The objective of this review is to report the pharmacologic and pharmacokinetic properties of prasugrel, the potential advantages and disadvantages over the other agent in its class, clopidogrel, and the clinical data establishing its efficacy in the management of patients with acute coronary syndromes receiving stent implantation. A MEDLINE (1966 to May 2008) search using the key word prasugrel was performed to identify pertinent literature. Additional references were selected from the bibliographies of the articles cited. Searches were not limited by time or human subject. Preclinical studies evaluating the pharmacologic and pharmacokinetic properties of prasugrel in humans were selected for review. Clinical trials assessing the efficacy of prasugrel for the treatment of patients with acute coronary syndromes receiving percutaneous coronary intervention were included as long as they were randomized, blinded, and controlled. The authors concluded that prasugrel is a thienopyridine antiplatelet agent with a faster onset of action and increased potency, in terms of inhibiting platelet aggregation, than clopidogrel. It has been shown in one major clinical trial that this enhanced pharmacological effect of prasugrel reduces the combined incidence of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke when compared with clopidogrel. However, this enhanced effect of prasugrel did result in an increased risk of bleeding.
FDA grants priority review for Daiichi Sankyo, Lilly drug, prasugrel . News release available at: http://www.sankyopharma.com/news/pdfs/Prasugrel_FDA_Grants_Priority_Review%20_2_.pdf. Accessed May 21, 2008.
2.
Daiichi Sankyo, Lilly, submit Marketing Authorization Application for investigational oral antiplatelet drug, prasugrel, to the European Medicines Agency. News release available at: http://www.sankyopharma.com/news/pdfs/EMEA_SUBMIT_FINAL_APPROVED.pdf . Accessed May 21, 2008.
3.
Mehta SR, Yusuf S., Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358: 527-533.
4.
Steinhubl SR , Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411-2420.
5.
King SB III, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the 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 (2007 Writing Group to Review New Evidence and Update the 2005 ACC/AHA/SCAI Guideline Update for Percutaneous Coronary Intervention) . J Am Coll Cardiol.2008;51: 172-209.
Siller-Matula J., Schror K., Wojta J., et al, Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost. 2007;97:385-393.
8.
Jakubowski JA , Winters KJ, Naganuma H., et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev.2007;25:357-374.
9.
Judge HM, Buckland RJ, Sugidachi A., et al. The active metabolite of prasugrel effectively blocks the P2Y12 receptor and inhibits procoagulant and pro-inflammatory platelet responses . Platelets. 2008;19:125-133.
10.
Ogawa T., Sugidachi A., Isobe T., et al. Greater in vivo potency of prasugrel (CS-747, LY640315) vs. clopidogrel is not explained by differential activity of active metabolites . European Society of Cardiology, 2005. Abstract P2954. Available at http://spo.escardio.org/ AbstractDetails.aspx?id=24613&eevtid=11. Retrieved June 13, 2008.
11.
Angiolillo DJ, Fernandez-Ortiz A., Bernardo E., et al. Identification of low-responders to 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res. 2005;115:101-108.
12.
Mobley JE, Bresee SJ, Wortham DC, et al. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol . 2004;93:456-458.
13.
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.
14.
Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and incidence of high-post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol. 2005;45: 1392-1396.
15.
Gurbel PA, Bliden KP, Zaman KA, et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation . 2005;111:1153-1159.
16.
von Beckerath N., Taubert D., Pogatsa-Murray G., et al. Absorption, metabolization, and antiplatelet effect 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. 2005;112:2946-2950.
Gurbel PA, Tantry USAspirin and clopidogrel resistance: consideration and management. J Interven Cardiol. 2006;19:439-448.
19.
Wenaweser P. , Dorffler-Melly J., Imboden K., et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol . 2005;45: 1748-1752.
20.
Gurbel PA, Bliden KP, Samara W., et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST study. J Am Coll Cardiol . 2005;46:1827-1832.
21.
Gurbel PA, Bliden KP, Guyer K., et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol . 2005;46:1820-1826.
22.
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.
23.
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.
24.
Sugidachi A. , Asai F., Ogawa T., et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129:1439-1446.
25.
Niitsu Y., Jakubowski JA, Sugidachi A., et al. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost. 2005;31:184-94.
26.
Sugidachi A. , Ogawa T., Kurihara A., et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite. J Thromb Haemost. 2007;5:1545-51.
27.
Williams ET, Jones KA, Ponsler GD, et al. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos [Epub ahead of print] . 2008. Available at: http://dmd.aspetjournals.org/cgi/reprint/dmd.107.020248v1 Retrieved April 29, 2008.
28.
Fayer 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.
29.
Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans . Drug Metab Dispos. 2007;35:1096-1104.
30.
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.
31.
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.e9-66.e16.
32.
Weerakkody GJ, Jakubowski JA, Brandt JT, et al. Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status. Am J Cardiol . 2007;100:331-336.
33.
Jernberg T. , Payne CD, Winters KJ, et al. 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;27:1166-1175.
34.
Wallentin L. , Varenhorst C., James S., et al. Prasugrel achieves greater and faster P2Y12 receptor-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.
35.
Wiviott SD, Trenk D., Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 Trial. Circulation. 2007;116:2923-2932.
36.
Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol. 2008;48:475-484.
37.
Farid NA, Payne CD, Ernest CS II, et al. Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol. 2008;48:53-59.
38.
Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y 12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medication to Block Platelets Optimally (JUMBO)-TIMI 26 Trial. Circulation. 2005;111: 3366-3373.
39.
Wiviott SD, Antman EM, Gibson M., et al. 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. 2006;152:627-635.
40.
Wiviott SD, Braunwald E., McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.
41.
Asai F., Jakubowski JA, Naganuma H., et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans. Platelets. 2006;17:209-217.
42.
Daiichi Sankyo , Lilly announce new prasugrel head-to-head phase III study against clopidogrel. News release available at: http://www.sankyopharma.com/news/pdfs/TRILOGY.pdf. Accessed June 6, 2008.
