PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes

Journal of Thrombosis and Thrombolysis - Tập 41 - Trang 374-383 - 2015
Jessica L. Mega1, Sandra L. Close2, Stephen D. Wiviott1, Michael Man3, Suman Duvvuru3, Joseph R. Walker4, Scott S. Sundseth5, Jean-Philippe Collet6, Jessica T. Delaney7, Jean-Sebastien Hulot8,9, Sabina A. Murphy1, Guillaume Paré10, Matthew J. Price11, Dirk Sibbing12, Tabassome Simon13, Dietmar Trenk14, Elliott M. Antman1, Marc S. Sabatine1
1Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
2Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA
3Eli Lilly and Company, Indianapolis, USA
4Celgene Corporation, Summit, USA
5Cabernet Pharmaceuticals, Durham, USA
6Institut de Cardiologie, INSERM U 937, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
7Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, USA
8Cardiovascular Research Center, Mount Sinai School of Medicine, New York, USA
9Pharmacology Department, INSERM UMR S 956, Université Pierre et Marie Curie-Paris 6, Pitié-Salpêtrière University Hospital, Paris, France
10Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac Vascular and Stroke Research Institute, McMaster University, Hamilton, Canada
11Scripps Clinic and Scripps Translational Science Institute, La Jolla, USA
12I. Medizinische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany
13Department of Clinical Pharmacology, AP-HP, Hôpital Saint Antoine, INSERM U-698, Paris, France
14Klinik für Kardiologie und Angiologie II, Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany

Tóm tắt

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84–1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77–2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77–1.27) and 1.23 (0.74–2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.

Tài liệu tham khảo

Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E (2005) Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179–1189 The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events Trial Investigators (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502 Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM (2003) Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107:2908–2913 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362. doi:10.1056/NEJMoa0809171 Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375. doi:10.1056/NEJMoa0808227 Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G (2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373:309–317. doi:10.1016/S0140-6736(08)61845-0 Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304:1821–1830. doi:10.1001/jama.2010.1543 Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302:849–857. doi:10.1001/jama.2009.1232 Bouman HJ, Schomig E, van Werkum JW, Velder J, Hackeng CM, Hirschhauser C, Waldmann C, Schmalz HG, ten Berg JM, Taubert D (2011) Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 17:110–116. doi:10.1038/nm.2281 Payne CD, Li YG, Small DS, Ernest CS 2nd, Farid NA, Jakubowski JA, Brandt JT, Salazar DE, Winters KJ (2007) Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 50:555–562 Small DS, Payne CD, Kothare PA, Yuen ES, Natanegara F, Loh MT, Jakubowski JA, Winters KJ, Farid NA, Ni L, Li YG, Salazar DE, Kelly RP (2008) Comparison of pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel loading doses in healthy Chinese and Caucasian subjects. Clin Pharmacol Ther 83(Suppl 1):S56 Payne CD, Li YG, Brandt JT, Jakubowski JA, Small DS, Farid NA, Salazar DE, Winters KJ (2008) Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects. Platelets 19:275–281 Small DS, Farid NA, Li YG, Ernest CS II, Payne CD, Salazar DE, Winters KJ (2008) Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Curr Med Res Opin 24:2251–2257 Farid NA, Small DS, Payne CD, Jakubowski JA, Brandt JT, Li YG, Ernest CS, Salazar DE, Konkoy CS, Winters KJ (2008) Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacotherapy 28:1483–1494. doi:10.1592/phco.28.12.1483 H7T-FWTAAQ. Data on file, Eli Lilly, Data on file Farid NA, McIntosh M, Garofolo F, Wong E, Shwajch A, Kennedy M, Young M, Sarkar P, Kawabata K, Takahashi M, Pang H (2007) Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 21:169–179 Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015 Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM (2008) Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 371:1353–1363 Wiviott SD, Antman EM, Gibson CM, Montalescot G, Riesmeyer J, Weerakkody G, Winters KJ, Warmke JW, McCabe CH, Braunwald E (2006) Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J 152:627–635 Sibbing D, Koch W, Massberg S, Byrne RA, Mehilli J, Schulz S, Mayer K, Bernlochner I, Schomig A, Kastrati A (2011) No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J 32:1605–1613. doi:10.1093/eurheartj/ehr155 Trenk D, Hochholzer W, Fromm MF, Zolk O, Valina CM, Stratz C, Neumann FJ (2011) Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ Cardiovasc Genet 4:429–436. doi:10.1161/CIRCGENETICS.111.960112 Cayla G, Hulot JS, O’Connor SA, Pathak A, Scott SA, Gruel Y, Silvain J, Vignalou JB, Huerre Y, de la Briolle A, Allanic F, Beygui F, Barthelemy O, Montalescot G, Collet JP (2011) Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 306:1765–1774. doi:10.1001/jama.2011.1529 Campo G, Ferraresi P, Marchesini J, Bernardi F, Valgimigli M (2011) Relationship between paraoxonase Q192R gene polymorphism and on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Thromb Haemost 9:2106–2108. doi:10.1111/j.1538-7836.2011.04457.x Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, Scott SA, Montalescot G (2011) CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv 4:422–428. doi:10.1161/CIRCINTERVENTIONS.111.963025 Simon T, Steg PG, Becquemont L, Verstuyft C, Kotti S, Schiele F, Ferrari E, Drouet E, Grollier G, Danchin N (2011) Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction. Clin Pharmacol Ther 90:561–567. doi:10.1038/clpt.2011.193 Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC (2012) Predicting clopidogrel response using DNA samples linked to an electronic health record. Clin Pharmacol Ther 91:257–263. doi:10.1038/clpt.2011.221 Pare G, Ross S, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Fox KA, Eikelboom JW (2012) Effect of PON1 Q192R genetic polymorphism on clopidogrel efficacy and cardiovascular events in the clopidogrel in the unstable angina to prevent recurrent events trial and the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Circ Cardiovasc Genet 5:250–256. doi:10.1161/CIRCGENETICS.111.961417 Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, Schork NJ, Teirstein PS, Topol EJ (2012) Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol 59:1928–1937. doi:10.1016/j.jacc.2011.11.068 Chen DY, Wang CY, Wen MS, Lee TH, Chu Y, Hsieh MJ, Chang SH, Lee CH, Wang JL, Chen CC, Lu LS, Lee MT, Yeh SJ, Lin FC, Hsieh IC (2012) Paraoxonase-1 is not a major determinant of stent thrombosis in a Taiwanese population. PLoS One 7:e39178. doi:10.1371/journal.pone.0039178 Cuisset T, Morange PE, Quilici J, Bonnet JL, Gachet C, Alessi MC (2011) Paraoxonase-1 and clopidogrel efficacy. Nat Med 17:1039; author reply 42–4. doi:10.1038/nm.2367 Dansette PM, Rosi J, Bertho G, Mansuy D (2011) Paraoxonase-1 and clopidogrel efficacy. Nat Med 17: 1040–1041; author reply 2–4. doi:10.1038/nm.2436 Gong IY, Crown N, Suen CM, Schwarz UI, Dresser GK, Knauer MJ, Sugiyama D, Degorter MK, Woolsey S, Tirona RG, Kim RB (2012) Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response. Eur Heart J 33:2856–2864. doi:10.1093/eurheartj/ehs042 Regieli JJ, Jukema JW, Doevendans PA, Zwinderman AH, Kastelein JJ, Grobbee DE, van der Graaf Y (2009) Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention. J Am Coll Cardiol 54:1238–1245. doi:10.1016/j.jacc.2009.05.061 Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, Fu X, Shao M, Brennan DM, Ellis SG, Brennan ML, Allayee H, Lusis AJ, Hazen SL (2008) Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299:1265–1276. doi:10.1001/jama.299.11.1265 Lawlor DA, Day IN, Gaunt TR, Hinks LJ, Briggs PJ, Kiessling M, Timpson N, Smith GD, Ebrahim S (2004) The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women’s Heart and Health cohort study and a meta-analysis. BMC Genet 5:17. doi:10.1186/1471-2156-5-17
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Journal of Thrombosis and Thrombolysis

Tập 41

374-383

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