Human in Vivo Regional Intestinal Permeability: Importance for Pharmaceutical Drug Development

Abstract

Both the development and regulation of pharmaceutical dosage forms have undergone significant improvements and development over the past 25 years, due primarily to the extensive application of the biopharmaceutical classification system (BCS). The Biopharmaceutics Drug Disposition Classification System, which was published in 2005, has also been a useful resource for predicting the influence of transporters in several pharmacokinetic processes. However, there remains a need for the pharmaceutical industry to develop reliable in vitro/in vivo correlations and in silico methods for predicting the rate and extent of complex gastrointestinal (GI) absorption, the bioavailability, and the plasma concentration-time curves for orally administered drug products. Accordingly, a more rational approach is required, one in which high quality in vitro or in silico characterizations of active pharmaceutical ingredients and formulations are integrated into physiologically based in silico biopharmaceutics models to capture the full complexity of GI drug absorption. The need for better understanding of the in vivo GI process has recently become evident after an unsuccessful attempt to predict the GI absorption of BCS class II and IV drugs. Reliable data on the in vivo permeability of the human intestine (Peff) from various intestinal regions is recognized as one of the key biopharmaceutical requirements when developing in silico GI biopharmaceutics models with improved predictive accuracy. The Peff values for human jejunum and ileum, based on historical open, single-pass, perfusion studies are presented in this review. The main objective of this review is to summarize and discuss the relevance and current status of these human in vivo regional intestinal permeability values.

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

“…These similarities can be also explained by the similar nature of the intestinal membrane along the human SI; while there are SA differences between the ileum and the upper jejunum, they are not as dramatic as when the SA is compared with, for instance, the colonic membrane. Yet, no direct colonic P eff data is available to perform such comparison (4,5). Further investigations were performed by evaluating the use of P eff,int compared to P eff for the predictions of f abs .…”

“…This was done for a recently published dataset of 11 drugs whose in vivo absorption was measured in different segments of the human SI during single-pass open perfusion experiments (4,5). Regional P eff values were originally derived by Lennernäs by re-arranging the reported absorption data to a parallel tube model (4,5,12,18). Selection of this model was based on its ability to describe the hydrodynamics of the absorption process during open and/ or semi-open single-pass perfusion experiments (12,18), as shown in Eq.…”

“…Several assumptions were made for the estimation of GI drug absorption following oral dosing when using the mSAT model in this study, including: (a) no significant absorption can occur from the stomach (33); (b) the drug is emptied from the stomach by means of a first-order process (53-55); (c) drug release and dissolution are instantaneous (unless stated differently), and-as in the first development of the CAT model-no precipitation and/or changes in solubility due to differences in luminal pH or bile salts were included in this version of the mSAT model (31)(32)(33); (d) all the GI compartments are well mixed, and the drug concentration is homogenous within each GI compartment (31)(32)(33); (e) the lengths of each of the intestinal compartment are representative of their anatomy (23,40); (f) drug transit between the small-intestinal compartments is related to the segment's anatomical length (23,40) and the mean small-intestinal transit time (SITT) (31,32,56); (g) drug absorption occurs only by means of non-saturable processes, where only the dissolved drug can be absorbed (2); (h) there is no drug c,e For the estimation of the mSA, the jejunal and ileal radii were assumed as 1.75 and 1.5 cm, respectively, as per references (4,5) degradation in the GI lumen and (i) the colonic transit is described as a first-order process (57,58). It is clear that these assumptions are valid to make when the regional differences in permeation is the main biopharmaceutical parameter affecting both rate and extend of drug absorption.…”

“…Due to the established correlation between human effective jejunal permeability (P eff ) and the fraction of the administered oral dose that becomes absorbed in the GI tract (f abs or f a ), P eff has been widely used for the a priori estimation of drug absorption in different stages of the drug development process (1)(2)(3). P eff is one of the fundamental biopharmaceutical parameters in the Biopharmaceutics Classification System (BCS) and has been extensively used in drug development (2,4,5). As a consequence, it has often been applied in mechanistic GI absorption models, i.e.…”

“…Given that such values were determined mostly using open perfusion systems, their comparison with the ones obtained from the double-balloon technique is limited (4,5). Recent works have highlighted the necessity for regional P eff estimates in humans, which are of particular interest during early stages of drug and formulation development (4,5,21,25). Yet, due to the vast economic cost associated with clinical perfusion studies, further investigations on regional P eff determination might be limited in the near future.…”