title: Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon.
abstract: Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials.
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht.
authors.forename: Talitha I
authors.initials: TI
authors.lastname: Verhoef
authors.forename: William K
authors.initials: WK
authors.lastname: Redekop
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Rianne M F
authors.initials: RM
authors.lastname: van Schie
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Anke-Hilse
authors.initials: AH
authors.lastname: Maitland-van der Zee
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic; D003362:Cost-Benefit Analysis; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D054796:Drug Dosage Calculations; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics / Q000191:economics; D010644:Phenprocoumon / Q000008:administration & dosage* / Q000493:pharmacokinetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol; D010644:Phenprocoumon
keywords: CYP2C9; VKORC1; acenocoumarol; pharmacogenetics; phenprocoumon; warfarin
references.citation: J Hum Genet. 2011 Apr;56(4):290-5
references.pmid: 21326313
references.citation: Blood. 2008 Apr 15;111(8):4106-12
references.pmid: 18250228
references.citation: Eur J Clin Pharmacol. 2010 Jun;66(6):591-8
references.pmid: 20376629
references.citation: Clin Pharmacol Ther. 2010 May;87(5):572-8
references.pmid: 20375999
references.citation: Arch Intern Med. 2008 Sep 22;168(17):1890-6
references.pmid: 18809816
references.citation: Thromb Haemost. 2004 Jan;91(1):87-94
references.pmid: 14691573
references.citation: PLoS Med. 2005 Oct;2(10):e312
references.pmid: 16201835
references.citation: Pharmacogenetics. 2004 Jan;14(1):19-26
references.pmid: 15128047
references.citation: Pharmacogenomics. 2012 Dec;13(16):1917-23
references.pmid: 23215884
references.citation: Thromb Haemost. 2012 Jun;107(6):1083-91
references.pmid: 22534826
references.citation: Hum Genet. 2007 Mar;121(1):23-34
references.pmid: 17048007
references.citation: Pharmacogenomics. 2012 Sep;13(12):1405-17
references.pmid: 22966889
references.citation: Blood. 2008 Aug 15;112(4):1013-21
references.pmid: 18523153
references.citation: Arch Intern Med. 2011 Jul 25;171(14):1285-6
references.pmid: 21788545
references.citation: Chest. 2001 Jan;119(1 Suppl):176S-193S
references.pmid: 11157648
references.citation: Clin Pharmacol Ther. 2008 Dec;84(6):722-8
references.pmid: 18754001
references.citation: Clin Pharmacol Ther. 2004 Nov;76(5):409-17
references.pmid: 15536456
references.citation: Clin Pharmacol Ther. 2004 May;75(5):394-402
references.pmid: 15116052
references.citation: Clin Pharmacol Ther. 2011 Nov;90(5):701-6
references.pmid: 22012312
references.citation: JAMA. 2006 Oct 18;296(15):1858-66
references.pmid: 17047216
references.citation: Thromb Res. 2010 Jun;125(6):e259-64
references.pmid: 20421126
references.citation: Pharmacogenet Genomics. 2009 Mar;19(3):226-34
references.pmid: 19177029
references.citation: Chest. 2004 Dec;126(6):1938-45
references.pmid: 15596696
references.citation: N Engl J Med. 2000 Dec 14;343(24):1758-64
references.pmid: 11114314
references.citation: J Thromb Thrombolysis. 2011 Jan;31(1):113-8
references.pmid: 20585834
references.citation: Eur J Nutr. 2007 Apr;46(3):147-54
references.pmid: 17356795
references.citation: Pharmacogenomics. 2012 Dec;13(16):1937-50
references.pmid: 23215886
references.citation: Blood. 2009 Jan 22;113(4):784-92
references.pmid: 18574025
references.citation: Haematologica. 2002 Nov;87(11):1185-91
references.pmid: 12414349
references.citation: Clin Pharmacol Ther. 2009 Nov;86(5):540-7
references.pmid: 19571807
references.citation: Pharmacol Ther. 1997;73(1):67-74
references.pmid: 9014207
references.citation: Thromb Haemost. 2012 Dec;108(6):1132-40
references.pmid: 23015069
references.citation: Circulation. 2011 Oct 4;124(14):1573-9
references.pmid: 21900088
references.citation: Pharmacogenomics J. 2005;5(4):262-70
references.pmid: 15883587
references.citation: Circulation. 1985 Nov;72(5):1059-63
references.pmid: 3899404
references.citation: Blood. 2005 Oct 1;106(7):2329-33
references.pmid: 15947090
references.citation: Ann Intern Med. 2007 Jun 19;146(12):857-67
references.pmid: 17577005
references.citation: J Thromb Thrombolysis. 2009 Aug;28(2):211-4
references.pmid: 18629445
references.citation: Circulation. 2007 Nov 27;116(22):2563-70
references.pmid: 17989110
references.citation: Clin Pharmacokinet. 1979 Jan-Feb;4(1):1-15
references.pmid: 369763
references.citation: Eur J Clin Pharmacol. 2005 Jul;61(5-6):381-8
references.pmid: 15952022
references.citation: J Thromb Haemost. 2008 Oct;6(10):1663-70
references.pmid: 18680536
references.citation: Eur J Clin Pharmacol. 2003 Jul;59(3):213-9
references.pmid: 12728288
references.citation: Pharmacogenet Genomics. 2006 Feb;16(2):101-10
references.pmid: 16424822
references.citation: Genet Med. 2011 Jun;13(6):509-18
references.pmid: 21423021
references.citation: J Thromb Thrombolysis. 2014 Apr;37(3):338-44
references.pmid: 23771743
references.citation: Curr Pharm Des. 2010;16(2):187-203
references.pmid: 20205664
references.citation: Hum Mol Genet. 2010 Dec 1;19(23):4735-44
references.pmid: 20833655
references.citation: Blood. 2011 Sep 15;118(11):3163-71
references.pmid: 21725053
references.citation: Pharmacogenetics. 2004 Jan;14(1):27-33
references.pmid: 15128048
references.citation: J Thromb Thrombolysis. 2006 Feb;21(1):73-7
references.pmid: 16475046
references.citation: Pharmacogenetics. 2004 Aug;14(8):539-47
references.pmid: 15284536
references.citation: Lancet. 1999 Feb 27;353(9154):717-9
references.pmid: 10073515
references.citation: Clin Pharmacol Ther. 2004 Mar;75(3):204-12
references.pmid: 15001972
references.citation: Clin Pharmacol Ther. 2001 Sep;70(3):292-8
references.pmid: 11557918
references.citation: Thromb Haemost. 2006 May;95(5):782-7
references.pmid: 16676068
references.citation: Circulation. 1994 Feb;89(2):635-41
references.pmid: 8313552
references.citation: Pharmacogenomics J. 2012 Aug;12(4):306-11
references.pmid: 21358752
references.citation: Pharmacoeconomics. 2010;28(1):61-74
references.pmid: 20014877
references.citation: Thromb Haemost. 2005 Apr;93(4):700-5
references.pmid: 15841315
references.citation: Clin Pharmacokinet. 2005;44(12):1227-46
references.pmid: 16372822
references.citation: Lancet. 2009 Aug 15;374(9689):565-76
references.pmid: 19683642
references.citation: PLoS One. 2012;7(7):e41360
references.pmid: 22911785
references.citation: Pharmacogenomics. 2008 Nov;9(11):1631-8
references.pmid: 19018719
references.citation: Trials. 2010 Nov 17;11:108
references.pmid: 21083927
references.citation: Clin Cardiol. 2013 Feb;36(2):61-7
references.pmid: 23338902
references.citation: Clin Pharmacol Ther. 2008 Jul;84(1):83-9
references.pmid: 18183038
references.citation: Clin Ther. 2011 Oct;33(10):1371-80
references.pmid: 21981797
references.citation: Thromb Haemost. 2004 Jul;92(1):61-6
references.pmid: 15213846
references.citation: J Am Coll Cardiol. 2010 Jun 22;55(25):2804-12
references.pmid: 20381283
references.citation: South Med J. 2000 May;93(5):448-54; quiz 455
references.pmid: 10832939
references.citation: Pharmacogenomics. 2012 Aug;13(11):1239-45
references.pmid: 22920394
references.citation: Blood. 2008 Aug 15;112(4):1022-7
references.pmid: 18535201
references.citation: Circulation. 1959 Jan;19(1):97-107
references.pmid: 13619027
references.citation: Clin Chim Acta. 2011 Nov 20;412(23-24):2063-9
references.pmid: 21827742
references.citation: Eur Heart J. 2011 Aug;32(15):1909-17
references.pmid: 21636598
references.citation: J Thromb Haemost. 2012 Dec;10(12):2610-2
references.pmid: 23016521
references.citation: Health Technol Assess. 2007 Oct;11(38):iii-iv, ix-66
references.pmid: 17903392
references.citation: Nature. 2004 Feb 5;427(6974):541-4
references.pmid: 14765195
references.citation: J Hum Genet. 2012 Oct;57(10):665-9
references.pmid: 22854539
references.citation: J Thromb Haemost. 2012 Apr;10(4):606-14
references.pmid: 22252093
references.citation: J Bone Joint Surg Br. 2006 Mar;88(3):386-91
references.pmid: 16498018
references.citation: J Thromb Thrombolysis. 2009 Apr;27(3):293-9
references.pmid: 18392557
references.citation: N Engl J Med. 2009 Feb 19;360(8):753-64
references.pmid: 19228618
references.citation: Blood. 2005 Jul 1;106(1):135-40
references.pmid: 15790782
references.citation: Am J Health Syst Pharm. 2004 Jun 15;61(12):1258-64
references.pmid: 15259756
references.citation: Pharmacogenomics. 2009 Oct;10(10):1687-95
references.pmid: 19842940
references.citation: Nature. 2004 Feb 5;427(6974):537-41
references.pmid: 14765194
references.citation: J Thromb Haemost. 2008 Oct;6(10):1655-62
references.pmid: 18662264
references.citation: Int J Med Sci. 2012;9(6):472-9
references.pmid: 22927772
references.citation: Eur J Clin Pharmacol. 2009 Apr;65(4):365-75
references.pmid: 19031075
references.citation: Arch Intern Med. 2005 Jul 11;165(13):1527-32
references.pmid: 16009869
references.citation: Clin Med Res. 2005 Aug;3(3):137-45
references.pmid: 16160068
references.citation: Trials. 2012 Dec 13;13:239
references.pmid: 23237631
references.citation: Clin Pharmacokinet. 1996 Jun;30(6):416-44
references.pmid: 8792056
references.citation: J Thromb Thrombolysis. 2007 Apr;23(2):83-91
references.pmid: 17221328
references.citation: Drug Metab Dispos. 2000 Nov;28(11):1284-90
references.pmid: 11038154
references.citation: Circulation. 2012 Apr 24;125(16):1997-2005
references.pmid: 22431865
references.citation: J Clin Pharmacol. 2011 Oct;51(10):1418-28
references.pmid: 21148049
references.citation: Cochrane Database Syst Rev. 2003;(4):CD003464
references.pmid: 14583979
references.citation: Pharmacogenomics. 2009 Aug;10(8):1257-66
references.pmid: 19663670
references.citation: Eur J Clin Pharmacol. 2012 Aug;68(8):1167-74
references.pmid: 22349464
references.citation: Chest. 2006 May;129(5):1155-66
references.pmid: 16685005
references.citation: Thromb Haemost. 2012 Feb;107(2):232-40
references.pmid: 22186998
references.citation: Thromb Res. 2010 Sep;126(3):183-90
references.pmid: 20553802
references.citation: J Thromb Thrombolysis. 2013 Apr;35(3):391-8
references.pmid: 23389753
references.citation: Genet Med. 2005 Feb;7(2):97-104
references.pmid: 15714076
references.citation: Clin Pharmacol Ther. 2008 Mar;83(3):460-70
references.pmid: 17851566
references.citation: Clin Pharmacol Ther. 2008 Sep;84(3):326-31
references.pmid: 18305455
references.citation: Br J Haematol. 2012 Jul;158(2):256-261
references.pmid: 22571356
references.citation: Eur J Clin Pharmacol. 2010 Mar;66(3):253-60
references.pmid: 20020283
references.citation: N Engl J Med. 1995 Jul 6;333(1):11-7
references.pmid: 7776988
references.citation: Eur Heart J. 2012 Nov;33(21):2719-47
references.pmid: 22922413
references.citation: Clin Pharmacol Ther. 1976 Sep;20(3):342-9
references.pmid: 954354
references.citation: Pharmacogenomics J. 2012 Oct;12(5):417-24
references.pmid: 21606949
references.citation: Thromb Haemost. 2001 Aug;86(2):569-74
references.pmid: 11522005
references.citation: Chem Res Toxicol. 1992 Jan-Feb;5(1):54-9
references.pmid: 1581537
references.citation: Thromb Res. 2010 Apr;125(4):e159-66
references.pmid: 19942260
references.citation: Chest. 2008 Jun;133(6 Suppl):160S-198S
references.pmid: 18574265
references.citation: PLoS One. 2012;7(6):e39640
references.pmid: 22745801
references.citation: Clin Pharmacol Ther. 2006 Oct;80(4):346-55
references.pmid: 17015052
references.citation: Thromb Haemost. 2013 Jan;109(1):146-53
references.pmid: 23196355
references.citation: Eur J Clin Pharmacol. 2004 May;60(3):173-82
references.pmid: 15054565
references.citation: Pharmacoeconomics. 2006;24(10):1021-33
references.pmid: 17002484
references.citation: PLoS Genet. 2009 Mar;5(3):e1000433
references.pmid: 19300499
references.citation: BMC Med Genet. 2011 Jun 06;12:80
references.pmid: 21639946
references.citation: Ther Drug Monit. 2010 Jun;32(3):338-45
references.pmid: 20386359
references.citation: Pharmacogenetics. 1995 Dec;5(6):389-92
references.pmid: 8747411
references.citation: Pharmacogenetics. 2001 Nov;11(8):735-7
references.pmid: 11692083
references.citation: Pharmacogenomics. 2008 Feb;9(2):169-78
references.pmid: 18370846
references.citation: Hum Mol Genet. 2009 Oct 1;18(19):3758-68
references.pmid: 19578179
references.citation: Br J Haematol. 2008 Dec;143(5):727-33
references.pmid: 18950464
references.citation: PLoS One. 2012;7(5):e37844
references.pmid: 22629463
references.citation: Pharmacogenomics. 2011 Jan;12(1):15-25
references.pmid: 21174619
references.citation: Circulation. 2011 Jun 7;123(22):2562-70
references.pmid: 21606397
references.citation: J Thromb Thrombolysis. 2006 Dec;22(3):191-7
references.pmid: 17111199
references.citation: Eur J Clin Pharmacol. 2011 Apr;67(4):371-381
references.pmid: 21110013
references.citation: Blood Coagul Fibrinolysis. 2010 Sep;21(6):558-63
references.pmid: 20581661
references.citation: Chest. 2001 Jan;119(1 Suppl):8S-21S
references.pmid: 11157640