In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Journal of Pharmaceutical Sciences
C M Bowman, L Z Benet

Abstract

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.

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Citations

Sep 26, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christine M Bowman, Leslie Z Benet
Mar 4, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Keiichi MoritaKiyomi Ito
Apr 2, 2020·Expert Opinion on Drug Metabolism & Toxicology·Ravindra V AlluriManthena V S Varma
Apr 20, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jasleen K SodhiLeslie Z Benet
Aug 28, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Beth WilliamsonDermot F McGinnity
Oct 11, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiaomin LiangYurong Lai
Mar 26, 2021·Journal of Medicinal Chemistry·Jasleen K Sodhi, Leslie Z Benet
Nov 2, 2021·Expert Opinion on Drug Metabolism & Toxicology·Veronica Di PaoloLuigi Quintieri

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