Pharmacodynamic Comparisons for Single Loading Doses of Prasugrel (30mg) and Clopidogrel (600mg) in Healthy Korean Volunteers

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp let agent approved for the reduction of atherothrombotic cardiovascular events in patients presenting with ACS and undergoing percutaneous coronary intervention. 11,12 Several studies have reported greater, more rapid and more consistent platelet inhibition with prasugrel than with clopidogrel in healthy subjects as well as in patients with stable coronary artery disease. 13-15 Preclinical studies indicate that prasugrel is approximately 10-fold more potent than clopidogrel at inhibiting platelet aggregation, inhibiting thrombus formation and prolonging bleeding times. 16 The benefit of prasugrel relative to clopidogrel, however, can be accompanied by a higher risk of major bleeding. The large TRITON-TIMI 38 study provided the first conclusive evidence that prasugrel is associated with excess bleeding relative to clopidogrel (2.4% vs. 1.8%, P=0.03). 12 Although the approved LD is 60 mg, previous studies with prasugrel suggest that active metabolite exposure and pharmacodynamic response may be higher in Asian than in Caucasian subjects. 17 These findings prompted the current study, in which the pharmacodynamic responses to a lower prasugrel LD were ual anti-platelet therapy (aspirin and clopidogrel) is often recommended for patients undergoing stent implantation with acute coronary syndrome (ACS). 1-3 Clopidogrel is a thienopyridine prodrug, which, given orally, is metabolized to an active sulfhydryl form that binds to and irreversibly antagonizes the P2Y12 class of platelet adenosine diphosphate (ADP) receptor. 4 When an approved clopidogrel loading dose (LD) regimen of 600 mg is compared to a 300-mg LD, more rapid onset and a higher level of platelet inhibition can be achieved. 5,6 While the mechanisms of patient variability and resistance to clopidogrel therapy are not fully understood, genetic, clinical and cellular factors have been investigated. 7,8 Several studies have found that clopidogrel resistance has a significant correlation with higher risk of cardiovascular events. 9,10 Editorial p 1150As with other thienopyridines, prasugrel is an oral antiplate- Background: Previous studies involving a loading dose (LD) of 60 mg prasugrel have suggested that active metabolite exposure and pharmacodynamic responses may be higher in persons of Asian ethnicity than in Caucasian subjects. The aim of this study was to determine the pharmacodynamic effect of an LD of 30 mg prasugrel and 600 mg clopidogrel in healthy Korean volunteers.

Comparison of pharmacodynamics between low dose ticagrelor and clopidogrel after loading and maintenance doses in healthy Korean subjects

“…The platelet responses to clopidogrel were expressed in P2Y 12 Reaction Unit (PRU). The inhibition of platelet aggregation (IPA) calculated by VerifyNow assays were similar to LTA [15].…”

“…Therefore, the ACC/AHA/SCAI PCI guidelines give a Class I recommendation for oral loading doses of 180 mg, followed by doses of 90 mg twice daily when administered with percutaneous coronary intervention in coronary artery disease patients [11,12]. In previous studies, we observed that Asian patients showed higher active metabolite exposure rates and stronger pharmacodynamic responses than their Caucasian counterparts when treated with the same oral doses of prasugrel [13][14][15]. These findings prompted the current study, in which the pharmacodynamic responses to lower ticagrelor loading doses (LDs) and maintenance doses (MDs) were investigated in Korean subjects, which has not been widely investigated.…”

World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI

“…38 The higher exposure of the prasugrel active metabolite in East Asian individuals than in white patients translates into the pharmacodynamic profile. [36][37][38][39][40][41][42] In a single-centre study of healthy volunteers, the level of inhibition of platelet aggregation induced by 20 μmol/l ADP in East Asian individuals taking 5 mg of prasugrel daily did not differ from that in white individuals taking 10 mg of p rasugrel daily (mean value at 4 h last-dose: 68.9% vs 70.1%). 40 In Japanese patients undergoing PCI, 15 mg loading and 3.75 mg maintenance doses of prasugrel achieved a faster, higher, and more-consistent antiplatelet effect than 300 mg loading and 75 mg maintenance doses of clopidogrel.…”

Comparison of Prasugrel and Ticagrelor Antiplatelet Effects in Korean Patients Presenting With ST-Segment Elevation Myocardial Infarction

“…The results from our previous pharmacodynamic comparison studies revealed that lower doses of prasugrel or ticagrelor elicited more rapid, potent platelet inhibition than clopidogrel in healthy Korean subjects. 21, 22 Subsequently, we confirmed the pharmacodynamic effects of half doses of prasugrel in Korean patients with stable or unstable angina, 23 which resulted in a lower incidence of LPR without increasing the HPR rate compared with conventional doses. In addition, the PRASFIT-ACS, and PRASFIT-Elective studies published in Japan 24, 25 showed that much lower doses of prasugrel (20/3.75 mg) are appropriate for Japanese patients with stable or acute coronary artery disease undergoing PCI, with a low incidence of ischemic and bleeding events.…”