Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects

Clinical Pharmacology and Therapeutics

Volumn 90, Issue 2, 2011, Pages 287-295

  Simon, T ^a   Bhatt, D L ^b   Bergougnan, L ^c   Farenc, C ^c   Pearson, K ^d   Perrin, L ^c   Vicaut, E ^e   Lacreta, F ^f   Hurbin, F ^c   Dubar, M ^c  

^a ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS   (France)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c SANOFI   (France)

^d Global Metabolism and Pharmacokinetic Department   (United States)

^e HÔPITAL FERNAND WIDAL   (France)

^f BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CLOPIDOGREL; CYTOCHROME P450 2C19; DRUG METABOLITE;

ADULT; ARTICLE; CROSSOVER PROCEDURE; CYP 2C19 GENE; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE COMPARISON; DRUG EFFECT; DRUG EXPOSURE; DRUG METABOLISM; FEMALE; GENE; GENETIC POLYMORPHISM; GENOTYPE; HUMAN; HUMAN EXPERIMENT; LOADING DRUG DOSE; MAINTENANCE DRUG DOSE; MALE; NORMAL HUMAN; PHARMACOGENETICS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; THROMBOCYTE AGGREGATION;

ADENOSINE DIPHOSPHATE; ADULT; ARYL HYDROCARBON HYDROXYLASES; CROSS-OVER STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; FEMALE; HUMANS; MALE; MIDDLE AGED; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; POLYMORPHISM, GENETIC; TICLOPIDINE; YOUNG ADULT;

EID: 79960603688     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2011.127     Document Type: Article

References (50)

1. S avi, P. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb. Haemost. 84, 891-896 (2000).
2. Kazui, M. et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab. Dispos. 38, 92-99 (2010).
3. Tuffal, G. et al. An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. Thromb. Haemost. 105, 696-705 (2011).
4. Snoep, J.D., Hovens, M.M., Eikenboom, J.C., van der Bom, J.G., Jukema, J.W. & Huisman, M.V. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am. Heart J. 154, 221-231 (2007). (Pubitemid 47069129)
5. Sibbing, D. et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J. Thromb. Haemost. 8, 250-256 (2010).
6. Suh, J.W. et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 174, 1715-1722 (2006).
7. Taubert, D. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin. Pharmacol. Ther. 80, 486-501 (2006). (Pubitemid 44767878)
8. Mega, J.L. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N. Engl. J. Med. 360, 354-362 (2009).
9. Brandt, J.T. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J. Thromb. Haemost. 5, 2429-2436 (2007). (Pubitemid 350154353)
10. Fontana, P. et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 108, 989-995 (2003). (Pubitemid 37048230)
11. Umemura, K., Furuta, T. & Kondo, K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J. Thromb. Haemost. 6, 1439-1441 (2008). (Pubitemid 352016331)
12. Chen, B.L. et al. Inhibition of ADP-induced platelet aggregation by clopidogrel is related to CYP2C19 genetic polymorphisms. Clin. Exp. Pharmacol. Physiol. 35, 904-908 (2008).
13. Kim, K.A., Park, P.W., Hong, S.J. & Park, J.Y. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin. Pharmacol. Ther. 84, 236-242 (2008).
14. Hulot, J.S. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108, 2244-2247 (2006).
15. Geisler, T. et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 9, 1251-1259 (2008).
16. Giusti, B. et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet. Genomics 17, 1057-1064 (2007). (Pubitemid 351339490)
17. Frere, C. et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am. J. Cardiol. 101, 1088-1093 (2008).
18. Trenk, D. et al. Cytochrome P450 2C19 681G A polymorphism and high onclopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or baremetal stents. J. Am. Coll. Cardiol. 51, 1925-1934 (2008). (Pubitemid 351636443)
19. Hochholzer, W. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J. Am. Coll. Cardiol. 55, 2427-2434 (2010).
20. Maeda, A. et al. Differential impacts of CYP2C19 gene polymorphisms on the antiplatelet effects of clopidogrel and ticlopidine. Clin. Pharmacol. Ther. 89, 229-233 (2011).
21. Lee, J.M. et al. Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Am. J. Cardiol. 104, 46-51 (2009).
22. G ladding, P. et al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC. Cardiovasc. Interv. 1, 620-627 (2008).
23. Fre, C., Cuisset, T., Gaborit, B., Alessi, M.C. & Hulot, J.S. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J. Thromb. Haemost. 7, 1409-1411 (2009).
24. Sibbing, D. et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J. Thromb. Haemost. 8, 1685-1693 (2010).
25. Sibbing, D. et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur. Heart J. 30, 916-922 (2009).
26. Collet, J.P. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373, 309-317 (2009).
27. Simon, T. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med. 360, 363-375 (2009).
28. Mega, J.L. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 376, 1312-1319 (2010).
29. Wallentin, L. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLAT O trial. Lancet 376, 1320-1328 (2010).
30. Tiroch, K.A. et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am. Heart J. 160, 506-512 (2010).
31. Par G. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N. Engl. J. Med. 363, 1704-1714 (2010).
32. Bonello-Palot, N. et al. Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention. Am. J. Cardiol. 104, 1511-1515 (2009).
33. G ough, K. et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK join working party. Drug Inf. J. 29, 1039-1048 (1995).
34. Mehta, S.R. et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 376, 1233-1243 (2010).
35. Bhatt, D.L. Tailoring antiplatelet therapy based on pharmacogenomics: how well do the data fit? JAMA 302, 896-897 (2009).
36. Varenhorst, C. et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur. Heart J. 30, 1744-1752 (2009).
37. Shuldiner, A.R. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302, 849-857 (2009).
38. Jakubowski, J.A. et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb. Haemost. 99, 215-222 (2008).
39. Bhatt, D.L. et al. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 363, 1909-1917 (2010).
40. Garsa, A.A., McLeod, H.L. & Marsh, S. CYP3A4 and CYP3A5 genotyping by Pyrosequencing. BMC Med. Genet. 6, 19 (2005).
41. S weeny, J.M., Gorog, D.A. & Fuster, V. Antiplatelet drug 'resistance'. Part 1: mechanisms and clinical measurements. Nat. Rev. Cardiol. 6, 273-282 (2009).
42. Kolandaivelu, K. & Bhatt, D.L. Overcoming 'resistance' to antiplatelet therapy: targeting the issue of nonadherence. Nat. Rev. Cardiol. 7, 461-467 (2010).
43. Bouman, H.J. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat. Med. 17, 110-116 (2011).
44. Bhatt, D.L. Resisting the temptation to oversimplify antiplatelet resistance. JACC. Cardiovasc. Interv. 1, 660-662 (2008).
45. Angiolillo, D.J. et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin. Pharmacol. Ther. 89, 65-74 (2011).
46. S tephens, M. & Donnelly, P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162-1169 (2003). (Pubitemid 37414228)
47. Stephens, M., Smith, N.J. & Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978-989 (2001). (Pubitemid 32289743)
48. Fontana, P., Gaussem, P., Aiach, M., Fiessinger, J.N., Emmerich, J. & Reny, J.L. P2Y12 H2 haplotype is associated with peripheral arterial disease: a casecontrol study. Circulation 108, 2971-2973 (2003). (Pubitemid 37553564)
49. Born, G.V. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194, 927-929 (1962).
50. Jakubowski, J.A., Boulay-Moine, D., Bourguet, N., Sugidachi, A., Barragan, P. & Moulard, M. Abstract: Comparison of a novel elisa-based VASP whole blood (WB) assay with the flow cytometric (FC) technique. J. Thromb. Haemost. 7(Suppl 2), PP-MO-787 (2009).