5). In the same line, only minor differences in the trends for fa and

FG were observed. These subtle differences might be an indication of a possible competition between CYP3A4 and P-gp for the substrate in the enterocyte compartments within the ADAM model. However, the reasons for such differences are not clear yet. Further discussion about these results is included in Sections 5 and 6 of the Supplementary Material. Previous multi-scale studies have investigated click here the complex interplay between the factors governing drug absorption and intestinal first pass metabolism and absorption such as the study by Darwich et al. (2010), using the same ADAM model, or the study by Heikkinen et al. (2012) using the Advanced Compartmental Absorption and Transit (ACAT) model

in Gastroplus™. Nevertheless, to our understanding, this is the first study that has investigated the impact of the release characteristics from the formulation on oral bioavailability, specially focused on the interplay between the physicochemical, biopharmaceutical and biochemical properties. From a biopharmaceutics point of view, there are an increasing number of examples of the use of PBPK models for the optimization of new dosage forms, in particular for CR formulations. Some of these examples have recently been reviewed MK0683 nmr by Brown et al. (2012). The use of PBPK models for the evaluation of the impact of biopharmaceutical properties on absorption has recently been encouraged by the regulatory agencies such as by the United States Food and Drug Administration (Zhang and Lionberger, 2014). found In addition, our study provides a systematic analysis of the available data on the relative bioavailability of CYP3A4 substrates as well as the impact of drug- and formulation-specific factors on the oral bioavailability. The outcome of this study can be considered as a first step in the line of providing examples of possible applications of PBPK M&S in the formulation development

process, in particular for the evaluation of the possible impact of controlled release dosage forms on the drug candidate’s absorption and bioavailability. This applies in particular for drugs candidates that are considered as CYP3A4 substrates; however more work is needed in order to fully validate this approach. Due to the complexity of the analysis, we simplified several aspects that would have a clear impact on predicted Frel. One of them was to assume a virtual reference human, thus eliminating the inter-individual variability on the physiological factors that influence drug absorption ( Jamei et al., 2009a). A factorial sensitivity analysis was performed for the investigation of the differences between immediate release and controlled release formulations on drug absorption, first pass metabolism and systemic exposure. This was complemented with a literature survey of the observed differences in oral bioavailability of CR formulations of CYP3A4 substrates.