Premium
Comprehensive Assessment of Human Pharmacokinetic Prediction Based on In Vivo Animal Pharmacokinetic Data, Part 2: Clearance
Author(s) -
Lombardo Franco,
Waters Nigel J.,
Argikar Upendra A.,
Dennehy Michelle K.,
Zhan Jenny,
Gunduz Mithat,
Harriman Shawn P.,
Berellini Giuliano,
Liric Rajlic Ivana,
Obach R. Scott
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270012440282
Subject(s) - pharmacokinetics , in vivo , human plasma , pharmacology , chemistry , medicine , biology , chromatography , microbiology and biotechnology
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 in‐house 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.