Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

Maarten Beinema; Jacobus R. B. J. Brouwers; Tom Schalekamp; Bob Wilffert

doi:10.1160/TH08-04-0116

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(06): 1052-1057
DOI: 10.1160/TH08-04-0116

Review Article

Schattauer GmbH

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

Authors

Maarten Beinema

¹Thrombosis Centre, Deventer Hospital, Deventer, The Netherlands
Jacobus R. B. J. Brouwers

²Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, The Netherlands
Tom Schalekamp

³Division of Pharmacoepidemiology and Pharmacotherapy, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
Bob Wilffert

²Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, The Netherlands

Abstract

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Summary

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of theVKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 andVKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect ofVKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anti-coagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Keywords

Clinical trials - oral anticoagulants - pharamacogenetics - pharmacodynamics

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Referenzen

References
1 Cranenburg ECM, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 2007; 98: 120-125.
2 Van der Meer FJ, Rosendaal FR, Vandenbroucke JP. et al. Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Throm Haemost 1996; 76: 12-16.
3 Torn M, Bollen WL, van der Meer FJ. et al. Risks of anticoagulant therapy with increasing age. Arch Intern Med 2005; 165: 1527-1532.
4 Zu Schwabedissen CM, Mevissen V, Schmitz F. et al. Obesity is associated with a slow response to initial phenprocoumon therapy whereas CYP2C9 genotypes are not. Eur J Clin Pharmacol 2006; 62: 713-720.
5 Tanaka E. In vivo age-related changes in hepatic drug-oxidizing capacity in humans. J Clin Pharm Ther 1998; 23: 247-255.
6 Sotaniemi EA, Arranto AJ, Pelkonen O. et al. Age and cytochrome P450 linked drug metabolism in humans : an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 1997; 61: 331-339.
7 Oden A, Fahlén M. Oral anticoagulation and risk of death: a medical record linkage study. Br Med J 2002; 325: 1073-1075.
8 Kamali F. Genetic influences on the response to warfarin. Curr Opin Hematol 2006; 13: 357-361.
9 Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv 2006; 06: 223-227.
10 Xie HG, Prasad HC, Kim RB. et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 2002; 54: 1257-1270.
11 Daly AK, King BP. Pharamcogenetics of oral anticoagulants. Pharmacogenetics 2003; 13: 247-252.
12 Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40: 587-603.
13 Tabrizi AR, Zehnbauer BA, Borecki IB. et al. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 2002; 194: 267-273.
14 Aithal GP, Day CP, Kesteven PJ. et al. Association of polymorphisms in the Cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding Complications. Lancet 1999; 353: 717-719.
15 Margaglione M, Colaizzo D, Brancaccio V. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775-778.
16 Higashi MK, Veenstra DL, Kondo LM. et al. Association Between CYP2C9 Genetic variants and anticoagulation-related outcomes during warfarin therapy. J Am Med Assoc 2002; 287: 1690-1698.
17 Caldwell MD, Awad T, Johnson JA. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106-4112.
18 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
19 Oldenburg J, Bevans CG, Fregin A. et al. Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thromb Haemost 2007; 98: 570-578.
20 Schwarz UI, Ritchie MD, Bradford Y. et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
21 Wadelius M, Chen LY, Lindh JD. et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2008 prepub online doi:10.1182/blood-2008–04–149070.
22 Daly AK, Aithal GP. Genetic regulation of warfarin metabolism and response. Semin Vasc Med 2003; 03: 231-238.
23 Carlquist JF, Horne BD, Muhlestein JB. et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 2006; 22: 191-197.
24 Wilms EB, Touw DJ, Conemans JM. et al. A new VKORC1 allelic variant –p.Trp59Arg- in a patient with partial resistance to acenocoumarol and phenprocoumon. J Thromb Haemost 2008; 06: 1224-1226.
25 Loebstein R, Dvoskin I, Halkin H. et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 06: 2477-2480.
26 Lal S, Jada SR, Xiang X. et al. Pharmacogenetics of target genes across the warfarin pharmacological pathway. Clin Pharmacokinet 2006; 45: 1189-1200.
27 Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28: 1284-1290.
28 Thijssen HH, Ritzen B. Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype. Clin Pharmacol Ther 2003; 74: 61-68.
29 Morin S, Bodin L, Loriot MA. et al. Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Pharmacol Ther 2004; 75: 403-414.
30 Takahashi H, Wilkinson GR, Padrini R. et al. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther 2004; 75: 376-380.
31 Thijssen HH, Drittij MJ, Vervoort LM. et al. Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 2001; 70: 292-298.
32 Verstuyft C, Morin S, Robert A. et al. Early acenocoumarol overanticoagulation among cytochrome P450 2C9 poor metabolizers. Pharmacogenetics 2001; 11: 735-737.
33 Andre-Kerneis E, Leroy-Matheron C, Gouault-Heilmann M. Early overanticoagulation with acenocoumarol due to a genetic polymorphism of cytochrome P450 CYP2C9. Blood Coagul Fibrinolysis 2003; 14: 761-764.
34 Thijssen HH, Verkooijen IW, Frank HL. The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogenetics 2000; 10: 757-760.
35 Thijssen HH, Drittij MJ, Vervoort LM. et al. Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 2001; 70: 292-298.
36 Hermida J, Zarza J, Alberca I. et al. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood 2002; 99: 4237-4239.
37 Visser LE, van Vliet M, van Schaik RH. et al. The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 2004; 14: 27-33.
38 Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA. et al. The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. Br J Haematol 2006; 133: 183-187.
39 Bodin L, Verstuyft C, Tregouet DA. et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005; 106: 135-140.
40 Schalekamp T, Brassé BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006; 80: 13-22.
41 Rettie AE, Farin FM, Beri NG. et al. A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9. Br J Clin Pharmacol 2006; 62: 617-620.
42 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005; 44: 1227-1246.
43 Ufer M, Svensson JO, Krausz KW. et al. Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol 2004; 60: 173-182.
44 Kamerer B, Kahlich R, Ufer M. et al. Stereospecific pharmacokinetic characterisation of phenprocoumon metabolites, and mass-spectrometic identification of two novel metabolites in human plasma and liver microsomes. Anal Bioanal Chem 2005; 383: 909-917.
45 Ufer M, Kammerer B, Kahlich R. et al. Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo. Xenobiotica 2004; 34: 847-859.
46 He M, Korzekwa KR, Jones JP. et al. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch Biochem Biophys 1999; 372: 16-28.
47 Ufer M. Effects of CYP2C9 polymorphisms on phenprocoumon anticoaglation status (letter). Clin Pharmacol Ther 2005; 77: 335.
48 Toon S, Heimark LD, Trager WF. et al. Metabolic fate of phenprocoumon in humans. J Pharm Sci 1985; 74: 1037-1040.
49 Kirchheiner J, Ufer M, Walter EC. et al. Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics 2004; 14: 19-26.
50 He M, Korzekwa KR, Jones JP. et al. Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9. Arch Biochem Biophys 1999; 372: 16-28.
51 Schalekamp T, Brassé BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 2007; 81: 185-193.
52 Hummers-Pradier E, Hess S, Adham IM. et al. Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur J Clin Pharmacol 2003; 59: 213-219.
53 Visser LE, van Schaik RH, van Vliet M. et al. The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost 2004; 92: 61-66.
54 Fihn SD, Gadisseur AA, Pasterkamp E. et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003; 90: 260-266.
55 Gadisseur AP, Van der Meer FJ, Adriaansen HJ. et al. Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon. Br J Haematol 2002; 117: 940-946.
56 Kohl C, Steinkellner M. Prediction of pharmacokinetic drug-drug interactions from In vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants. Drug Metab Dispos 2000; 28: 161-168.
57 Visser LE, van Schaik RH, van Vliet M. et al. Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants. Clin Pharmacol Ther 2005; 77: 479-485.
58 Van Dijk KN, Plat AW, van Dijk AA. et al. Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype. Thromb Haemost 2004; 91: 95-101.
59 Zarza J. Major bleeding during combined treatment with indomethacin and low doses of acenocoumarol in a homozygous patient for 2C9*3 variant of cytochrome p-450 CYP2C9. Thromb Haemost 2003; 90: 161-162.
60 Beinema MJ, de Jong PH, Salden HJ. et al. The influence of NSAIDs on coumarin sensitivity in patients with CYP2C9 polymorphism after total hip replacement surgery. Mol Diagn Ther 2007; 11: 123-128.
61 Masche UP, Rentsch KM, von Felten A. et al. Opposite effects of lornoxicam co-administration on phenprocoumon pharmacokinetics and pharmacodynamics. Eur J Clin Pharmacol 1999; 54: 857-864.
62 Gage BF, Lesko LL. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008; 25: 45-51.
63 Daly AK, King BP. Pharmacogenetics of oral anticoagulants. Pharmacogenetics 2003; 13: 247-252.
64 Schwarz UI, Stein CM. Genetic determinants of dose and clinical outcomes in patients receiving oral anticoagulants. Clin Pharmacol Ther 2006; 80: 7-12.
65 Shurin SB, Nabel EG. Pharmacogenomics – Ready for prime time?. N Engl J Med 2008; 358: 1061-1063.
66 Voora D, Eby C, Linder MW. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005; 93: 700-705.
67 Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 – rationale and perspectives. Thromb Res 2007; 120: 1-10.
68 Vegter S, Boersma C, Rozenbaum M. et al. Phar-macoeconomic evaluations of pharmacogenetic and genomic screening programmes: a systematic review on content and advherance to guidelines. Pharmacoeconomics 2008; 26: 569-587.
69 You JHS, Chan FWh, Wong RSM. et al. The potential clinical and economic outcomes of pharmacogenetics-orientated management of warfarin therapy – a decision analysis. Thromb Haemost 2004; 92: 590-597.