A comparative evaluation of models to predict human intestinal metabolism from nonclinical data.
Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The 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 Fgand, based on the outcome, to provide recommendations for the prediction of human Fgduring drug discovery and early drug development. The use of in vitro intrinsic clearance from human liver microsomes (HLM) in three mechanistic models - the ADAM, Qgutand 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 Fgwas also explored. The ADAM, Qgutand 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 with the Qgutand 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 systematically to under-predict human Fg. Hence, we would recommend the use of rat to identify the need for Fgassessment, followed by the use of HLM in simple models to predict human Fg. © 2017 Merck KGaA. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons, Ltd.
Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD), Merck, Darmstadt, Germany.
Estelle
http://orcid.org/0000-0001-8323-5080
E
Yau
Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD), Merck, Darmstadt, Germany.
Carl
C
Petersson
Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD), Merck, Darmstadt, Germany.
Hugues
H
Dolgos
Global Early Development/Quantitative Pharmacology and Drug Disposition (QPD), Merck, Darmstadt, Germany.
Sheila Annie
SA
Peters
D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D004364:Pharmaceutical Preparations
ADAM; HLM; Qgut; competing rates; intestinal metabolism; rat