Cytochrome P450 2B6 and 2C9 genotype polymorphism – a possible cause of prasugrel low responsiveness

Cora C. Franken; Andreas F. C. Kaiser; Jan C. Krüger; Kristina Overbeck; Andreas Mügge; Horst Neubauer

doi:10.1160/TH13-01-0021

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 110(01): 131-140
DOI: 10.1160/TH13-01-0021

Platelets and Blood Cells

Schattauer GmbH

Cytochrome P450 2B6 and 2C9 genotype polymorphism – a possible cause of prasugrel low responsiveness

Autoren

Cora C. Franken

¹Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
Andreas F. C. Kaiser

¹Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
Jan C. Krüger

¹Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
Kristina Overbeck

¹Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
Andreas Mügge

¹Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany
Horst Neubauer

¹Cardiovascular Center, St. Josef – Hospital, Ruhr University Bochum, Bochum, Germany

Abstract

Summary

The cytochrome P450 (CYP) isoenzymes are essential for the metabolic activation of the prodrug prasugrel. Little is known about the impact of polymorphism of these isoenzymes on the prevalence of prasugrel low responsiveness (PLR) in patients with coronary artery disease. We investigated the frequency of PLR and the question whether PLR is associated with decreased/non-function polymorphisms of the CYP isoenzymes (2C9*2, 2C9*3, 2C19*2, 2C19*3, and 2B6*6). Our study included 355 patients who underwent percutaneous coronary stenting. The patients were initially treated with either prasugrel (n=90; 60/10 mg: loading/daily maintenance dose) or 600/75 mg clopidogrel hydrogensulfate (n=265) in combination with 500/100 mg acetylsalicylic acid (ASA). Platelet function was tested by impedance aggregometry 48 hours after taking the loading dose. Prasugrel achieved on the average significantly higher levels of platelet inhibition as compared to clopidogrel (mean 27.3 U vs 41.2 U). The frequencies of low response for prasugrel, clopidogrel and ASA were 9.8%, 35.1% and 14.9%, respectively. We identified only body mass index to be associated with PLR. PLR was not caused by a loss of ADP P2Y12-receptor function. Half of the patients with PLR were carriers of the reducedfunction allele CYP2B6*6, and 41.7% had the genetic variant CYP2C9*2. The allele CYP2C9*3 was detected in three patients with PLR (25%) and two patients with PLR (16.7%) carried the gene variant CYP2C19*2. In conclusion, the rate of low responders was significantly lower among patients treated with prasugrel than with clopidogrel. PLR are more often carriers of CYP2C9*2 (50% in PLR) than when compared to the prevalence described in literature. Also, there is a trend to an increased frequency of CYP2B6*6 in PLR. In conclusion, CYP2B6 and CYP2C9 polymorphisms seem to be associated with prasugrel low-response.

Keywords

Prasugrel - clopidogrel - low responder - platelet aggregation - cytochrome P450

Volltext

Referenzen

References
1 Sigwart U, Puel J, Mirkovitch V. et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987; 316: 701-706.
2 Cutlip DE, Baim DS, Ho KK. et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001; 103: 1967-1971.
3 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
4 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
5 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
6 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
7 Wenaweser P, Hess O. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005; 46: CS5-6.
8 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
9 Geisler T, Grass D, Bigalke B. et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost 2008; 06: 54-61.
10 DeWitt DL, el-Harith EA, Kraemer SA. et al. The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. J Biol Chem 1990; 265: 5192-5198.
11 Montalescot G, Wiviott SD, Braunwald E. et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731.
12 Ma Q, Lu AY. Pharmacogenetics, Pharmacogenomics, and Individualized Medicine. Pharmacological Rev 2011; 63: 437-459.
13 Ancrenaz V, Daali Y, Fontana P. et al. Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability. Curr Drug Metab 2010; 11: 667-677.
14 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
15 Neubauer H, Kaiser A, Busse B. et al. Identification, evaluation and treatment of prasugrel low-response after coronary stent implantation--a preliminary study. Thromb Res 2010; 126: e389-391.
16 Mega JL, Close SL, Wiviott SD. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-2560.
17 Bernlochner I, Mayer K, Morath T. et al. Antiplatelet efficacy of prasugrel in patients with high on-clopidogrel treatment platelet reactivity and a history of coronary stenting. Thromb Haemost 2013; 109: 517-524.
18 Neubauer H, Lask S, Engelhardt A. et al. How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 2008; 99: 357-362.
19 Kuliczkowski W, Witkowski A, Polonski L. et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2009; 30: 426-435.
20 Lang T, Klein K, Fischer J. et al. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 2001; 11: 643.
21 Schwab M, Marx C, Zanger UM. et al. Pharmakogenetik der Zytochrom- P-450-Enzyme: Bedeutung für Wirkungen und Nebenwirkungen von Medikamenten. Dtsch Arztebl 2002; 99: 497-504.
22 Kirchheiner J, Brockmöller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1-16.
23 Buzoianu AD, Trifa AP, Popp RA. et al. Screening for CYP2C19*2, *3 and *4 gene variants in a Romanian population study group. Farmacia 2010; 58: 806-817.
24 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
25 Weerakkody GJ, Jakubowski JA, Brandt JT. et al. Greater inhibition of platelet aggregation and reduced response variability with prasugrel versus clopidogrel: an integrated analysis. J Cardiovasc Pharmacol Ther 2007; 12: 205-212.
26 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: 66. e9–16.
27 Price MJ, Nayak KR, Barker CM. et al. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 103: 1339-1343.
28 Neubauer H, Kaiser AF, Endres HG. et al. Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance--the BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy. BMC Med 2011; 09: 3.
29 Geisler T, Gawaz M, Steinhubl SR. et al. Current strategies in antiplatelet therapy--does identification of risk and adjustment of therapy contribute to more effective, personalized medicine in cardiovascular disease?. Pharmacol Ther 2010; 127: 95-107.
30 Small DS, Farid NA, Payne CD. et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of Prasugrel. Clin Pharmacokinet 2010; 49: 777-798.
31 Mega JL, Close SL, Wiviott SD. 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 2010; 376: 1312-1319.
32 Brandt JT, Close SL, Iturria SJ. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 05: 2429-2436.
33 Rehmel JL, Eckstein JA, Farid NA. et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006; 34: 600-607.
34 Farid NA, Payne CD, Small DS. et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 2007; 81: 735-741.
35 Ingelman-Sundberg M, Sim SC, Gomez A. et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116: 496-526.
36 Mega JL, Close SL, Wiviott SD. et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-2560.
37 Ancrenaz V, Déglon J, Samer C. et al. Pharmacokinetic Interaction Between Prasugrel and Ritonavir in Healthy Volunteers. Basic Clin Pharmacol Toxicol. 2012 Epub ahead of print..
38 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
39 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
40 Bonello L, Pansieri M, Mancini J. et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011; 58: 467-473.
41 Alexopoulos D, Dimitropoulos G, Davlouros P. et al. Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping. JACC Cardiovasc Interv 2011; 04: 403-410.
42 Orban M, Riegger J, Joner M. et al. Dual thienopyridine low-response to clopidogrel and prasugrel in a patient with STEMI, cardiogenic shock and early stent thrombosis is overcome by ticagrelor. Platelets 2012; 23: 395-398.

Zusatzmaterial

Zusatzmaterial (PDF) (opens in new window)