Improving accuracy in food effect predictions: Application of in-vitro absorption experiments as a useful tool for the evaluation of ten drug products

Abstract

Predicting the magnitude and direction of food effects on oral drug delivery can be challenging, especially for compounds with absorption limited by changes in the permeation rate. Currently available in-vitro tools assess the impact of increased bile flow and food on drug solubilization, potentially leading to increased absorption under fed conditions. However, the presence of bile can sequester the drug within bile/food colloids, reducing free drug availability and resulting in unanticipated absorption. The aim of this study is to explore the application and outcome of a combined dissolution/permeation (MacroFLUX™) assay of ten drug products for a more accurate prediction of clinical food effects in the context of given dose and formulation. The ratio of the fed-to-fasted dissolution and Flux were used to correlate each experimental model to clinical food effect in humans. Assessing the flux across a biomimetic artificial membrane provided superior predictability over dissolution alone. Food effects were predicted accurately for 60% of compounds within 1.25-fold based on flux analysis, while dissolution analysis only predicted 30% of compounds evaluated. The most interesting outcome is that dissolution did not pick up on any of the negative food effects. Notably, the study revealed that the common assumption of compounds exhibiting a positive food effect due to increased dissolution/solubility from fasted to fed state does not always hold true. This in-vitro absorption experiment proved to be a valuable in-vitro biopharmaceutic tool that can predict clinical food effects, support (pre-)formulation development, and guide the design of dedicated clinical pharmacology studies.