Phys-DAT: A physiologically-based pharmacokinetic model for unraveling the dissolution, transit and absorption processes using PhysPK?

Background and Objective: In silico methods have become the key for efficiently testing and qualifying drug properties. Due to the complexity of the LADME processes and drug characteristics associated to oral drug absorption, there is a growing demand in the development of Physiologically-based Pharmacokinetic (PBPK) software with greater flexibility. Thus, the aims of this work are (i) to develop a mechanistic-based modeling framework of dissolution, transit and absorption (Phys-DAT) processes in the PhysPK platform and (ii) to assess the predictive power of the acausal MOOM methodology embedded in Phys-DAT versus reference ODE-based PBPK software. Methods: A PBPK model was developed including unreleased, undissolved and dissolved thermodynamic states of the drug. The gastrointestinal tract (GI) was represented by nine compartments and first-order transit kinetics was assumed for the drug fractions. Dissolution processes were described using solubility-independent or solubility-dependent mechanisms and pH effects. Linear transit and linear absorption mechanisms including gradual decrease absorption rate were considered to represent the passive diffusion process. Internal validation of the Phys-DAT model was performed through simulation-based analysis, considering different theoretical scenarios. External validation was carried out using in silico and in vivo data of GI segments and plasma concentrations. Both BCS I and II class drugs were included. Results: The model predicts plasma-concentration profiles of each compartment for undissolved, dissolved, and absorbed fractions using PhysPK (R) v.2.4.1. Internal and external validations demonstrate that the model aligned with the theoretical assumptions and accurately predicted Cmax, Tmax, and AUC 0-t for both BCS I and II drugs. Average Fold Error (AFE), Absolute Average Fold Error (AAFE), and Percent Prediction Error (PPE) calculations indicate good predictive performance, with predicted/observed ratios falling within the acceptable range. Conclusions: Phys-DAT represents a mechanistic model for predicting oral absorption, including the dissolution, pH effect, transit, and absorption processes. PhysPK has shown to be a tool with strong prediction accuracy, similar to the obtained by ODE-based PBPK reference software, and the results obtained with the Phys-DAT model for oral administered drugs showed predictive reliability in healthy volunteers, setting the basis to determine the interchangeability of the acausal MOOM methodology with other modeling approaches.