Reply to "Comment on 'In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models'".

This is a reply to the comment on "In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models" by Turner and other Simcyp associates. In the reply we address the major concerns raised by Turner et al. regarding the methodology to compare the predictive performance of the different absorption models and at the same time ensure that the systemic pharmacokinetic input was exactly the same for the different models; the selection of the human effective permeability value of fexofenadine; the adoption of model default values and settings; and how supersaturation/precipitation was handled. In addition, we also further discuss aspects related to differences in in silico models and the potential implications of such differences. Our original report should be viewed as the starting point in a thorough and transparent review of absorption prediction models with the overall aim of improving their application as validated tools for bridging studies of active pharmaceutical ingredients from various sources and origins in a regulatory context. With this reply we encourage other independent investigators to perform further model evaluations of commercial as well as other existing or recently implemented models. This will boost the overall progression of physiologically based biopharmaceutical models for predicting and simulating intestinal drug absorption both in research and development and in a regulatory context.