Pharmacodynamic Comparisons for Single Loading Doses of

Circulation Journal Vol.77, May 2013

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

let agent approved for the reduction of atherothrombotic car-diovascular events in patients presenting with ACS and under-going 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 dis-ease.13–15 Preclinical studies indicate that prasugrel is approxi-mately 10-fold more potent than clopidogrel at inhibiting plate-let aggregation, inhibiting thrombus formation and prolonging bleeding times.16 The benefit of prasugrel relative to clopido-grel, 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 Al-though the approved LD is 60 mg, previous studies with pra-sugrel suggest that active metabolite exposure and pharmaco-dynamic 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 im-plantation 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 inhibi-tion 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 in-vestigated.7,8 Several studies have found that clopidogrel re-sistance has a significant correlation with higher risk of car-diovascular events.9,10

Editorial p 1150

As with other thienopyridines, prasugrel is an oral antiplate-

D

Received June 18, 2012; revised manuscript received October 28, 2012; accepted December 10, 2012; released online January 30, 2013 Time for primary review: 44 days

Department of Cardiology (M.H.K., H.-Z.Z.), Clinical Trial Center (M.H.K., H.-Z.Z., D.K.J.), Dong-A University Hospital, Busan; Depart-ment of Biomedical Engineering, College of Medicine, Dong-A University, Busan (D.K.J.), South Korea

The first two authors contributed equally to this work (M.H.K., H.-Z.Z.).Mailing address: Moo-Hyun Kim, MD, FACC, Department of Cardiology, College of Medicine, Dong-A University, 3-1 Dongdaeshin-

Dong, Seo-Gu, Busan 602-715, South Korea. E-mail: [email protected] doi: 10.1253/circj.CJ-12-0783All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Pharmacodynamic Comparisons for Single Loading Doses of Prasugrel (30 mg) and Clopidogrel (600 mg)

in Healthy Korean VolunteersMoo Hyun Kim, MD; Hong-Zhe Zhang, MD; Dong Keun Jung, MD

Background: Previous studies involving a loading dose (LD) of 60 mg prasugrel have suggested that active me-tabolite 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.

Methods and Results: Twelve volunteers were randomly assigned to a prasugrel or a clopidogrel group. Following a 2-week washout period, group designations and treatments were switched (6 per group). Platelet function was serially measured via light transmission aggregometry (LTA), VerifyNow and multiple electrode platelet aggregome-try (MEA) assays at baseline and 0.5, 2, 6, and 24 h after LD. Inhibition of platelet aggregation (IPA) at 0.5–24 h after prasugrel was significantly higher (P<0.001) than that achieved by clopidogrel. The prasugrel peak IPA at 2 h after LD was 93.7% (±6.2%) compared to the clopidogrel peak IPA at 6 h after LD at 65.8% (±17.2%). The VerifyNow and MEA assay yielded results similar to those obtained by LTA.

Conclusions: In healthy Korean subjects, a 30-mg LD of prasugrel yields a more rapid, potent and consistent inhi-bition of platelet function than a 600-mg LD of clopidogrel. (Circ J 2013; 77: 1253 – 1259)

Key Words: Clopidogrel; Light transmission aggregometry; Multiple electrode platelet aggregometry; Prasugrel; VerifyNow

ORIGINAL ARTICLEIschemic Heart Disease


1254 KIM MH et al.

Laboratory MeasurementsBlood samples for pharmacodynamic assessment were collected via direct venipuncture at baseline and 0.5, 2, 6, and 24 h after dosage. Platelet aggregation was assessed using 4 methods: traditional light transmission aggregometry (LTA), the Veri-fyNow P2Y12 assay (Accumetrics, San Diego, CA, USA), multiple electrode platelet aggregometry (MEA, Dynabyte Medical, Munich, Germany).

Platelet Function TestLTA was performed as previously described.18 Citrate antico-agulated whole blood was centrifuged at 120 g for 10 min at room temperature to obtain platelet-rich plasma. Platelet-poor plasma was obtained from the remaining specimen by re-centrifugation at 1,200 g for 10 min. Platelet-rich plasma was adjusted to a platelet count of 2.5×105/μl by adding platelet-poor plasma. Light transmission was calibrated using a cuvette with platelet-poor plasma, equated to 0% and a second cuvette containing platelet-rich plasma equated to 100%. To measure platelet function, 10 μmol/L ADP was added to induce platelet aggregation, before response curves were continuously record-ed for 6 min.

The VerifyNow assay (Accumetrics) is a whole-blood, car-tridge-based, optical detection system designed to measure platelet aggregation.19 The ADP P2Y12 receptor is measured in a cartridge channel of the VerifyNow P2Y12 assay contain-ing ADP, a platelet agonist and prostaglandin E1 (PGE1), a suppressor of intracellular free calcium level that reduces the non-specific contribution of ADP binding to P2Y1 receptors. The numerical results are then expressed as P2Y12 reaction units (PRU), baseline platelet function independent of P2Y12 receptor inhibition (BASE) and % inhibition. The % inhibition was calculated as follows: [(BASE – PRU) / BASE] × 100%. To avoid confusion of terminology, we define this value as P2Y12% inhibition, in contrast to % inhibition of PRU.

MEA was performed with a Multiplate Analyzer (Dynabyte Medical). The method has been described in detail elsewhere.20 Specifically, the adhesion and aggregation of platelets on sen-sor surfaces enhances the electrical resistance between 2 sen-sor electrodes. We used an ADP test (6.4 μmol/L ADP) to mon-itor the antiplatelet effects of clopidogrel. In the test cuvette, hirudin-anticoagulated whole blood (300 μl) was diluted (1:2 vol/vol) with 0.9% NaCl solution for 6.4 μmol/L, and ADP was stirred in for 3 min at 37°C, ADP in the absence of PGE1 was added, and the increase in electrical impedance was re-corded continuously for 6 min and converted into arbitrary aggregation units (AU; 8 AU corresponds approximately to 1 Ohm). The means of the 2 independent determinations were expressed as the area under the curve of aggregation tracing (AUC) in AU · min. The manufacturer recommended the use of arbitrary units (U) to simplify the expression of results (1 U = 10 AU · min = 1 AUC).

Definition of IPA and % InhibitionUsing the LTA, VerifyNow and MEA devices, we recorded MPA, P2Y12 PRU and U.

IPA (=% inhibition of MPA) from baseline was calculated using the following formula: % inhibition of MPA = [(MPA0 – MPAt) / MPA0] × 100%, in which MPAt is MPA at time (t) after dosing and MPA0 is MPA at baseline. The decrease in MPA (ΔMPA) was calculated as (MPA0 – MPAt).

Percent inhibition of PRU was determined using the Veri-fyNow assay. Percent inhibition was calculated using baseline PRU as follows: % inhibition of PRU = [(PRU0 – PRUt) / PRU0 × 100%], where PRU0 is the baseline PRU before dosing of

investigated in Korean subjects.The aim of this study was to compare the effects of a single

prasugrel 30-mg LD to a single clopidogrel LD of 600 mg on the inhibition of platelet aggregation (IPA) in healthy Korean volunteers.

MethodsSubjects and Study DesignThe subjects were 12 healthy men, aged 23–28 years (mean, 24.9 years), with body mass index (BMI) of 18.5–28.9 kg/m2 (mean, 23.7 kg/m2), screened for a baseline maximum platelet aggregation (MPA) response ≥55% to 10 μmol/L ADP and hav-ing standard results on usual clinical tests (including a hepatic function test, renal function test, complete blood count and coagulation study). Clinical laboratory testing was conducted at the Department of Laboratory Medicine, Dong-A Univer-sity Hospital in Busan, South Korea. The exclusion criteria included the taking of aspirin, other antiplatelet agent or anti-inflammatory drugs, a history of bleeding tendency, reason-able suspicion of vascular malformations, or abnormal co-agulation values and the presence of a disorder that might potentially change the absorption, metabolism or removal of the drugs, or those that could constitute a risk to the subject during the study. No concurrent medications were permitted during the study. Each subject provided fully informed con-sent prior to entering the study.

This was a randomized, 2-way cross-over, open-label study in healthy subjects conducted at a single center from August to September 2011. Twelve subjects were randomly assigned to receive either 30 mg of prasugrel (prasugrel group) or 600 mg of clopidogrel (clopidogrel group) during the initial dosing period. Following a 2-week washout period, the sub-jects received the alternate thienopyridine (prasugrel or clopi-dogrel, Figure 1). Each dose of prasugrel or clopidogrel was given with 200 ml of water following an overnight fast. Ve-nous blood samples were obtained for pharmacodynamic mea-surements before dosing (baseline) and at regular intervals in the 24 h afterwards.

Figure 1. Study design overview.


1255Pharmacodynamic Effect of Prasugrel and Clopidogrel

>46.8 U,9 at 24 h after the LD.

SafetySafety assessments performed during volunteer screening vis-its included physical examination, measurement of vital signs, 12-lead electrocardiogram, hematology, clinical chemistry, coagulation, urinalysis, fecal occult blood test, fundoscopy anal-ysis and examination for petechiae. Adverse events were re-corded and monitored throughout the study.

prasugrel or clopidogrel, and PRUt is the value for each sub-ject at selected time points.

For % inhibition of U, the MEA assays were similar to LTA and VerifyNow.

Comparison of the percentage of pharmacodynamic non-responders in the prasugrel and clopidogrel groups was per-formed 24 h after the LD. For this analysis, a pharmacody-namic non-responder was defined as 10 μmol/L ADP MPA ≥55%,21 VerifyNow P2Y12 >240 PRU9 and MEA assay

Figure 2. Mean (SD) inhibition of platelet ag-gregation after a single dose of 30 mg prasu-grel and a single dose of 600 mg clopidogrel in Korean subjects, as measured by (A) light transmission aggregometry (LTA); (B) Veri-fyNow; and (C) multiple electrode platelet aggregometry (MEA). Data have been stag-gered around the time points to improve leg-ibility. *P<0.001, prasugrel vs. clopidogrel.


1256 KIM MH et al.

P<0.001; Figure 2A). The prasugrel 30-mg LD also achieved greater IPA at 2 h (93.7%) and 6 h (93.3%) after dosage, com-pared to the 2-h and 6-h peak IPA for clopidogrel 600 mg (65.7% and 65.8%, all P<0.001). Using the criteria for 10 μmol/L ADP in the LTA assay, 8.3% of subjects at 24 h were classified as pharmacodynamics non-responders to clopidogrel, whereas all subjects responded to the prasugrel 30-mg LD.

As measured by the VerifyNow assay, the mean % inhibi-tion of PRU after a 30-mg dose of prasugrel was significantly higher than for the clopidogrel 600-mg dose at all time points (P<0.001; Figure 2B; Table). Thirty minutes after dosage, the % inhibition of PRU was nearly 6-fold higher in the prasugrel group than in the clopidogrel group (58.3% vs. 10.6%, P<0.001). The VerifyNow assay showed that peak % inhibition of PRU was achieved at 2 h (91.3%) after dosage in the prasugrel group compared to the 6-h (46.3%) and 24-h (48.5%) peak % inhibi-tion in the clopidogrel group (P<0.001; Figure 2B).

Similar to LTA and VerifyNow, the MEA assay showed the mean % inhibition of AUC after a 30-mg dose of prasugrel to be significantly higher than that following a 600-mg dose of clopidogrel at all time points (all P<0.01; Figure 2C; Table). The MEA assay showed that peak % inhibition was achieved at 2 h (78.9%) in the prasugrel group compared to a 6-h (46%) peak % inhibition for the clopidogrel group (Figure 2C). By VerifyNow and MEA criteria, pharmacodynamics non-respond-ers to clopidogrel comprised 25% of the subjects at 24 h, where-as all subjects responded to the prasugrel 30-mg LD.

Comparison of Degree of Inhibition of Platelet Function and Correlation Between DevicesThe calculated IPA by LTA testing and % inhibition by Veri-fyNow assays (IPA and % inhibition of PRU) showed that the 30-mg LD regimen of prasugrel resulted in greater inhibition of platelet function than that measured by MEA (% inhibition of U). The LTA assay after a 600-mg clopidogrel LD, how-ever, showed higher % inhibition than that determined by VerifyNow and MEA (Table). The correlation between the calculation of IPA and % inhibition after LDs of prasugrel and clopidogrel were as follows (baseline up to 24 h after LD): LTA vs. MEA, r=0.73; LTA vs. VerifyNow, r=0.83; and MEA vs. VerifyNow, r=0.67 (P<0.001). As measured by IPA and % inhibition at 6 h after dosage response to ADP, prasugrel pro-duced higher and more consistent IPA than clopidogrel (Figure 3).

The VerifyNow device can calculate % inhibition using its

Statistical AnalysisThe cross-over study design allowed the extent of a subject’s IPA after clopidogrel dosing to be contrasted with the same subject’s response to prasugrel. In 2 previous studies, the probability of detecting a mean difference in IPA was 15–20% between groups at any time point.14,22 The present hypothesis was therefore based on a calculation to provide 90% power to detect a mean difference in IPA of 20% between groups at any time point on a 2-sided test at a 0.1 level of significance, with the assumption that the standard deviation of IPA response for each study drug LD treatment is 15%. Accordingly, 12 subjects in each group were required.

A mixed-effect ANCOVA model was used to compare mean IPA and % inhibition between prasugrel and clopidogrel at each time point. The model allowed for different variability across time after the LD and across the 2 treatments. To ac-count for the multiple IPA or % inhibition measurements taken from each subject, each subject was treated as a random effect; time and treatment were used as fixed effects in the model. Pearson’s correlation coefficient was used for evaluation of the association between LTA, VerifyNow and MEA assay systems. Statistical analysis was performed using SPSS ver-sion 14 (SPSS, Chicago, IL, USA). All statistical tests were carried out at the 0.05 significance level.

The primary endpoint included the differences in mean IPA or % inhibition between the 30-mg prasugrel LD and the 600-mg clopidogrel group at each time point.

ResultsTwelve healthy male subjects with a mean BMI of 23.7± 3.3 kg/m2 were enrolled in the study. Both LD treatments were well tolerated, with no volunteer leaving the study due to ad-verse events. There were no clinically significant bleeding events or occurrences of thrombocytopenia. These data were not statistically different, indicating that the 2-week washout period provided enough time for the reversal of platelet inhibi-tion associated with the first dosing period.

IPA and % InhibitionThe mean IPA to 10 μmol/L ADP was significantly higher after the prasugrel 30-mg dose than after the clopidogrel 600-mg dose, at all time points (P<0.001; Figure 2A; Table). At 30 min after LD, prasugrel 30 mg achieved a greater mean IPA to 10 μmol/L ADP (70.3%) than clopidogrel 600 mg (21%;

Table. Inhibition of Platelet Aggregation

0.5 h 2 h 6 h 24 h

LTA (%)

Prasugrel 75.8±11.3 93.7±6.2　　 93.3±5.5　　 85.9±8.3　　 Clopidogrel 16.3±15.5 65.7±21.1 65.8±17.2 59.7±17.7

P-value <0.001 <0.001 <0.001 <0.001

VerifyNow (%)

Prasugrel 58.3±31.6 91.3±8.5　　 90.6±8.7　　 88.7±7.1　　 Clopidogrel 10.6±8.9 43.1±17.7 46.3±21.7 48.5±18.1

P-value <0.001 <0.001 <0.001 <0.001

MEA (%)

Prasugrel 70.3±10.6 78.9±13.8 67.7±10.5 67.3±9.0　　 Clopidogrel 21.0±19.9 45.3±23.6 46.0±23.6 30.4±17.0

P-value <0.001 <0.001 0.017 <0.001

Data given as mean ± SD. LTA, light transmission aggregometry; MEA, multiple electrode platelet aggregometry.



In that study,22 peak levels of prasugrel active metabolites (Cmax) were 67% higher in Chinese and 39% higher after ad-justment for differences in bodyweight, than for Caucasian volunteers. Taking into account ethnic differences in body-weight and BMI, the Asian ethnic group could have at least 30–70% higher active metabolite concentrations than the Caucasian group. The present study showed that 10 μmol/L ADP induced 85.9% IPA after 24 h. These results reflect pre-viously published work reporting a 60-mg LD in mean IPA (using 20 μmol/L ADP as agonist) to be 72% for Caucasian, 83% for Chinese, 81% for Korean and 78% for Japanese sub-

own references (base values). The correlation between % in-hibition calculated using baseline PRU and its own base value was high (r=0.97), therefore they can be used interchangeably (Figure 4).

DiscussionIn the present study, a 30-mg LD of prasugrel achieved faster onset, higher levels, and less variability in the inhibition of platelet activity than an LD of clopidogrel at 600 mg. A faster onset for IPA after prasugrel was evident in a number of pa-rameters. As early as 30 min after LD, the IPA (% inhibition of platelet function) was greater in response to prasugrel than clopidogrel. The maximum effect began to plateau at 2 h after prasugrel compared to 6 h after clopidogrel. The magnitude of IPA or % inhibition was higher at 30 min after LD in the pra-sugrel group than it was at any point during the 24-h period of observation for the clopidogrel group. In addition, on the basis of previously defined criteria, 8.3–25% of the subjects at 24 h were pharmacodynamics non-responders to the clopidogrel LD, whereas all subjects were classified as responders to the prasugrel LD.

Rationale for Low LD and Maintenance Doses in Asian PatientsIn the TRITON-TIMI 38 trial, patients who received prasugrel had improved cardiovascular outcomes but also experienced more bleeding events, compared to those receiving clopido-grel.23 An ideal dosing regimen would include LD and main-tenance doses that are adequate to yield the clinical benefits of increased platelet inhibition without an increased risk of bleed-ing. Small et al reported that even after normalization for body-weight, prasugrel active metabolite exposure was approximate-ly 30% higher in Asian subjects when compared with Caucasian subjects after an LD of 60 mg prasugrel, concluding that pra-sugrel may not be appropriate for Asian subjects.17 Another study demonstrated that LDs of 60 mg or 40 mg of prasugrel did not show any difference in IPA with 20 μmol/L of ADP.24 Other reports indicated that 30 mg of prasugrel produces great-er platelet inhibition and higher prasugrel active metabolite concentrations than 300 mg of clopidogrel in Chinese subjects.22

Figure 3. Relationship between inhibition of platelet aggregation and % inhibition by 30 mg prasugrel or 600 mg clopidogrel in response to light transmission aggregometry, VerifyNow and multiple electrode aggregometry (MEA), 6 h after loading dose. Subjects were given both prasugrel and clopidogrel in a cross-over fashion.

Figure 4. Relationship between reported VerifyNow % inhibi-tion and calculated % inhibition of P2Y12 reaction units from baseline before medication. Correlation coefficient (r) was calculated by the Pearson method. Blue circles, clopidogrel; red triangles, prasugrel. Symbols represent individual simul-taneous measurements at baseline up to 24 h after loading dose.


1258 KIM MH et al.

inhibition using the present standard definitions. The LTA and MEA assays use ADP as an agonist for assessing P2Y12 ef-fects, which can confound the results through the possible activation of ADP receptor subtypes other than P2Y12, con-tributing to platelet aggregation. In contrast, VerifyNow uses 2 reagents (ADP and PGE1) as contributors to ADP-induced aggregation via the P2Y1 receptor in response to ADP. There-fore, it can be concluded that VerifyNow is more suitable for comparing the specific P2Y12 inhibitory effects of thieno-pyridine. This may also partially explain inconsistencies in data arising from the different devices.

Study LimitationsThis study was performed with normal male volunteers with-out aspirin medication, which is not always reflective of typi-cal patients. We did not measure the active metabolites of pra-sugrel and clopidogrel.

ConclusionsIn this direct cross-over comparison of healthy Korean sub-jects, a 30-mg LD of prasugrel yielded a more rapid, potent and consistent inhibition of platelet function than a 600-mg LD of clopidogrel.

AcknowledgmentsThis study was supported by a grant from the Korea Healthcare Technol-ogy R&D Project, Ministry of Health and Welfare (A070001) and by the Basic Science Research Program through the National Research Founda-tion of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2012R1A1A2005932), Republic of Korea. The authors thank Ju Yeong Lee for technical assistance with platelet function mea-surement. We also thank Lee Farrand for assistance with the manuscript.

DisclosuresThe authors declare no conflicts of interest.

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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.

2. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernandez-Aviles F, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598 – 1660.

3. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, et al. Addi-tion of clopidogrel to aspirin in 4582 patients with acute myocardial infarction: Randomized placebo controlled trial. Lancet 2005; 366: 1607 – 1621.

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5. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Reg-imen: Choose Between 3 High Oral Doses for immediate Clopido-grel Effect) Trial. Circulation 2005; 112: 2946 – 2950.

6. Montelascot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, et al. A randomized comparison of high clopidogrel load-ing doses in patients with non-ST-segments elevation acute coronary syndromes. J Am Coll Cardiol 2006; 48: 931 – 938.

7. Nishio R, Shinke T, Otake H, Sawada T, Haraguchi Y, Shinohara M, et al. Effect of cytochrome P450 polymorphism on target lesion out-come after drug-eluting stent implantation in Japanese patients re-ceiving clopidogrel. Circ J 2012; 76: 2348 – 2355.

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jects at 24 h afterwards.17 The VerifyNow % inhibition of PRU for the prasugrel group and the clopidogrel group at 2 h was 91.3% vs. 43.1%, respectively. These results are also in line with those reported for Swedish subjects using a 60-mg LD of prasugrel and a 600-mg LD of clopidogrel at 2 h, as 93.8% vs. 43.9%.25 The present results suggest that a lower LD of prasu-grel (30 mg) might be an alternative option for patients of East Asian ethnicity. These findings need to be validated in coro-nary stent patients in the future. Regarding the pharmacody-namics of prasugrel maintenance doses in Caucasian subjects, Jakubowski et al tested multiple doses of prasugrel (20 mg, 10 mg, 5 mg), which resulted in a dose-dependent inhibition of platelet activity and IPA (5 μmol/L ADP) that were signifi-cantly greater with prasugrel (77.2%, 70.5% and 52.7%) com-pared with clopidogrel 75 mg (36.5%).16 In an Asian study, Yokoi et al compared several different LDs and MDs (10-mg LD/2.5-mg MD, 15-mg LD/3.75-mg MD, 20-mg LD/5-mg MD and 300-mg clopidogrel LD and 75-mg MD).26 In that study,26 a 10-mg LD/2.5-mg MD regimen was similar to clop-idogrel 300-mg LD/75-mg MD. These dosages are 1/6 and 1/4 of the current manufacturer recommended LD and MD.

Differences in Metabolic Pathways Between Prasugrel and ClopidogrelIn relation to clopidogrel, the faster onset of prasugrel platelet aggregation effects can be attributed to a difference in the meta-bolic pathways leading to the formation of the respective ac-tive metabolites.23,27,28 Prasugrel and clopidogrel require cyto-chrome P450 (CYP) metabolism for the generation of active metabolites, but the pathways leading to these metabolites differ between the pro-drugs.28 The esterase-mediated step for prasugrel occurs predominantly in the intestine, as does the CYP-mediated oxidative step leading to active metabolite for-mation. Hydrolysis of the remaining 15% of clopidogrel, how-ever, also occurs by 2 CYP-dependent steps. The slower met-abolic alteration of clopidogrel lowers the rate and level of active metabolite formation compared to the process for pra-sugrel active metabolite formation.29 Differences in the me-tabolism of the 2 drugs also lead to markedly different plasma concentrations of the active metabolites. The exposure to pra-sugrel following an LD of 60 mg was approximately 12-fold greater than that following 300-mg clopidogrel.30 The metabo-lism of prasugrel to its active metabolite therefore has greater pharmacokinetic benefits than the same process for clopido-grel. These differences underpin the relative efficacy of prasu-grel vs. clopidogrel.

Assessment of IPA or % Inhibition After Prasugrel and Clopidogrel LDThe pharmacodynamic responses to prasugrel, as measured by IPA and % inhibition, were also consistently higher than re-sponses to clopidogrel. Given the present cross-over study design, individual responses to each agent and the degree of variability of IPA and % inhibition could be assessed. It was observed from the intra-individual responses to the 2 agents that although variability was present in response to both agents, each individual participant had a significant increase in IPA (as measured through the different tests) with prasugrel rela-tive to clopidogrel (Figure 3). In addition, even in subjects with poor response to clopidogrel, platelet inhibition was suc-cessful following prasugrel, thereby minimizing the possibil-ity of variations in P2Y12 function potentially causing clopi-dogrel response variability.

IPA and % inhibition of PRU was >90% on LTA and the VerifyNow after prasugrel, but on MEA it was <80% platelet



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21. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, et al. High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myo-cardial infarction in acute coronary syndrome patients receiving coro-nary stenting. Thromb Haemost 2010; 104: 279 – 286.

22. Small DS, Payne CD, Kothare P, Yuen E, Natanegara F, Loh MY, et al. Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese and white volunteers: An open-label trial. Clin Ther 2010; 32: 365 – 379.

23. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzylio W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001 – 2015.

24. Jakubowski JA, Payne CD, Brandt JT, Weerakkody GJ, Farid NA, Small DS, et al. The platelet inhibitory effects and pharmacokinetics of prasugrel after administration of loading and maintenance doses in healthy subjects. J Cardiovasc Pharmacol 2006; 47: 377 – 384.

25. Varenhorst C, James S, Erlinge D, Braun OO, Brandt JT, Winters KJ, et al. Assessment of P2Y12 inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin. Am Heart J 2009; 157: 562.e1 – e9.

26. Yokoi H, Kimura T, Isshiki T, Ogawa H, Ikeda Y. Pharmacodynamic assessment of a novel P2Y12 receptor antagonist in Japanese pa-tients with coronary artery disease undergoing elective percutaneous coronary intervention. Thromb Res 2012; 129: 623 – 628.

27. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, 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 – e16.

28. Norgard NB, Abu-fadel M. Comparison of prasugrel and clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Vasc Health Risk Manag 2009; 5: 873 – 882.

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