Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel

Journal of Thrombosis and Haemostasis

Volumn 5, Issue 12, 2007, Pages 2429-2436

  Brandt, John T ^a   Close, S L ^a   Iturria, S J ^a   Payne, C D ^a   Farid, N A ^a   Ernest, C S ^a   Lachno, D R ^a   Salazar, D ^b   Winters, K J ^a  

^a ELI LILLY AND COMPANY   (United States)

^b DAIICHI SANKYO INC   (United States)

Author keywords

Clopidogrel; Cytochrome P450 enzymes; P2Y12 receptor; Platelet function; Prasugrel; Thienopyridines

Indexed keywords

CLOPIDOGREL; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; PRASUGREL;

ADULT; AREA UNDER THE CURVE; ARTICLE; CLINICAL TRIAL; DRUG METABOLISM; ENZYME METABOLISM; ENZYME POLYMORPHISM; FEMALE; GENE IDENTIFICATION; GENETIC ANALYSIS; GENETIC VARIABILITY; GENOTYPE; HUMAN; HUMAN EXPERIMENT; IN VITRO STUDY; LIQUID CHROMATOGRAPHY; LOADING DRUG DOSE; MALE; MAXIMUM PLASMA CONCENTRATION; PRIORITY JOURNAL; TANDEM MASS SPECTROMETRY; THROMBOCYTE AGGREGATION; THROMBOCYTE FUNCTION;

ADULT; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; BLOOD PLATELETS; CLINICAL TRIALS AS TOPIC; CROSS-OVER STUDIES; FEMALE; GENOTYPE; HUMANS; MALE; MIDDLE AGED; MIXED FUNCTION OXYGENASES; PHENOTYPE; PIPERAZINES; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; POLYMORPHISM, GENETIC; PRODRUGS; RECEPTORS, PURINERGIC P2; REFERENCE VALUES; RESEARCH DESIGN; RETROSPECTIVE STUDIES; THIOPHENES; TICLOPIDINE;

EID: 36348943475     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/j.1538-7836.2007.02775.x     Document Type: Article

References (39)

1. Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005; 31: 174-83.
2. Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-46.
3. Goto S, Tamura N, Ishida H, Ruggeri ZM. Dependence of platelet thrombus stability on sustained glycoprotein IIb/IIIa activation through adenosine 5'-diphosphate receptor stimulation and cyclic calcium signaling. J Am Coll Cardiol 2006; 47: 155-62.
4. Cattaneo M. The platelet P2Y receptors as targets for new antithrombotic drugs. J Thromb Haemost 2003; 1: 1133-5.
5. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002; 288: 2411-20.
6. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
7. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction-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). J Am Coll Cardiol 2002; 40: 1366-74.
8. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB III, Morrison DA, O'Neil WW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Nishimura R, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006; 113: E166-286.
9. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Barrera-Ramirez C, Sabate M, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Macaya C. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005; 115: 101-8.
10. Gurbel PA, Bliden KP, Hiatt BL, O'connor CM. Clopidogrel for coronary stenting: Response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-13.
11. Gurbel PA, Tantry US. Drug insight: Clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006; 3: 387-95.
12. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-6.
13. Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol 2004; 93: 456-8.
14. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-7.
15. Ajzenberg N, Aubry P, Huisse MG, Cachier A, El AW, Feldman LJ, Himbert D, Baruch D, Guillin MC, Steg PG. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: A case-control study. J Am Coll Cardiol 2005; 45: 1753-6.
16. Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, Lafont A, Camoin L, Walter U, Eigenthaler M. Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302.
17. Cuisset T, Frere C, Quilici J, Barbou F, Morange PE, Hovasse T, Bonnet JL, Alessi MC. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 4: 542-9.
18. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-32.
19. Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, Tantry US. Platelet reactivity in patients and recurrent events post-stenting: Results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46: 1820-6.
20. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-5.
21. Asai F, Jakubowski JA, Naganuma H, Brandt JT, Matsushima N, Hirota T, Freestone S, Winters KJ. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A single ascending dose study in healthy humans. Platelets 2006; 17: 209-17.
22. Jakubowski JA, Payne CD, Brandt JT, Weerakkody GJ, Farid NA, Small DS, Naganuma H, Li GY, Winters KJ. The platelet inhibitory effects and pharmacokinetics of prasugrel after administration of loading and maintenance doses in healthy subjects. J Cardiovasc Pharmacol 2006; 47: 377-84.
23. Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-73.
24. Matsushima N, Jakubowski JA, Asai F, Naganuma H, Brandt JT, Hirota T, Freestone S, Winters KJ. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A multiple-dose study in healthy humans. Platelets 2006; 17: 218-26.
25. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ. 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.
26. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F. The greater in vivo antiplatelet effects of prasugrel compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to clopidogrel's active metabolite. J Thromb Haemost 2007; 5: 1545-51.
27. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, Wrighton SA, Ring BJ. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006; 34: 600-7.
28. Caplain H, Donat F, Gaud C, Necciari J. Pharmacokinetics of clopidogrel. Semin Thromb Hemost 1999; 25 (Suppl. 2): 25-8.
29. Lins R, Broekhuysen J, Necciari J, Deroubaix X. Pharmacokinetic profile of 14C-labeled clopidogrel. Semin Thromb Hemost 1999; 25 (Suppl. 2): 29-33.
30. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-6.
31. Kurihara A, Hagihara K, Kazui M, Ishizuka T, Farid NA, Ikeda T. In vitro metabolism of antiplatelet agent clopidogrel: Cytochrome P450 isoforms responsible for two oxidation steps involved in active metabolite formation. Drug Metab Rev 2005; 37 (Suppl. 2): 99.
32. Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS, Brandt JT, Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 2007; 81: 735-41.
33. Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1-16.
34. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41: 913-58.
35. Weerakkody GJ, Brandt JT, Payne CD, Jakubowski JA, Naganuma H, Winters KJ. Clopidogrel poor responders: An objective definition by Bayesian classification. Platelets 2007; 18: 428-35.
36. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708-16.
37. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-7.
38. Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ, Lee DS, Sohn DW, Lee MM, Kim HS. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006; 174: 1715-22.
39. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E, Sabate M, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Pignatti PF, Macaya C. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006; 26: 1895-900.