Contemporary trends in the pharmaceutical development emphasize the utility of advanced computer tools to facilitate formulation of new medicines. A special attention has been given to the formulation and characterization of dosage forms for targeted drug delivery that can improve therapeutic outcome. The objective of this study was to apply the combined in vitro-in silico approach to optimize the design of gastroretentive floating system for sustained release of ranitidine hydrochloride. Formulation of the floating systems was based on the effervescent effect of sodium-bicarbonate, whereas prolonged release of ranitidine hydrochloride was provided by the hydrophilic polyethylene oxide polymers which swell and form a gel layer on the surface of the floating tablets. Dosage form floating characteristics and drug dissolution were investigated under biorelevant conditions simulating stomach environment. The obtained dissolution data were used as inputs in ranitidine-specific physiologically-based pharmacokinetic model within GastroPlus™ software to predict the expected pharmacokinetic profiles following oral administration of the designed formulations. The predictive power of the designed model was tested by comparing the simulation outcomes with literature values on drug plasma concentration-time profiles following intravenous and oral administration of different ranitidine doses. In addition, simulation results demonstrated increased extent of drug absorption with prolonged gastric residence times.