predicted that less than 20% free base in prasugrel HCl product ensures in vivo BE of the generic product including in subjects that may be taking PPI.