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Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 2: Clearance

Lombardo, Franco and Waters, Nigel and Argikar, Upendra and Dennehy, Michelle and Zhan, Yu and Gunduz, Mithat and Harriman, Shawn and Berellini, Giuliano and Liric Rajlic, Ivana and Obach, Scott (2013) Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 2: Clearance. Journal of Clinical Pharmacology, 53 (2). pp. 178-191. ISSN 0091-2700

Abstract

A comprehensive analysis on the prediction of human clearance based on intravenous pharmacokinetic data from rat, dog, and monkey for approximately 400 compounds was undertaken. This data set has been carefully compiled from literature reports and expanded with some inhouse determinations for plasma protein binding and rat clearance. To the authors' knowledge, this is the largest publicly available data set. The present examination offers a comparison of 37 different methods for prediction of human clearance across compounds of diverse physicochemical properties. Furthermore, this work demonstrates the application of each prediction method to each charge class of the compounds, thus presenting an additional dimension to prediction of human pharmacokinetics. In general, the observations suggest that methods employing monkey clearance values and a method incorporating differences in plasma protein binding between rat and human yield the best overall predictions as suggested by approximately 60% compounds within 2-fold geometric mean-fold error. Other single-species scaling or proportionality methods incorporating the fraction unbound in the corresponding preclinical species for prediction of free clearance in human were generally unsuccessful. © The Author(s) 2012.

Item Type: Article
Keywords: Allometry Clearance Interspecies scaling Pharmacokinetics and drug metabolism (PDM) Protein binding
Date Deposited: 13 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/5720

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