Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Abstract

Abstract. Regional intestinal effective permeability (P eff ) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P eff values. These new intestinal P eff values or Bintrinsic^P eff (P eff,int ) were subsequently employed for the prediction of the ileal absorption clearance (CL abs,ileum ) for a set of structurally diverse compounds. Additionally, the method was combined with a semimechanistic absorption PBPK model for the prediction of the fraction absorbed (f abs ). The results showed that P eff,int can successfully be employed for the prediction of the ileal CL abs and the f abs . P eff,int also showed to be a robust predictor of the f abs when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f abs observed for lowly permeable compounds when using the historical P eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.KEY WORDS: intestinal permeability; oral drug absorption; physiologically based pharmacokinetic modelling.

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

“…The mSAT model is a multi-compartmental absorption model that has been recently proposed and used for the prediction of the fraction absorbed using different intestinal permeability approaches (26). The model structure was based on the original Compartmental Absorption and Transit (CAT) model developed in the late 1990s by Yu and co-workers (50-52).…”

“…The main difference with respect to the CAT model, however, was that the new model describes the small intestine with only three anatomically defined compartments, duodenum, jejunum and ileum, instead of seven in the CAT model. In order to adequately describe the mean small intestinal transit time (SITT) with a reduced number of compartments, the mSAT model was implemented with a Weibull transit function that was optimized based upon the same SITT data used for the development of the CAT model (26,52). As in the first version of the CAT model, the mSAT model structure was kept relatively simple as the initial goal was only to predict the fraction absorbed based on permeability data (26).…”

“…That is, intestinal effective permeability (P eff ) was assumed to be same for all intestinal segments implemented in the absorption model, including the colon (21). In an attempt to address this issue, and given the lack of an implementation of regional intestinal (passive) permeability within in the PBPK framework, two novel approaches to implement regional P eff for prospective PBPK simulations were recently proposed (26). The approaches were based on the translation of regional intestinal variations in the available mucosal surface area (mSA) into segment-dependent permeability and absorption (26).…”

“…The approaches were based on the translation of regional intestinal variations in the available mucosal surface area (mSA) into segment-dependent permeability and absorption (26). When the approaches were combined with a novel simplified absorption PBPK model, or minimal Segmented Absorption and Transit (mSAT) model, they showed a potential to decrease the observed overestimation of the colonic f abs (26), especially when applying the so-called Method 3 (M3) which was based on the intestinal mSA values derived recently by Helander and Fändriks (26,27).…”

“…The model was expanded to prospectively predict OXY's oral bioavailability for both IR and MR formulations (26).…”