Population-Based Mechanistic Prediction of Oral Drug Absorption

Abstract

The bioavailability of drugs from oral formulations is influenced by many physiological factors including gastrointestinal fluid composition, pH and dynamics, transit and motility, and metabolism and transport, each of which may vary with age, gender, race, food, and disease. Therefore, oral bioavailability, particularly of poorly soluble and/or poorly permeable compounds and those that are extensively metabolized, often exhibits a high degree of inter- and intra-individual variability. While several models and algorithms have been developed to predict bioavailability in an average person, efforts to accommodate intrinsic variability in the component processes are less common. An approach that incorporates such variability for human populations within a mechanistic framework is described together with examples of its application to drug and formulation development.

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

“…For instance, the majority of the aforementioned models can incorporate some of the physiological factors known to affect the drug's regional absorption. Remarkable progress has been made in the field of solubility and dissolution, where factors such as the pH-dependent solubility for ionisable compounds, variable GI fluid volumes, supersaturation and precipitation, presence of bile micelles and bile salt-mediated solubility enhancement, to name a few, have already been incorporated in these models (6,7,(26)(27)(28)(29)(30). Nevertheless, in terms of regional intestinal membrane permeability (once the intraluminal and intracellular processes have been accounted for), there is a need for improvements (6)(7)(8)26,28).…”

“…While in most of these mechanistic models, regional differences in the expression/abundance of intestinal transporters are already accounted to some extent (6)(7)(8)26,28), the approach with regard to the passive permeation along the GI tract is still not well defined. For example, in the physiologically based pharmacokinetic (PBPK) modelling of orally administered drugs, it is a common practice to assume that colonic absorption is insignificant compared to that in the small intestine.…”

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

“…Advanced models such as the advanced dissolution, absorption, and metabolism (ADAM) model and the advanced compartmental absorption and transit model (ACAT) are based on adaptations of the original compartmental absorption and transit (CAT) model which accounts for small intestinal transit time (SI), permeability, and radii. Most importantly, these advanced models incorporate gastrointestinal transporter-metabolism interplay [55,56]. A study by Bruyere and co-workers has highlighted the importance of obtaining regional intestinal transporter expression data for incorporation in PBPK models [57].…”

“…Transfer of mass between adjacent segments was considered to follow first-order kinetics, controlled by a rate constant of gastric emptying. The dissolution rate of OXY was modeled based on spherical particles dissolving over time [55]. Further, OXY's regional intestinal metabolism was modeled through an enterocyte compartment, with the assumptions that the metabolism in the liver and intestine was equal, and there was no binding to enterocytes.…”

Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

“…Current models range from simple equations to complex computer simulations. For instance, a simple model may use as few as four parameters to estimate drug absorption (e.g., the maximum absorbable dose (MAD) model considers only the absorption rate constant and solubility) (18,19), whereas computer models (e.g., GastroPlus™, Stella®, Intellipharm®, and Simcyp®) may utilize over 20 parameters (7,17,(19)(20)(21)(22)(23)(24).…”