Applications of Physiologically Based Absorption Models in Drug Discovery and Development

TLDR

Physiologically based absorption models are applied from lead optimization through phase 2 formulation, and improved accuracy is expected with better in‑vitro solubility/permeability data and transporter effect modeling. The article describes using physiologically based intestinal absorption models to guide new drug research and development. Early preclinical simulations combine multiple screening data to predict in‑vivo absorption. Simulations compared to animal plasma levels reveal unexpected behavior and sensitivity analysis identifies limiting absorption factors, while refined physiological models reliably predict human absorption and guide market formulation development.

Abstract

This article describes the use of physiologically based models of intestinal drug absorption to guide the research and development of new drugs. Applications range from lead optimization in the drug discovery phase through clinical candidate selection and extrapolation to human to phase 2 formulation development. Early simulations in preclinical species integrate multiple screening data and add value by transforming these individual properties into a prediction of in vivo absorption. Comparison of simulations to plasma levels measured after oral dosing in animals highlights unexpected behavior, and parameter sensitivity analysis can explore the impact of uncertainties in key properties, point toward factors which are limiting absorption and contribute to assessment of compound developability. Physiological models provide reliable prediction of human absorption and with refinement based on phase 1 data are useful guides to further market formulation development. Improvements in the accuracy of simulations are expected as better in vitro methods generate more in vivo relevant solubility and permeability data, and modeling will play a central role in the development of more predictive methods for transporter-related effects on drug absorption.