The use of physiologically based biopharmaceutics modeling (PBBM) and bioequivalence safe space is increasingly common for immediate-release drug products. However, for extended-release (ER) formulations there are only a few examples of this application. In this study, we developed ER formulations containing cyclobenzaprine 15 mg, supported by PBBM and bioequivalence safe space. Four formulations were prepared, F1, F2, F3 (ER mini-tablet formulations) and F4 (ER tablet formulation), and the dissolution profiles were evaluated. The dissolution profile of the reference drug product was also evaluated and used to set a bioequivalence safe space. A PBBM was set up, evaluated, and used to predict the in vivo behavior of the formulations. The bioequivalence safe space was calculated to be between – 25% and + 75% of the k1 and Tlag values of the dissolution profile of the reference drug product when applying the first-order dissolution kinetic model. All time points of the dissolution profile of the ER mini-tablet formulation F2, were within the safe space, and was approved in 10 of 10 trials of crossover virtual bioequivalence studies. Based on the PBBM strategy and bioequivalence safe space, it was possible to develop an ER mini-tablet formulation virtually bioequivalent to the reference drug product, even though this formulation failed the f2 test.