Experience with Regulatory Submissions Using GastroPlus Mechanistic Absorption and PBPK Modeling:
Recent experiences with PBPK model-based regulatory submissions used to obtain product development and DDI waivers will be discussed. FDA and EMA requirements will be presented, with examples of FDA and EMA submission outcomes highlighting key points that need to be addressed to regulators.

Case Study: Using GastroPlus Simulation to Justify Drug PS Specs for an ER Formulation in Support of NDA Filling:
API particle size (PS) could significantly affect the manufacture and performance of drug product. Biopharmaceutical simulation was used to justify the use of existing IR PS spec for an ER formulation without performing additional tablet manufacture and dissolution studies. A GastroPlus model was built to integrate physicochemical properties and multiple human PK profiles, including IV, oral IR and ER tablets. The key simulation input parameters, such as regional permeability and particle release rate in GI tract, were supported by available independent studies. The results show that small excursion of PS would have minimal impact on bioavailability of ER formulation for current IR PS spec. The justification using IR PS spec for ER formulation was included in the NDA filing and accepted by FDA. The systematic and semi-validated biopharmaceutical modeling proved to be a powerful and effective tool to accelerate drug product development and ease the approval processes.

By Grace Fraczkiewicz