title: Practical anticipation of human efficacious doses and pharmacokinetics using in vitro and preclinical in vivo data.
abstract: Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and "developable" dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the "anticipation" of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for "AHD" demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via "reverse pharmacology strategies" that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.
authors.affiliation: DMPK-Translational Sciences, Novartis Institutes for BioMedical Research, One Health Plaza 436/3253, East Hanover, NJ 07470, USA. tycho.heimbach@novartis.com
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Wenyu
authors.initials: W
authors.lastname: Hu
authors.forename: Handan
authors.initials: H
authors.lastname: He
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D010599:Pharmacokinetics
references.citation: Clin Pharmacol Ther. 1996 Dec;60(6):601-7
references.pmid: 8988062
references.citation: J Pharmacokinet Pharmacodyn. 2005 Apr;32(2):185-97
references.pmid: 16283534
references.citation: Pharm Res. 1993 Jul;10(7):1093-5
references.pmid: 8378254
references.citation: Drug Metab Dispos. 1997 Dec;25(12):1329-36
references.pmid: 9394021
references.citation: Biopharm Drug Dispos. 1999 Apr;20(3):137-44
references.pmid: 10211866
references.citation: Mol Pharm. 2004 Jan 12;1(1):85-96
references.pmid: 15832504
references.citation: Biopharm Drug Dispos. 2008 Nov;29(8):455-68
references.pmid: 18989850
references.citation: Adv Drug Deliv Rev. 2008 Mar 17;60(6):717-33
references.pmid: 18199522
references.citation: J Pharm Sci. 2000 Jan;89(1):16-35
references.pmid: 10664535
references.citation: Drug Metab Dispos. 2007 Oct;35(10):1766-80
references.pmid: 17620347
references.citation: Adv Drug Deliv Rev. 2001 Oct 1;50 Suppl 1:S41-67
references.pmid: 11576695
references.citation: J Pharm Sci. 2006 Jun;95(6):1238-57
references.pmid: 16639716
references.citation: Xenobiotica. 2009 Sep;39(9):637-48
references.pmid: 19480559
references.citation: Pharm Res. 1998 Nov;15(11):1792-5
references.pmid: 9834005
references.citation: Drug Discov Today. 2009 Apr;14(7-8):358-72
references.pmid: 19162219
references.citation: J Pharm Sci. 2001 Apr;90(4):436-47
references.pmid: 11170034
references.citation: J Pharm Sci. 2005 Jun;94(6):1259-76
references.pmid: 15858854
references.citation: Drug Metab Dispos. 2005 Sep;33(9):1294-6
references.pmid: 15919851
references.citation: AAPS J. 2008 Dec;10(4):516-25
references.pmid: 19002590
references.citation: J Pharm Sci. 2003 Oct;92(10):1990-2007
references.pmid: 14502539
references.citation: J Pharm Sci. 2006 Aug;95(8):1810-21
references.pmid: 16795002
references.citation: Drug Metab Dispos. 2005 Sep;33(9):1297-303
references.pmid: 15958605
references.citation: J Pharm Sci. 2004 May;93(5):1165-75
references.pmid: 15067693
references.citation: Drug Metab Dispos. 2008 Jul;36(7):1385-405
references.pmid: 18426954
references.citation: J Pharmacol Exp Ther. 1997 Oct;283(1):46-58
references.pmid: 9336307
references.citation: Int J Pharm. 2004 Jan 9;269(1):241-9
references.pmid: 14698595
references.citation: Basic Clin Pharmacol Toxicol. 2005 Mar;96(3):193-9
references.pmid: 15733214
references.citation: Clin Pharmacol Ther. 1994 Oct;56(4):406-19
references.pmid: 7955802
references.citation: Clin Pharmacokinet. 2006;45(5):511-42
references.pmid: 16640456
references.citation: Pharm Res. 1995 Mar;12(3):413-20
references.pmid: 7617530
references.citation: Drug Metab Dispos. 2007 Oct;35(10):1886-93
references.pmid: 17646280
references.citation: J Pharm Sci. 2005 Jul;94(7):1396-417
references.pmid: 15920764
references.citation: Clin Pharmacokinet. 2006;45(12):1213-26
references.pmid: 17112297
references.citation: J Pharm Sci. 1979 Sep;68(9):1203-5
references.pmid: 501558
references.citation: J Clin Pharmacol. 2009 May;49(5):513-33
references.pmid: 19299532
references.citation: Cancer Chemother Rep. 1970 Apr;54(2):95-101
references.pmid: 5003581
references.citation: Science. 1949 Jun 10;109(2841):579-85
references.pmid: 17835379
references.citation: Pharm Res. 2005 Jan;22(1):103-12
references.pmid: 15771236
references.citation: Clin Pharmacokinet. 2008;47(1):35-45
references.pmid: 18076217
references.citation: Adv Drug Deliv Rev. 1996 Jun 12;19(3):359-76
references.pmid: 11540095
references.citation: Pharm Res. 2008 Apr;25(4):713-26
references.pmid: 17899327
references.citation: J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
references.pmid: 11274893
references.citation: AAPS J. 2009 Jun;11(2):225-37
references.pmid: 19381840
references.citation: Adv Drug Deliv Rev. 2007 Jul 30;59(7):591-602
references.pmid: 17599644
references.citation: Clin Pharmacokinet. 1999 Mar;36(3):211-31
references.pmid: 10223169
references.citation: Int J Clin Pharmacol Ther. 1997 Oct;35(10):401-13
references.pmid: 9352388
references.citation: Xenobiotica. 2007 Oct-Nov;37(10-11):1331-54
references.pmid: 17968748
references.citation: J Pharm Sci. 2004 Jul;93(7):1890-900
references.pmid: 15176076
references.citation: Expert Opin Drug Metab Toxicol. 2006 Aug;2(4):591-608
references.pmid: 16859407