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by: Shriram M. Pathak & Amitava Mitra

pathak-shriram_headshotmitro-amitava_headshotEstablishing bioequivalence is the most crucial component of a generic drug application, which is indeed a time consuming and costly process. Hence, assessing in vivo equivalence of drug products virtually has always been a subject of great interest for pharmaceutical scientists. In recent times, advancements in in-silico modeling techniques have enhanced the ability of scientists to predict comparable in vivo performance of the test product with that of the innovator product.

Physiologically based pharmacokinetic (PBPK) models can differentiate the “drug” (formulation) properties from the “system” (physiological) parameters. Therefore, they can be effectively used to predict formulation population variability and assess the likelihood of products being bioequivalent using virtual trial design. Use of such virtual trials-based in-silico tools in early stages can help in guiding systematic formulation development and identifying appropriate enabling formulations in BA/BE studies, thereby substantially reducing the cost and time of product development. Moreover, accounting for “population variability” in these virtual trials can have far-reaching consequences in several areas of drug product development including: formulation safe space design, clinically relevant dissolution specification setting, aiding justification of biowaivers, and beyond. Further predicting population variability can play an important role in strengthening the existing quality by design (QbD) programs in a more meaningful way.

Both inter-individual and intra-individual variabilities are observed in bioequivalence studies and both need to be accounted in virtual trials. Although in the current PBPK models, inter-individual variability can be incorporated reasonably well, there still exists fundamental gaps in the reliable estimation and incorporation of intra-individual variability in the models. Recently, many efforts have been undertaken that aim at gathering variability data in physiological parameters for use in PBPK modelling to predict bioequivalence. Availability of such datasets, along with the powerful algorithms within PBPK framework, can definitely help in achieving this goal more effectively.

If you relate to this research topic and would like to voice your opinion, we would be happy to listen to your perspective in the upcoming 2016 AAPS Annual Meeting hot topic discussion- Establishing Bioequivalence Virtually- A Distant Dream or a Close Reality?   The session will host talks form two speakers- Dr. Robert Lionberger, director, Office of Research and Standards, US FDA and Dr. Kiyohiko Sugano, associate professor, Toho University.

This session seeks to foster discussions related to the applications of this novel approach and also to highlight the present challenges and limitations of PBPK-modelling in the context of data requirement and model verification. It should be an interesting opportunity to reflect on where we have been and where we are heading to!

The views and opinions expressed in this blog are solely those of the authors and do not necessarily reflect the official policy or position of either of their affiliations.

Dr. Shriram M Pathak is an employee of Simcyp Ltd. (A Certara Company) since 2013, where he is a part of modelling & simulation group and is involved in development and improvement of absorption and bioavailability models implemented within Simcyp® Population-based Simulator.
Dr. Amitava Mitra is a Principal Scientist in the Biopharmaceutics group at Merck Research Labs. He has a PhD in Pharmaceutical Sciences from University of Maryland, Baltimore.