Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants

British Journal of Clinical Pharmacology

Volumn 73, Issue 1, 2012, Pages 93-105

  Kelly, Ronan P ^a   Close, Sandra L ^b,d   Farid, Nagy A ^b   Winters, Kenneth J ^b   Shen, Lei ^b   Natanegara, Fanni ^b   Jakubowski, Joseph A ^b   Ho, Mary ^a   Walker, Joseph R ^c   Small, David S ^b  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b ELI LILLY AND COMPANY   (United States)

^c DAIICHI SANKYO INC   (United States)

^d INDIANA UNIVERSITY   (United States)

Author keywords

Clopidogrel; CYP2C19; Genetic polymorphism; Pharmacodynamic; Pharmacokinetic; Prasugrel

Indexed keywords

CLOPIDOGREL; CYTOCHROME P450 2C19; PRASUGREL;

ADULT; ARTICLE; BLEEDING; BLOOD ANALYSIS; CHINESE; CONTROLLED STUDY; CONTUSION; CROSSOVER PROCEDURE; DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG WITHDRAWAL; FEMALE; GENETIC VARIABILITY; GENOTYPE; HETEROZYGOTE; HUMAN; HUMAN EXPERIMENT; MALE; NORMAL HUMAN; PHENOTYPE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; THROMBOCYTE AGGREGATION; TREATMENT RESPONSE;

ADULT; ARYL HYDROCARBON HYDROXYLASES; BLOOD PLATELETS; CROSS-OVER STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INTERACTIONS; FEMALE; HUMANS; MALE; PEDIGREE; PIPERAZINES; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; POLYMORPHISM, GENETIC; PURINERGIC P2Y RECEPTOR ANTAGONISTS; THIOPHENES; TICLOPIDINE; YOUNG ADULT;

EID: 83155173178     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/j.1365-2125.2011.04049.x     Document Type: Article

References (43)

1. Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol 2010; 50: 126-42.
2. 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.
3. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. 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 2010; 38: 92-9.
4. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in ABCB1, CYP2C19, and cardiovascular outcomes following treatment with clopidogrel and prasugrel. Lancet 2010; 376: 1312-9.
5. Farid NA, Smith RL, Gillespie TA, Rash TJ, Blair PE, Kurihara A, Goldberg MJ. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 2007; 35: 1096-104.
6. Williams ET, Jones KO, Ponsler GD, Lowery SM, Perkins EJ, Wrighton SA, Ruterbories KJ, Kazui M, Farid NA. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos 2008; 36: 1227-32.
7. Payne CD, Li YG, Small DS, Ernest CS 2nd, Farid NA, Jakubowski JA, Brandt JT, Salazar DE, Winters KJ. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50: 555-62.
8. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite. J Thromb Haemost 2007; 5: 1545-51.
9. 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.
10. Combescure C, Fontana P, Mallouk N, Berdague P, Labruyere C, Barazer I, Gris JC, Laporte S, Fabbro-Peray P, Reny JL, CLOpidogrel and Vascular ISchemic Events Meta-analysis Study Group. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 923-33.
11. 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.
12. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429-36.
13. Fontana P, Hulot JS, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. J Thromb Haemost 2007; 5: 2153-5.
14. Kim KA, Park PW, Hong SJ, Park JY. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther 2008; 84: 236-42.
15. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-62.
16. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119: 2553-60.
17. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Buonamici P, Antoniucci D, Abbate R, Gensini GF. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 2009; 103: 806-11.
18. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL. 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: 1744-52.
19. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363-75.
20. Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KAA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-14.
21. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121: 512-8.
22. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103-13.
23. Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF. Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J 2011; 11: 199-206.
24. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership [Internet]. Plavix® (clopidogrel bisulfate) tablets: highlights of prescribing information. Available at (last accessed 2 September 2010).
25. Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY, Eddy SM, Dostalik J, Mount J, Azuma J, Fujio Y, Jang IJ, Shin SG, Bleavins MR, Williams JA, Paulauskis JD, Wilner KD. 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: 347-61.
26. Man M, Farmen M, Dumaual C, Teng CH, Moser B, Irie S, Noh GJ, Njau R, Close S, Wise S, Hockett R. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 2010; 50: 929-40.
27. Farid NA, McIntosh M, Garofolo F, Wong E, Shwajch A, Kennedy M, Young M, Sarkar P, Kawabata K, Takahashi M, Pang H. Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007; 21: 169-79.
28. Takahashi M, Pang H, Kawabata K, Farid NA, Kurihara A. Quantitative determination of clopidogrel active metabolite in human plasma by LC-MS/MS. J Pharm Biomed Anal 2008; 48: 1219-24.
29. Weerakkody GJ, Brandt JT, Payne CD, Jakubowski JA, Naganuma H, Winters KJ. Clopidogrel poor responders: an objective definition based on Bayesian classification. Platelets 2007; 18: 428-35.
30. Patti G, Nusca A, Mangiocapra F, Gatto L, D'Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention: results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008; 52: 1128-33.
31. Bonello L, Paganelli F, Arpin-Bornet M, Auquier P, Sampol J, Dignat-George F, Barragan P, Camoin-Jau L. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 5: 1630-36.
32. Dumaual C, Miao X, Daly TM, Bruckner C, Njau R, Fu DJ, Close-Kirkwood S, Bauer N, Watanabe N, Hardenbol P, Hockett RD. Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System. Pharmacogenomics 2007; 8: 293-305.
33. Human Cytochrome P450 (CYP) Allele Nomenclature Committee [Internet]. Available at (last accessed 2 September 2010).
34. Special report: genotyping for cytochrome P450 polymorphisms to determine drug-metaboliser status. Technol Eval Cent Asses Program Exec Summ 2004; 19: 1-2.
35. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352: 2211-21.
36. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76: 391-6.
37. Small DS, Li YG, Ernest CS 2nd, April JH, Farid NA, Payne CD, Winters KJ, Rohatagi S, Ni L. Integrated analysis of pharmacokinetic data across multiple clinical pharmacology studies of prasugrel, a new thienopyridine antiplatelet agent. J Clin Pharmacol 2011; 51: 321-32.
38. Giusti B, Gori AM, Marcucci R, Saracini C, Vestrini A, Abbate R. Drug and medical device interactions: stent thrombosis and personalizing clopidogrel therapy. Curr Pharmacogenomics Pers Med 2010; 8: 124-38.
39. Mega JL, Simon T, Anderson JL, Bliden K, Collet JP, Danchin N, Giusti B, Gurbel P, Horne BD, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. CYP2C19 genetic variants and clinical outcomes with clopidogrel: a collaborative meta-analysis. Circulation 2009; 120: S598-9.
40. Payne CD, Li YG, Brandt JT, Jakubowski JA, Small DS, Farid NA, Salazar DE, Winters KJ. Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects. Platelets 2008; 19: 275-81.
41. Montalescot G, Sideris G, Cohen R, Meuleman C, Bal dit Sollier C, Barthelemy O, Henry P, Lim P, Beygui F, Collet JP, Marshall D, Luo J, Petitjean H, Drouet L. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study. Thromb Haemost 2010; 103: 213-23.
42. 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. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-15.
43. Farid NA, Payne CD, Winters KJ, Ernest CS 2nd, 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.