Prasugrel: A novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile

Cardiovascular Drug Reviews

Volumn 25, Issue 4, 2007, Pages 357-374

  Jakubowski, Joseph A ^a   Winters, Kenneth J ^a   Naganuma, Hideo ^b   Wallentin, Lars ^c  

^a ELI LILLY AND COMPANY   (United States)

^b DAIICHI SANKYO CO   (Japan)

^c UPPSALA UNIVERSITY   (Sweden)

Author keywords

Acute coronary syndrome; Clopidogrel; P2Y12; Platelets; Prasugrel; Thienopyridines

Indexed keywords

3 [7 [2 (3,4 DIFLUOROPHENYL)CYCLOPROPYLAMINO] 5 PROPYLTHIO 1,2,3 TRIAZOLO[4,5 D]PYRIMIDIN 3 YL] 5 HYDROXYMETHOXY 1,2 CYCLOPENTANEDIOL; ACETYLSALICYLIC ACID; ADENOSINE DIPHOSPHATE; CANGRELOR; CLOPIDOGREL; CYTOCHROME P450; DRUG METABOLITE; PRASUGREL; PURINE P2Y12 RECEPTOR; R 138727; TICLOPIDINE; UNCLASSIFIED DRUG;

ACUTE CORONARY SYNDROME; BLEEDING; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG BINDING; DRUG POTENCY; DRUG STRUCTURE; HEMATOLOGIC DISEASE; HEMATOMA; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LOADING DRUG DOSE; LOW DRUG DOSE; MONOTHERAPY; NONHUMAN; PERCUTANEOUS CORONARY INTERVENTION; PRIORITY JOURNAL; REVIEW; SKIN BRUISING; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION; THROMBOGENESIS; THROMBOSIS;

ANIMALS; DRUG EVALUATION, PRECLINICAL; HUMANS; MODELS, BIOLOGICAL; MOLECULAR STRUCTURE; PIPERAZINES; PLATELET AGGREGATION INHIBITORS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; THIOPHENES;

EID: 36849074168     PISSN: 08975957     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1527-3466.2007.00027.x     Document Type: Review

References (74)

1. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA (2007) Variability in individual responsiveness to clopidogrel: Clinical implications, management, and future perspectives. J Am Coll Cardiol 49 : 1505 1516.
2. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, et al. (2004) ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Available at http://www.acc.org/qualityandscience/clinical/guidelines/stemi/Guideline1/index. pdf. Accessed 1 May 2007.
3. 12 inhibitor: A single-ascending dose study in healthy humans. Platelets 17 : 209 217.
4. Badimon L, Badimon JJ, Fuster V (2002) Platelets in thrombotic and non thrombotic disorders. In : Pathophysiology of arterial thrombosis New York : Cambridge University Press, 727 737.
5. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH CLASSICS Investigators (2000) 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 102 : 624 629.
6. Born GV, Cross MJ (1963) The aggregation of blood platelets. J Physiol 168 : 178 195.
7. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ (2007a) A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153 : 66. e9-e16.
8. Brandt JT, Close SL, Iturria CD, Payne CD, Farid NA, Ernest II. CS, Lachno DR, Salazar D, Winters KJ (2007b) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost, published online September 27, 2007.
9. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al. (2002) ACC/AHA 2002 Guidelines for the management of patients with unstable angina non-ST segment elevation myocardial infarction. Available at http://www.acc.org/ qualityandscience/clinical/guidelines/unstable/incorporated/UA_incorporated.pdf. Accessed 2 May 2007.
10. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D (2007) Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 49 : 2312 2317.
11. Cattaneo M (2007) Platelet P2 receptors: Old and new targets for antithrombotic drugs. Expert Rev Cardiovasc Ther 5 : 45 55.
12. The Clopidogrel in Unstable Angina to Prevent Recurrent 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.
13. 12 receptor in platelet activation. J Clin Invest 113 : 340 345.
14. Emmons KL, Taylor NR (2007) Contemporary issues in clopidogrel therapy: New evidence shaping clinical practice. Pharmacotherapy 27 : 553 563.
15. Eshaghian S, Kaul S, Amin S, Shah PK, Diamond GA (2007) Role of clopidogrel in managing atherothrombotic cardiovascular disease. Ann Intern Med 146 : 434 441.
16. Farid NA, Smith RL, Gillespie TA, Rash TJ, Blair PE, Kurihara A, Goldberg MJ (2007a) The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 35 : 1096 1104.
17. Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd., Brandt JT, Darstein C, Jakubowski JA, Salazar DE (2007b) Cytochrome P450 3A inhibition by ketoconazole affects prsaugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 81 : 735 741.
18. Frelinger AL III., Jakubowski JA, Li YF, Barnard MR, Fox ML, Linden MD, Sugidachi A, Winters KJ, Furman MI, Michelson AD (2005) The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Leukocyte-platelet and platelet-platelet aggregation and platelet surface p-selecting and activated GPIIb-IIIa. Circulation 112 (Suppl S U449.
19. Frelinger AL III., Jakubowski JA, Li Y, Barnard MR, Fox ML, Linden MD, Sugidachi A, Winters KJ, Furman MI, Michelson AD (2006a) The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin. Thromb Haemost 98 : 192 200.
20. Frelinger AL III., Jakubowski JA, Li YF, Barnard MR, Fox ML, Linden MD, Sugidachi A, Winters KJ, Furman MI, Michelson AD (2006b) The active metabolite of prasugrel inhibits platelet procoagulant activities. Circulation 114 (Suppl S 699.
21. Gachet C, Hechler B (2005) The platelet P2 receptors in thrombosis. Semin Thromb Hemost 31 : 162 167.
22. de Gaetano G (2001) Historical overview of the role of platelets in hemostasis and thrombosis. Haematologica 86 : 349 356.
23. Geisler T, Gawaz M (2007) Variable response to clopidogrel in patients with coronary artery disease. Semin Thromb Hemost 33 : 196 202.
24. Goldschmidt PJ, Lopes N, Crawford LE (2002) Atherosclerosis and coronary artery disease. In Platelets San Diego : Elsevier Science, 375 398.
25. Gurbel PA, Tantry US (2006) Drug insight: clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 3 : 387 395.
26. Hochholzer W, Trenk D, Frundi D, Blanke P, Fischer B, Andris K, Bestehorn HP, Büttner HJ, Neumann FJ (2005) Time dependence of platelet inhibition after 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 111 : 2560 2564.
27. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Büttner HJ, Neumann FJ (2006) 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 48 : 1742 1750.
28. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, et al. (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409 : 202 207.
29. Hulot JS, Bura A, Villard E, Azizi M, Remomes V, Goyenvalle C, Aiach M, Lechat P, Gaussem P (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108 : 2244 2247.
30. 12 antagonist AZD6140 with aspirin in patients with atherosclerosis: A double-blind comparison to clopidogrel with aspirin. Eur Heart J 27 : 1038 1047.
31. Jackson SP (2007) The growing complexity of platelet aggregation. Blood 109 : 5087 5095.
32. Jacobsson F, Swahn E, Wallentin L, Dellborg M (2002) Safety profile and tolerability of intravenous AR-C69931 MX, a new antiplatelet drug, in unstable angina pectoris and non-Q-wave myocardial infarction. Clin Ther 24 : 752 765.
33. 12 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharm 63 : 421 430.
34. Jakubowski JA, Payne CD, Weerakkody GJ, Brandt JT, Farid NA, Li YG, Naganuma H, Lachno DR, Winters KJ (2007) Dose-dependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects. J Cardiovasc Pharmocol 49 : 167 173.
35. Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L (2006) 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 27 : 1166 1173.
36. 12 receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets (in press).
37. Kahner BN, Shankar S, Murugappan S, Prasad L, Kunapuli SP (2006) Nucleotide receptor signaling in platelets. J Thromb Haemost 4 : 2317 2326.
38. Kurihara A, Kazui M, Hagihara T, Isobe T, Ogawa T, Sugidachi A, Farid NA, Ikeda T (2005) Potent inhibition of platelet aggregation by prasugrel (CS-747, LY640315), a novel thienopyridine antiplatelet agent, is associated with covalent binding of active metabolite to ADP receptor. Eur Heart J 26 (Suppl 1 485.
39. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KL, Giambartolomei A, Diver DJ, Lasorda DM, Kuntz RE, et al. (1998) A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. New Engl J Med 339 : 1665 1671.
40. 14C-labeled clopidogrel. Semin Thromb Hemost 25 (Suppl 2 29 33.
41. Massberg S, Schulz C, Gawaz M (2003) Role of platelets in the pathophysiology of acute coronary syndrome. Semin Vasc Med 3 : 147 162.
42. 12 inhibitor: A multiple-dose study in healthy humans. Platelets 17 : 218 226.
43. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, et al. (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358 : 527 533.
44. Michelson AD, Frelinger III AL, Furman MI (2006) Current options in platelet function testing. Am J Cardiol 98 (Suppl 4N 10N.
45. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, Slama M, Milleron O, Collet JP, Henry P, et al. (2006) A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: The ALBION trial. J Am Coll Cardiol 48 : 931 8.
46. 12 receptor antagonist activity. Semin Thromb Hemost 31 : 184 194.
47. O'Donoghue M, Wiviott SD (2006) Clopidogrel response variability and future therapies: Clopidogrel: Does one size fit all? Circulation 114 : e600-606.
48. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Sciascio G (2005) Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 111 : 2099 2106.
49. Payne CD, Brandt JT, Weerakkody GJ, Farid NA, Small DS, Ernest CS, Jansen M, Jakubowski JA, Naganuma H, Wiviott SD, et al. (2005) Superior inhibition of platelet aggregation following a loading dose CS-747 (prasugrel, LY640315) versus clopidgrel: correlation with pharmacokinetics of active metabolite generation. J Thromb Haemost 3 (Suppl 1 P0952.
50. Payne CD, Li YG, Ernest CS, Jakubowski JA, Brandt JT, Salazar DE, Winters KJ (2006) A prasugrel 60 mg loading dose achieves faster onset and higher levels of platelet inhibition compared with 300 mg and 600 mg clopidogrel doses [abstract]. Am J Cardiol 98 (Suppl 1 8M.
51. Peters G, Robbie G (2004) Single-dose pharmacokinetics and pharmacodynamics of AZD6140-an oral reversible ADP receptor antagonist [abstract]. Haematologica 989 (Suppl 7 14.
52. ® United States Package Insert 2006) Bristol-Myers Squibb/Sanofi Pharmaceuticals.
53. Quinn MJ, Fitzgerald DJ (1999) Ticlopidine and clopidogrel. Circulation 100 : 1667 1672.
54. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, Wrighton SA, Ring BJ (2006) Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent with the cytochromes P450. Drug Metab Dispos 34 : 600 607.
55. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 84 : 891 896.
56. Sharis PJ, Cannon CP, Loscalzo J (1998) The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 129 : 394 405.
57. 12 inhibition by prasugrel compared to high dose clopidogrel assessed by VASP phosphorylation in patients with stable coronary artery disease [abstract]. J Thromb Haemost Available at http: //www.isth.org.
58. Siller-Matula J, Schrör K, Wojta J, Huber K (2007) Thienopyridines in cardiovascular disease: Focus on clopidogrel resistance. Thromb Haemost 97 : 385 393.
59. Smith SC, Feldman TE, Hirshfeld JW, Jacobs AK, Kern MJ, King SB, Morrison DA, ONeill WW, Schaff HV, Whitlow PL, et al. (2005) ACC/AHA/SCAI 2005 Guideline update for percutaneous coronary intervention. Available at http://www.acc.org/qualityandscience/clinical/guidelines/percutaneous/update/ index_rev.pdf. Accessed 2 May 2007.
60. Steinhubl SR, Berger PB, Mann JT, Fry ET, DeLago A, Wilmer C, Topol EJ CREDO Investigators (Clopidogrel for the Reduction of Events During Observation) (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 288 : 2411 2420.
61. Storey RF, Oldroyd KG, Wilcox RG (2001) Open multicentre study of the P2T receptor antagonist AR-C69931 MX assessing safety, tolerability and activity in patients with acute coronary syndrome. Thromb Haemost 85 : 401 407.
62. Storey RF, Wilcox RG, Heptinstall S (2002) Comparison of pharmcodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931 MX in patients with ischaemic heart disease. Platelets 13 : 407 413.
63. Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H (2000) The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 129 : 1439 1446.
64. Sugidachi A, Asai F, Yoneda K, Iwamura R, Ogawa T, Otsuguro, Koike H (2001) Antiplatelet action of R-99224, an active metabolite of a novel thienopyridine-type Gi-linked P2T antagonist, CS-747. Br J Pharmacol 132 : 47 54.
65. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, Asai F (2007) 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 5 : 1545 1551.
66. Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ, Lee DS, Sohn DW, Lee MM, Kim HS (2006) Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. Can Med Assoc J 174 : 1715 1722.
67. Tantry US, Bliden KP, Gurbel PA (2007) AZD6140. Expert Opin Investig Drugs 16 : 225 229
68. ® United States Package Insert 2001) Roche Pharmaceuticals.
69. Varenhorst C, Braun O, James S, Erlinge D, Winters KJ, Brandt JT, Jakubowski JA, Costigan T, Siegbahn A, Wallentin LC (2007) Greater inhibition of platelet aggregation with a prasugrel 60 mg loading dose in aspirin-treated patients [abstract]. Eur Heart J, 28 (Suppl 1 189.
70. von Beckerath N, Taubert D, Pogatsa-Murray G, Schömig E, Kastrati A, Schömig A (2005) Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose between 3 high oral doses for immediate clopidogrel effect) trial. Circulation 112 : 2946 2950.
71. Weerakkody GJ, Brandt JT, Payne CD, Jakubowski JA, Naganuma H, Winters KJ (2007) Clopidogrel poor responders: An objective definition based on Bayesian classification. Platelets 18 : 428 435.
72. 12 antagonist, with clopidogrel in percutaneous coronary intervention: Results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 111 : 3366 3373.
73. Wiviott SD, Antman EM, Gibson CM, Montalescot G, Riesmeyer J, Weerakkody G, Winters KJ, Warmke JW, McCabe CH, Braunwald E, for the TRITON-TIMI 38 Investigators (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.
74. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, et al 2007) A Clinical Trial of Prasugrel vs. Clopidogrel in Patients with Acute Coronary Syndromes. New Engl J Med 357: 2001-2015.