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By Nikunj Patel

Nikunjkumar Patel-finalPhysiologically-based pharmacokinetic (PBPK) modeling has been applied in drug development and discovery widely over the last decade to predict pharmacokinetics (PK) from suitable in vitro data as well as from preclinical in vivo data. These approaches have now been transformed from a research tool to incorporation within regulatory submissions and have already been shown to reduce and refine clinical trials in areas such as drug-drug interactions and special populations along with oral drug absorption predictions. However, in this era of industrialization and increasing utilization of PBPK, rather than being complacent we need to identify the limitations and gaps to be able to address them for future advancements of the field.

It is not difficult to find many successful examples of PBPK for prediction of oral drug absorption, formulation optimization and food effects, etc., in published literature and presentations at scientific conferences. However, it is rare that the failures make it to publications or open scientific forums while the failures actually allow the most learning. Also, the final successful models are typically developed from multiple failures in the process providing continuous learning. For example, which in vitro data or model options are better in prediction for what type of drug/formulation? Such useful learning typically remains in-house within individual organizations.

Moreover, current PBPK approaches are also known to have limited success in predicting absorption of certain classes of drugs and formulations such as BCS class IV drugs, enabling formulations of poorly soluble drugs, regional permeability of BCS class III/IV drugs, impact of bio-active excipients, and consideration of inter-occasion variability in absorption. The improvement of PBPK modeling requires a multi-disciplinary team effort as the success of PBPK depends not only on the mathematical algorithms but also in large part on our understanding of physiological processes to be able to model them, plus the associated physiological variability and suitable in vitro experiments to inform the models. If you are engaged in such type of research, please join the upcoming symposium, Where PBPK Modeling Has Not Yet Been Able to Deliver in Biopharmaceutics, at the 2015 AAPS Annual Meeting and Exposition.

In this session, case studies from a number of pharmaceutical companies will be presented to assess the current gaps in PBPK modeling of oral drug absorption and how to fill those gaps and improve their performance. Pharma case studies where current PBPK models have limited success will be presented by Amitava Mitra, Ph.D., followed by current gaps and new advancements in in vitro methods, in vivo characterization of oral absorption, and combination with PBPK to improve predictions of oral absorption with examples by Patrick Augustijns, Ph.D., among many others. Then David Turner, Ph.D., will discuss some of the gaps in PBPK modelling and some initiatives to improve PBPK models such as consideration of impact of in vivo gastrointestinal (GI) fluid hydrodynamics and role of mucus bound water in drug dissolution and permeation. He will then provide case studies illustrating the translation of in vitro dissolution, disintegration and precipitation data to in vivo situations including accounting for population variability particularly as it relates to the GI tract.

If you are unable to attend this year’s AAPS meeting, you can still access this session from your office or home through live streaming. Register today to stream this session!

Thank you to Rakesh Gollen for his support on this blog post.

Nikunj Patel is an employee of Simcyp Limited, a Certara Company, which provides PBPK modeling and simulations platform and consultancy services. The views expressed here are author’s own and not necessarily those of Certara or its entities.

Nikunj Patel is a senior research scientist in Simcyp’s modeling and simulation group where currently he is project lead oral and dermal absorption projects and a member of the Cardiac Safety Simulator development team. He joined Simcyp in 2011 and led the efforts in development of the physiologically based IVIVC (PB-IVIVC) module of the Simcyp Simulator and the Pharmaceutics module of SIVA (Simcyp In Vitro (data) Analysis) platform.