Extrapolation of preclinical pharmacokinetics and molecular feature analysis of "discovery-like" molecules to predict human pharmacokinetics

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Christopher A EvansKeith W Ward

Abstract

The prediction of human pharmacokinetics from preclinical species is an integral component of drug discovery. Recent studies with a 103-compound dataset suggested that scaling from monkey pharmacokinetic data tended to be the most accurate method for predicting human clearance. Additionally, interrogation of the two-dimensional molecular properties of these molecules produced a set of associations which predict the likely extrapolative outcome (success or failure) of preclinical data to project human pharmacokinetics. However, a limitation of the previous analyses was the relative paucity of data for typical "discovery-like" molecules (molecular weight >300 and/or clogP >3). The objective of this investigation was to generate preclinical data required for extension of this dataset for additional discovery-like molecules and determine whether the aforementioned findings continue to apply for these molecules. In vivo nonrodent intravenous pharmacokinetic data were generated for 13 molecules, and data for 8 additional molecules were obtained from the literature. Additionally, the various scaling methodologies and molecular features analysis were applied to this new dataset to predict human pharmacokinetics. Whereas the predictive ...Continue Reading

References

Oct 1, 1992·European Journal of Drug Metabolism and Pharmacokinetics·R BernasconiA Salimbeni
Dec 1, 1992·Journal of Veterinary Pharmacology and Therapeutics·M H Court, D J Greenblatt
Apr 1, 1992·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·O OkazakiH Tachizawa
Jan 1, 1992·Biopharmaceutics & Drug Disposition·Y F Cheng, L K Paalzow
Oct 1, 1991·Journal of Pharmacokinetics and Biopharmaceutics·L AaronsM Danhof
Nov 1, 1990·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·R M Ings
Oct 1, 1989·The Journal of Pharmacy and Pharmacology·Y KatagiriK Iwamoto
Feb 1, 1987·Chemical & Pharmaceutical Bulletin·E NakashimaT Yamana
Aug 1, 1985·Clinical Pharmacology and Therapeutics·B EdgarO Rönn
May 1, 1970·Proceedings of the Society for Experimental Biology and Medicine·S H CurryH M Maling
Nov 1, 1983·Journal of Cardiovascular Pharmacology·S R Hamann, R G McAllister
Dec 1, 1981·Journal of Pharmacological Methods·J E StaffordR F Palmer
Jun 1, 1994·Journal of Pharmacokinetics and Biopharmaceutics·J KawakamiT Iga
Oct 1, 1993·Biopharmaceutics & Drug Disposition·P Manitpisitkul, W L Chiou
Jul 1, 1993·Pharmaceutical Research·B Davies, T Morris
Oct 1, 1995·Journal of Clinical Pharmacology·H Boxenbaum, C DiLea
Sep 1, 1996·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·I Mahmood, J D Balian
Apr 1, 1999·Pharmaceutical Research·L A EliotF Jamali
Mar 29, 2001·Journal of Pharmacological and Toxicological Methods·C A Lipinski
Jan 24, 2002·The Journal of Pharmacy and Pharmacology·J SukbuntherngL Antonian
Mar 21, 2003·Journal of Medicinal Chemistry·Mark C WenlockPaul D Leeson
Sep 23, 2003·Journal of Pharmaceutical Sciences·Olivier LuttringerThierry Lavé
Oct 11, 2003·Cancer Chemotherapy and Pharmacology·Jamie RenbargerSusan Blaney
Oct 23, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hiroyoshi HayakawaAkira Tsuji
Jul 3, 2004·European Journal of Drug Metabolism and Pharmacokinetics·Gary W CaldwellWilliam Hageman
Aug 21, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Michael R UhingRobert E Kimura
May 28, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong Tang, Michael Mayersohn

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Citations

Jun 22, 2012·Journal of Chemical Information and Modeling·Giuliano BerelliniFranco Lombardo
Aug 10, 2010·Clinical Pharmacokinetics·Zvi TeitelbaumAdam F Cohen
May 18, 2012·Expert Opinion on Drug Metabolism & Toxicology·Peng ZouDuxin Sun
Jun 24, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·T A McIntyreC B Davis
Jun 29, 2011·Journal of Pharmaceutical Sciences·Kevin BeaumontMalcolm Rowland
Jul 31, 2010·Journal of Clinical Pharmacology·David Wexler, Kirk M Bertelsen
Apr 8, 2015·Chemical Biology & Drug Design·Wenkang HuangXuefeng Lu
Sep 7, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yeamin HuhMeihau Rose Feng
Apr 30, 2014·Journal of Medicinal Chemistry·Franco LombardoGiuliano Berellini
Aug 18, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Franco LombardoR Scott Obach
Apr 23, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·R Scott ObachNigel J Waters
Jan 30, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keith W WardMatthew S Lawrence
Jul 15, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hugues ChanteuxJean-Marie Nicolas
Aug 20, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Loren M BerryZhiyang Zhao
May 2, 2007·The Journal of Pharmacology and Experimental Therapeutics·Jon E HawkinsonAnnika B Malmberg
Jul 17, 2019·Journal of Translational Medicine·Cathalijn H C LeenaarsFranck L B Meijboom
Mar 13, 2009·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·K W WardM S Lawrence
Jun 2, 2009·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·T A McIntyreC B Davis
May 11, 2018·Chinese Medicine·Ru YanYijia Chen
Jan 20, 2017·MedChemComm·M C Wenlock
Jul 17, 2009·Journal of Medicinal Chemistry·Giuliano BerelliniFranco Lombardo

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