Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways

Oscar Ö. Braun; Dominick J. Angiolillo; Jose L. Ferreiro; Joseph A. Jakubowski; Kenneth J. Winters; Mark B. Effron; Suman Duvvuru; Timothy M. Costigan; Scott S. Sundseth; Joseph R. Walker; Jorge F. Saucedo; Neal S. Kleiman; Christoph Varenhorst

doi:10.1160/TH13-03-0263

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(06): 1223-1231
DOI: 10.1160/TH13-03-0263

Platelets and Blood Cells

Schattauer GmbH

Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways

Authors

Oscar Ö. Braun

¹Department of Cardiology, Lund University, Skåne University Hospital, Lund, Sweden
Dominick J. Angiolillo

²University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
Jose L. Ferreiro

³Heart Diseases Institute, Hospital Universitari de Bellvitge – IDIBELL, University of Barcelona, Barcelona, Spain
Joseph A. Jakubowski

⁴Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Kenneth J. Winters

⁴Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Mark B. Effron

⁴Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Suman Duvvuru

⁴Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Timothy M. Costigan

⁴Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
Scott S. Sundseth

⁵Cabernet Pharmaceuticals, Inc., Once Science Drive, Durham, North Carolina, USA
Joseph R. Walker

⁶Daiichi Sankyo, Inc., Edison, New Jersey, USA
Jorge F. Saucedo

⁷Division of Cardiology, North-Shore University HealthSystem, Evanston, Illinois, USA
Neal S. Kleiman

⁸Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA
Christoph Varenhorst

⁹Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Science Park, Uppsala, Sweden

Abstract

Summary

Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow^® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

Keywords

Clopidogrel - prasugrel - CYP2C19 - PON1 - ABCB1 - platelet function

Full Text

References

References
1 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569-2619.
2 Bertrand ME, Rupprecht HJ, Urban P. et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624-629.
3 Braunwald E, Antman EM, Beasley JW. et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002; 106: 1893-1900.
4 Hamm CW, Bassand JP, Agewall S. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054.
5 Gurbel PA, Tantry US. Clopidogrel resistance?. Thromb Res 2007; 120: 311-321.
6 Taubert D, Von Beckerath N, Grimberg G. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
7 Savi P, Combalbert J, Gaich C. et al. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450–1A. Thromb Haemost 1994; 72: 313-317.
8 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
9 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
10 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.
11 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.
12 Varenhorst C, James S, Erlinge D. 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 2009; 30: 1744-1752.
13 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
14 Wallentin L, James S, Storey RF. 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 PLATO trial. Lancet 2010; 376: 1320-1328.
15 Sibbing D, Koch W, Gebhard D. et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121: 512-518.
16 Cuisset T, Loosveld M, Morange PE. et al. CYP2C19*2 and *17 Alleles Have a Significant Impact on Platelet Response and Bleeding Risk in Patients Treated With Prasugrel After Acute Coronary Syndrome. JACC Cardiovasc Interv 2012; 5: 1280-1287.
17 Grosdidier C, Quilici J, Loosveld M. et al. Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications. Am J Cardiol 2013; 111: 985-990.
18 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.
19 Bouman HJ, Schomig E, van Werkum JW. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17: 110-116.
20 Angiolillo DJ, Saucedo JF, Deraad R. et al. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study. J Am Coll Cardiol 2010; 56: 1017-1023.
21 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.
22 Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116: 496-526.
23 Daly TM, Dumaual CM, Miao X. et al. Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport. Clin Chem 2007; 53: 1222-1230.
24 Aleil B, Ravanat C, Cazenave JP. et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005; 3: 85-92.
25 Myrand SP, Sekiguchi K, Man MZ. et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther 2008; 84: 347-361.
26 Center for Disease Control. U.S. Genome Variation Estimates: PON1 Allele and Genotype Frequencies. Available at: http://www.cdc.gov/genomics/population/genvar/frequencies/PON1.htm 2013 Accessed January 31, 2013.
27 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
28 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.
29 Frere C, Cuisset T, Gaborit B. et al. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost 2009; 7: 1409-1411.
30 Gurbel PA, Shuldiner AR, Bliden KP. et al. The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy. Am Heart J 2011; 161: 598-604.
31 Bauer T, Bouman HJ, van Werkum JW. et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. Br Med J 2011; 343: d4588.
32 Leschziner GD, Andrew T, Pirmohamed M. et al. ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 2007; 7: 154-179.
33 Simon T, Verstuyft C, Mary-Krause M. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-375.
34 Sibbing D, Koch W, Massberg S. et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J 2011; 32: 1605-1613.
35 Lewis JP, Fisch AS, Ryan K. et al. Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response. Clin Pharmacol Ther 2011; 90: 568-574.
36 Dansette PM, Rosi J, Bertho G. et al. Paraoxonase-1 and clopidogrel efficacy. Nat Med 2011; 17: 1040-1041.
37 Reny JL, Combescure C, Daali Y. et al. Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 2012; 10: 1242-1251.