Orally administered drugs are subject to a number of barriers impacting bioavailability (F oral ), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT Keywords:Physiologically-based pharmacokinetics (PBPK); modelling and simulation (M&S); absorption; oral bioavailability (F oral ); biopharmaceutics; drug database Abbreviations

Predicting oral bioavailability (F oral The OrBiTo database was found to be largely representative of previously published datasets.)43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics. Keywords:Physiologically-based pharmacokinetics (PBPK); modelling and simulation (M&S); absorption; oral bioavailability (F oral ); biopharmaceutics; drug database

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. F was also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

For the four drugs studied, it appears that the forecasting accuracy of the PBPK models is related to the BCS class (BCS I > BCS II, BCS III > BCS IV). These results will need to be verified with additional drugs.

In vitro-in vivo correlations (IVIVCs) play an important role in formulation development and drug approval. At the heart of IVIVC is deconvolution, the method of deriving an in vivo “dissolution profile” for comparison with in vitro dissolution data. IVIVCs are generally believed to be possible for highly permeable and highly soluble compounds with release/dissolution as the rate-limiting step. In this manuscript, we apply the traditional deconvolution methods, Wagner-Nelson and numerical deconvolution, to profiles simulated using a simplified small intestine absorption and transit model. Small intestinal transit, dissolution, and absorption rate constants are varied across a range of values approximately covering those observed in the literature. IVIVC plots and their corresponding correlation coefficients are analyzed for each combination of parameters to determine the applicability of the deconvolution methods under a range of rate-limiting conditions. For highly absorbed formulations, the correlation coefficients obtained during IVIVC are comparable for both methods and steadily decline with decreasing dissolution rate and increasing transit rate. The applicability of numerical deconvolution to IVIVC is not greatly affected by absorption rate, whereas the applicability of Wagner-Nelson falls when dissolution rate overcomes absorption rate and absorption becomes the rate-limiting step. The discrepancy between the expected and deconvolved input arises from the violation of a key assumption of deconvolution that the unknown input and unit impulse enter the system in the same location.

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