From Bench to Bioequivalence: In Vitro Mechanistic Understanding of ASD Drug Products in Simulated Gastrointestinal Conditions

From Bench to Bioequivalence: In Vitro Mechanistic Understanding of ASD Drug Products in Simulated Gastrointestinal Conditions – Project Abstract The findings from this project will enhance our comprehension of how food and gastric pH affects the release of drugs from ASDs, and how the variability arising from differences in

formulations and manufacturing can impact upon in vivo performance. This project will generate Tiny-TIMsg data on a series of amorphous solid dispersion (ASD) drug products under fasted; fed and reduced gastric pH conditions and correlate this in vitro data to in vivo clinical data. In the second step, a mechanistic modeling-based methodology will be employed to link the in vitro

dissolution obtained in the Tiny-TIMsg system to the in vivo performance of ASD drug products. Using this in silico model, clinical performances of ASD formulation variants will be simulated, and virtual BE (VBE) conducted to assess the impact of formulation and manufacturing process modification on API’s exposure.

The series of ASD drug products will be carefully selected to ensure that there is diversity in products based on: method of manufacture; excipient composition and the ratio of stabilizing polymer:API. Access to clinical data is critical in the selection of products hence the initial focus will be on the identification of relevant data sets. All products to be tested will be interrogated to

identify data on degree of solubility enhancement required; pH dependent solubility and reported food effect. Where formulations are not commercially available they will be manufactured to match reported parameters using dissolution matching as the primary target. Output data from the Tiny-TIMsg will report the ratio of bioaccessible dose in either the fed

or the reduced gastric pH state to the fasted state; this will be correlated to the clinical data of the ratio of the AUC in the fed or the reduced gastric pH state to the fasted state. Each formulation’s performance in the Tiny-TIMsg will be closely interrogated to identify the kinetics of precipitation to mechanistically understand ASD performance. The closely controlled and

reproducible nature of Tiny-TIMsg will enable discrimination at a level not possible with pre- clinical or clinical testing; hence the ability to discriminate between formulations and identify risks associated with food or reduced gastric pH in the prediction of in vivo outcomes. Coupling the Tiny-TIMsg data to PBPK models will support formulation development and minimize future

clinical testing thus accelerating the speed of development of safe and effective medicines. The developed and validated workflow will help to establish scientific and regulatory standards for supporting innovative development of ASDs and performing virtual bioequivalence evaluation of these generic drug products.