5B), likewise, an increase in CLint,P-gp resulted in a small increase on the FG ( Figs. S6–7B). These changes were dependent of both release rate and BCS classification, as the increase in fa was more prominent for IR formulations of BCS class 2 compounds ( Figs. 5B and S5B), whereas the impact of CLint,P-gp on FG was perceptible only for IR formulations of BCS class 1 compounds ( Fig. S6A). Analysis of the

relative bioavailability (Frel) of CR formulations showed that highly (CYP3A4) cleared BCS class 1 simulated compounds could display up to a 220% higher Frel compared to the IR formulations. When the trends for the simulations were compared with similar compounds derived from the literature survey, i.e., BCS class 1 and mainly CYP3A4 cleared, Nintedanib there was a very good agreement between the simulated Frel and the observed data ( Fig. 6). The back-calculated CYP3A4 clearance values (HLM)

BMN673 from the in vivo systemic clearance are reported in Table S3 of the Supplementary Material. Due to the selected inclusion criteria for the search, the analysis was limited only to 11 different compounds (Fig. 2). A larger set of drugs could have been included for this analysis if, for instance, the calculations of relative bioavailability were performed between different subjects and groups, i.e., the IR data was taken from one study whereas the CR data was taken from a separate study. However, this would have confounded the impact of the formulation with the inter-individual variability of the kinetics, leading to variable Frel. Therefore these studies were not considered. Of the total drugs investigated, only three drugs formulated as CR showed statistically significant higher relative bioavailability than their IR formulations (simvastatin, buspirone and oxybutynin). In contrast, a majority of the drugs showed either similar or lower relative bioavailability

Resminostat when formulated as CR. Judging from the BCS point of view an a priori trend for either higher of lower Frel was not clear. For instance CR formulations of fluvastatin (BCS class 1) and simvastatin (BCS class 2), both highly permeable compounds, showed opposite results in terms of Frel ( Fig. 2). Whereas CR formulations of low permeable compounds, such as propiverine and gepirone (both BCS class 3), showed similar Frel to their IR formulations. Therefore this justified the use of more mechanistic and multivariate models such as PBPK for M&S purposes in order to accommodate several factors influencing the observed differences. A general trend towards a reduction in drug exposure (AUC) was observed in simulations when varying the release rate, i.e., moving from an IR formulation to a CR formulation. These results were anticipated as, in general the CR formulations are intended to release the majority the drug content further distally in the intestine (e.g.