A comparative evaluation of models to predict human intestinal metabolism from nonclinical data

ABSTRACT Extensive gut metabolism is often associated with the risk of low and variable bioavailability. Prediction of the fraction of drug escaping gut wall metabolism as well as transporter‐mediated secretion (Fg) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate Fg, and based on the outcome to provide recommendations for the prediction of human Fg during drug discovery and early drug development. The use of in vitro intrinsic clearance from human liver microsomes (HLM) in three mechanistic models – ADAM, Qgut and Competing Rates – was evaluated for drugs whose metabolism is dominated by CYP450s assuming that the effect of transporters is negligible. The utility of rat as a model for human Fg was also explored. ADAM, Qgut and Competing Rates models had comparable prediction success (70%, 74%, 69% respectively) and bias (AFE = 1.26, 0.74 and 0.81 respectively). However, the ADAM model showed better accuracy compared to the Qgut and Competing Rates models (RMSE = 0.20 vs 0.30 and 0.25 respectively). Rat is not a good model (prediction success = 32%, RMSE = 0.48 and AFE = 0.44) as it seems to systematically under‐predict human Fg. Hence, we would recommend the use of rat to identify the need for Fg assessment, followed by the use of HLM in simple models to predict human Fg.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Special Issue Article Source Type: research