A Novel Approach to Justify Dissolution Differences in an Extended Release Drug Product using Physiologically Based Biopharmaceutics Modeling and Simulation.

Dr Reddy's Laboratories Ltd. developed generic version of XYZ extended release tablets (ER) and achieved bioequivalence as per criteria mentioned by USFDA in both fasting and fed conditions for higher strength formulation (1200 mg). However, on comparison of multimedia dissolution profiles in pH 4.5 acetate media, the f2 similarity value was <50. The lower strength formulation (600 mg) demonstrated faster dissolution profile. This was identified as strength-dependent sink condition difference and in vitro multiunit dissolution studies were used to justify sink differences between the higher and lower strengths. Additionally, a Physiologically Based Biopharmaceutics Model (PBBM) was developed using GastroPlus. The validity of this model was established using in-house human pharmacokinetic data. Further, this model was used to justify the insignificant in vivo impact of the faster dissolution profile for the lower strength formulation. This work provides a novel and less explored approach that can be used to obtain biowaiver for lower strength formulations when the standard biowaiver criteria cannot be met. This work also demonstrates the usefulness of PBBM to justify dissolution dissimilarity between dose proportional formulations and to evaluate its biopharmaceutics risk without the need for actual in vivo studies.