, 2010) it might prove difficult to differentiate the main driving forces behind this observed phenomenon, i.e., colonic absorption window vs. a decreased gut wall metabolism in the colon, or both (Tannergren et al., 2009). To our knowledge however there is a paucity of studies investigating these bioavailability Libraries differences in a prospective manner. In addition, no attempts have been made to either elucidate the drug Sorafenib purchase and formulation properties associated
with the occurrence of such phenomenon or to correlate its magnitude to the aforementioned drug’s physicochemical, biopharmaceutical and biochemical properties. Due to the multifactorial nature of the problem, modelling and simulation (M&S), in particular
physiologically-based pharmacokinetic (PBPK) M&S, can be useful for the prospective analysis of the impact of such properties on the absorption and first past metabolism of CR formulations of CYP3A substrates. In silico PBPK models integrate current knowledge of both the system, i.e., morphophysiological factors (and their population characteristics) and drug properties that may influence oral drug absorption ( Jamei et al., 2009c). This approach has the advantage to allow the theoretical exploration of the interplay between the system and the drug properties and therefore hypothesize on the main GSK1120212 order driving forces that control drug absorption, transport and metabolism ( Darwich et al., 2010). Herein the relative bioavailability between CR and IR formulations of CYP3A substrates was investigated in order to understand how the physicochemical, biochemical and pharmaceutical properties of a drug (or drug product) can affect its oral bioavailability. Firstly, a literature survey was performed to collate clinical studies in which the pharmacokinetics unless of CYP3A4 substrates were
simultaneously investigated in both IR and CR formulations. Secondly, a systematic analysis was performed to investigate the impact that drug release characteristics and the drug-related physicochemical and biochemical properties defining oral bioavailability have on oral drug absorption and CYP3A4-mediated intestinal first pass metabolism. This was performed using in silico PBPK M&S. The aims of this study were to investigate possible mechanisms involved in the observed differences in oral bioavailability between IR and CR formulations by analysing the trends in fa, FG, and the systemic exposure (AUC). In addition, an attempt was made to identify the parameter space associated with the higher relative bioavailability of drugs formulated as CR compared to their IR counterparts and to correlate simulations with the observed clinical data gathered from the literature search. A literature survey was conducted using PubMed and Google Scholar in order to identify studies in which the pharmacokinetics of CYP3A4 substrates formulated as IR and CR was investigated.