Mg Maintenance Dose Research Articles

Antiplatelet efficacy of ticagrelor versus clopidogrel in Mediterranean patients with diabetes mellitus and chronic coronary syndromes: A crossover pharmacodynamic investigation.

Patients with diabetes mellitus (DM) have augmented platelet reactivity and diminished responsiveness to clopidogrel. Ticagrelor, a more potent P2Y12 inhibitor, is clinically superior to clopidogrel in acute coronary syndromes, although its role in chronic coronary syndromes (CCS) is still the subject of debate. The aim of this investigation was to compare the pharmacodynamic effectiveness of ticagrelor and clopidogrel in Mediterranean DM patients with CCS. In this prospective, randomized, crossover study, patients (n = 20) were randomized (1:1) to receive, on top of aspirin therapy, either ticagrelor 180 mg loading dose (LD)/90 mg maintenance dose (MD) b.i.d. or clopidogrel 600 mg LD/75 mg MD o.d. for 1 week in a crossover fashion with a 2-4 week washout period between regimens. Platelet function measurements were performed at 4 timepoints in each period (baseline, 2 h and 24 h after LD, and 1 week), including light transmission aggregometry (LTA, primary endpoint), VASP assay, Multiplate and VerifyNow P2Y12. The ticagrelor LD achieved greater platelet inhibitory effect than clopidogrel LD, assessed with LTA (20 μM ADP as agonist), at 2 h (34.9 ± 3.9% vs. 63.6 ± 3.9%; p < 0.001) and 24 h (39.4 ± 3.5% vs. 52.3 ± 3.8%; p = 0.014). After 1 week of therapy, platelet reactivity was again significantly inferior with ticagrelor compared to clopidogrel (30.7 ± 3.0% vs. 54.3 ± 3.0%; p < 0.001). The results were consistent with the other platelet function assays employed. In Mediterranean patients with DM and CCS, ticagrelor provides a more potent antiplatelet effect than clopidogrel after the LD and during the maintenance phase of therapy. [ClinicalTrials.gov], identifier [NCT02457130].

Pharmacodynamics and Outcomes of a De-Escalation Strategy with Half-Dose Prasugrel or Ticagrelor in East Asians Patients with Acute Coronary Syndrome: Results from HOPE-TAILOR Trial.

East Asians treated with potent P2Y12 inhibitors (prasugrel or ticagrelor) generally experience more intense platelet inhibitory responses resulting in an increased risk of major bleeding. Whether a half-dose de-escalation strategy improves the net clinical benefit in Korean patients with acute coronary syndrome (ACS) remains uncertain. A total of 120 patients were pragmatically randomized to either prasugrel (n = 39, 60 mg loading dose (LD)/10 mg maintenance dose (MD)), ticagrelor (n = 40, 180 mg LD/90 mg MD), or clopidogrel (n = 41, 600 mg LD/75 mg MD) followed by a half-dose reduction at 1 month, or conventional dose 75 mg clopidogrel. The primary endpoint was the incidence of optimal platelet reactivity (OPR), defined as a P2Y12 reaction unit (PRU) value between 85 and 208 (by VerifyNow) at 3 months. Ticagrelor treatment achieved a significantly lower PRU compared with prasugrel and clopidogrel (31.0 ± 34.5 vs. 93.2 ± 57.1 vs. 153.1 ± 69.4), resulting in the lowest rate of OPR (12.5% vs. 48.7% vs. 63.4%). At 9 months, the minor bleeding was significantly higher with potent P2Y12 inhibitors than with clopidogrel (31.6% vs. 12.2%; HR, 2.93; 95% CI, 1.12–7.75). Only a few patients experienced ischemic complications. In Korean ACS patients, a de-escalation strategy with half-dose ticagrelor and prasugrel from standard dose increased the OPR rate significantly. Half-dose ticagrelor had a lower OPR rate and greater platelet inhibition compared with half-dose prasugrel as well as conventional-dose clopidogrel. Optimal dose reduction strategies for potent P2Y12 inhibitors require further investigation to balance safety and efficacy.

Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects.

Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease. The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic. A single oral dose of 180mg ticagrelor was administered to 14 healthy male subjects in a randomized study. Common single-nucleotide polymorphisms (SNPs) in biotransformation enzymes CYP3A4 and CYP3A5 (CYP3A4*1G and CYP3A5*3) were genotyped by PCR-direct sequencing. Blood samples were collected to measure plasma concentrations of ticagrelor and its active metabolite AR-C124910XX and maximal platelet inhibition. Various models were evaluated to characterize the pharmacokinetics of ticagrelor and AR-C124910XX as well as their PK-PD relationship. Covariates that may potentially affect PK or PD of ticagrelor and AR-C124910XX were included and assessed. Simulation for dosage regimen was performed based on the final PK-PD model. Ticagrelor and AR-C124910XX PK were best described by a two-compartment model with first-order transit absorption model. CYP3A4*1G increased clearance for AR-C124910XX, but had no significant effect on ticagrelor clearance. The relationship between concentration and platelet response of ticagrelor was best described by a turnover model. Simulation results indicated that a lower dosage regimen of 30mg maintenance dose (MD) could produce an anticipated anti-platelet response in comparison to the routine clinical dosage regimen (180mg loading dose (LD), 90mg MD). Our study developed a population PK-PD model for ticagrelor and further simulation for dosage regimen was performed based on the final model. Compared to the current recommended dosage regimen (180mg LD, 90mg MD), our simulation result of a relatively lower dose (30mg MD) could also obtain an acceptable anti-platelet response, which may provide a reference for further dosage regimen design in Chinese population.

Bleeding events and maintenance dose of prasugrel: BLESS pilot study

ObjectiveTo evaluate changes in residual platelet reactivity (RPR) over time, and bleeding and ischaemic events rate using 5 vs 10 mg maintenance dose (MD) regimens of prasugrel 1 month after...

Ticagrelor versus prasugrel in patients with high on-clopidogrel treatment platelet reactivity after PCI: The ISAR-ADAPT-PF study

Patients with high on-treatment platelet reactivity (HTPR) on clopidogrel are at high risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). The aim of the ISAR-ADAPT-PF study was to assess the antiplatelet efficacy of ticagrelor versus prasugrel in patients with HTPR on clopidogrel. In a prospective and randomized clinical study, 70 patients with HTPR on clopidogrel loading dose (LD) within 24 h post PCI were assigned to receive either ticagrelor [180 mg LD followed by 90 mg maintenance dose (MD) twice daily] or prasugrel (60 mg LD followed by 10 mg MD once daily). The adenosine diphosphate-induced platelet aggregation assessed on the Multiplate analyzer on day 2 after randomization (primary end point) was as follows: the mean difference between the two treatment groups was 6 aggregation units (AU) × min with an upper 95% confidence interval (CI) of 41 AU × min, which was greater than the predefined noninferiority margin of 18 AU × min (P for noninferiority = 0.29). However, no significant differences in absolute platelet reactivity levels between ticagrelor- versus prasugrel-treated patients at that time point were observed (138 ± 100 AU × min vs. 132 ± 64 AU × min, P for superiority = 0.77). In conclusion, neither drug was statistically more effective for inhibition of platelet aggregation in patients with HTPR on clopidogrel post PCI, although the study could not formally demonstrate the assumed noninferiority of ticagrelor versus prasugrel.

An analysis of TRITON-TIMI 38, based on the 12 month recommended length of therapy in the European label for prasugrel

Background:In TRITON-TIMI 38, patients with acute coronary syndromes were treated with prasugrel or clopidogrel, with aspirin, for a median of 14.5 (maximum of 15) months. Based on this trial, the EU label for prasugrel recommends treatment for up to 12 months and excludes patients with prior stroke/transient ischemic attack (TIA). Furthermore, the EU label recommends the 10 mg maintenance dose (MD) for patients with body weight ≥60 kg and age <75 years. A lower MD of 5 mg is recommended for those with body weight <60 kg; although generally not recommended, 5 mg can be prescribed to patients ≥75 years after individual risk–benefit evaluation. This paper presents the one-year outcome data for this ‘10 mg indicated cohort’.Methods and results:From the overall cohort of 13,608 patients in TRITON-TIMI 38, 10,804 fulfilled inclusion criteria for the 10 mg indicated cohort, of whom 22% had a history of diabetes, 73% an index diagnosis of unstable angina/non-ST-segment-elevation myocardial infarction (UA/NSTEMI), and 27% an index diagnosis of ST-segment-elevation myocardial infarction (STEMI). In this cohort at 12 months, those given prasugrel experienced significantly fewer ischemic events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, 7.8% vs 10.5%, hazard ratio (HR) = 0.73, p < 0.001, than those given clopidogrel, with a non-significant increase in non-coronary artery bypass graft (CABG) TIMI major bleeding, 1.7% vs 1.5%, HR = 1.15, p = 0.40; similarly, in the overall cohort these frequencies were 9.4% vs 11.4%, HR = 0.81, p < 0.001, for cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, and 2.2% vs 1.8%, HR = 1.24, p = 0.10, for non-CABG TIMI major bleeding. There was a significant reduction in stent thrombosis in the prasugrel group, with similar mortality rates and no excess of strokes.Conclusions:Treatment with prasugrel according to EU label recommendations results in a significant 27% and 57% relative risk reduction (absolute risk reductions of 2.7% and 1.2%) in ischemic events and stent thromboses respectively compared with clopidogrel, with a 15% relative risk increase (absolute risk increase of 0.2%) for major bleeds (p = 0.40), and no excess of strokes.Limitations:Although restricted to 365 days of follow-up, this analysis encapsulates 1366 of 1424 (95.9%) of all primary endpoint events and 244 of 257 (94.9%) of all first non-CABG TIMI major bleeds reported in the pivotal manuscript. Furthermore, the 10 mg indicated cohort was not a pre-specified subgroup in the study protocol, but due to European labeling restrictions, results for all outcomes in this cohort are presented through 12 months.

Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study

The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6±48.4% versus +0.8±53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %±24.8% vs. -72.9%±32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.

A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial

AimsPatients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM.Methods and resultsOptimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used.ConclusionIn patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.Clinical trial identifier: www.clinicaltrials.gov—NCT00642174

Increased Platelet Inhibition After Switching From Maintenance Clopidogrel to Prasugrel in Patients With Acute Coronary Syndromes: Results of the SWAP (SWitching Anti Platelet) Study

The objective was to evaluate the pharmacodynamic response of switching patients on maintenance phase clopidogrel therapy after an acute coronary syndrome (ACS) to prasugrel. Prasugrel P2Y(12) receptor blockade is associated with greater pharmacodynamic platelet inhibition and reduction of ischemic complications compared with that of clopidogrel in ACS patients undergoing percutaneous coronary intervention. The pharmacodynamic effects of switching patients during maintenance phase clopidogrel therapy after an ACS event to prasugrel are unknown. The SWAP (SWitching Anti Platelet) study was a phase 2, multicenter, randomized, double-blind, double-dummy, active-control trial. After a run-in of daily open-label clopidogrel 75 mg with aspirin therapy for 10 to 14 days, patients were randomly assigned to 1 of the following 3 treatments: placebo loading dose (LD)/clopidogrel 75 mg maintenance dose (MD), placebo LD/prasugrel 10 mg MD, or prasugrel 60 mg LD/10 mg MD. Platelet function was evaluated at 2 h, 24 h, 7 days, and 14 days using light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation. A total of 139 patients were randomized, of whom 100 were eligible for analysis. Maximum adenosine diphosphate-induced platelet aggregation (20 μM) by light transmittance aggregometry at 1 week (primary end point) was lower after prasugrel MD compared with clopidogrel MD (41.1% vs. 55.0%, p < 0.0001), and was also lower in the prasugrel LD+MD group compared with clopidogrel MD (41.0% vs. 55.0%, p < 0.0001). At 2 h, a prasugrel LD resulted in higher platelet inhibition compared with the other regimens. Similar results were found using light transmittance aggregometry with 5 μM adenosine diphosphate, VerifyNow P2Y(12), and vasodilator-stimulated phosphoprotein phosphorylation assays. For patients receiving maintenance clopidogrel therapy after an ACS event, switching from clopidogrel to prasugrel is associated with a further reduction in platelet function by 1 week using prasugrel MD or within 2 h with the administration of a prasugrel LD. (A Pharmacodynamic Comparison of Prasugrel [LY640315] Versus Clopidogrel in Subjects With Acute Coronary Syndrome Who Are Receiving Clopidogrel [SWAP]; NCT00356135).

Abstract 4946: Comparison of Prasugel With Clopidogrel on Platelet Function in Coronary Artery Disease Patients With Type 2 Diabetes Mellitus - Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3)

Introduction: Type 2 diabetes mellitus (T2DM) patients (pts) have decreased response to clopidogrel (Clop) compared to non-diabetic patients. Prasugrel (Pras) has shown to be more efficacious than Clop in reducing thrombotic cardiovascular events in T2DM pts with acute coronary syndrome undergoing percutaneous coronary interventions. However, the pharmacodynamic effects of Pras compared to Clop in T2DM have not been fully explored. The OPTIMUS-3 study evaluated pharmacodynamic responses of Pras compared with Clop in coronary artery disease (CAD) pts with T2DM. Methods: A total of 35 CAD pts with T2DM on chronic aspirin were randomized to Pras 60 mg loading dose (LD)/10 mg maintenance dose (MD) or Clop 600 mg LD/150 mg MD for 1 week in a double-blind cross-over design with a 2 week washout period between study drugs. Platelet function was assessed by the VerifyNow P2Y12 (VN-P2Y 12 ) assay, light transmission aggregometry (LTA) following 5 and 20 μ M ADP, and phosphorylation of vasodilator stimulated phosphoprotein (VASP), at baseline, 1 hr, 4 hr and 24 hr post LD, and 6 – 8 days post-MD. The primary comparison of inhibition of platelet aggregation (IPA) at 4 hours after LD between 60 mg Pras and 600 mg Clop was assessed by VN-P2Y 12 . Results: Significantly greater IPA by VN-P2Y 12 at 4 hr post LD was achieved by Pras vs. Clop (89.3 % vs. 27.7%, p&lt;0.0001). Significantly greater IPA was also observed at 1 hr and 24 hr post LD and 7 days post-MD (Figure ). Similar results were obtained when platelet function was assessed by VN-P2Y 12 Reaction Units, LTA and VASP. Conclusion: In CAD pts with T2DM, Pras is associated with significantly greater inhibition of platelet function than high LD and MD regimens of Clop.

Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease

AimsThe metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.Methods and resultsNinety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow™ P2Y12 were measured predose, 2, and 24 ± 4 h post-LD and predose during the MD period on Day 14 ± 3 and Day 29 ± 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow™ P2Y12 reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses.ConclusionVariation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y12 inhibition, but has no significant influence on the response to prasugrel.

Assessment of P2Y 12 inhibition with the point-of-care device Verify Now P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin

Variability in response to thienopyridines has led to the development of point-of-care devices to assess adenosine diphosphate (ADP)-induced platelet aggregation. These tests need to be evaluated in comparison to reference measurements of P2Y(12) function during different thienopyridine treatments. After a run-in on 75 mg aspirin, 110 subjects were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD. Antiplatelet effects were evaluated by VerifyNow P2Y12 (VN-P2Y12) device (Accumetrics, San Diego, CA), vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and light transmission aggregometry (LTA). Prasugrel's and clopidogrel's active metabolite concentration were also determined. Dose- and time-dependent inhibition of P2Y(12) was evident with VN-P2Y12. There was strong correlation with VN-P2Y12 and VASP or LTA for all treatments through a wide range of P2Y(12) function. At high levels of P2Y(12) inhibition, platelet function measured by VN-P2Y12 was maximally inhibited and could not reflect further changes seen with VASP or LTA methods. Correlation was also observed between exposure to clopidogrel's active metabolite and VN-P2Y12 during MD and LD, whereas it was observed only with prasugrel MD. The VN-P2Y12 correlated strongly with inhibition of P2Y(12) function, as measured with either VASP or LTA. VN-P2Y12 also correlated to exposure to the active metabolite of prasugrel and clopidogrel up to levels associated with assumed saturation of the P2Y(12) receptor.

Inhibition of platelet aggregation with prasugrel and clopidogrel: An integrated analysis in 846 subjects

This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 μM ADP were assessed by turbidimetric aggregometry. A linear mixed-effect model compared the MPA and IPA between treatments over time points evaluated in the integrated database, and covariates affecting platelet inhibition were identified. Prasugrel 60 mg LD resulted in faster onset, greater magnitude, and more consistent levels of inhibition of platelet function compared to either clopidogrel 300 mg or 600 mg LDs. Greater and more consistent levels of platelet inhibition were observed with the prasugrel 10 mg MD compared to the clopidogrel 75 mg MD. This integrated analysis confirms the findings of earlier individual studies, that prasugrel achieves faster onset of greater extent and more consistent platelet inhibition compared to the approved and higher loading doses of clopidogrel. Gender, race, body weight, and age were identified as statistically significant covariates impacting platelet inhibition.

Patients With Poor Responsiveness to Thienopyridine Treatment or With Diabetes Have Lower Levels of Circulating Active Metabolite, but Their Platelets Respond Normally to Active Metabolite Added Ex Vivo

We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel. In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo. The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo. Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.

Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease

The aim of the current analysis was to characterize the population PK of prasugrel and clopidogrel metabolites, the resulting PD response, and identification of covariates for key PK/PD parameters. Aspirin-treated subjects with coronary artery disease were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD) followed by daily 75 mg maintenance dose (MD) or prasugrel 60 mg LD and daily 10 mg MD for 28 days. Plasma concentrations of prasugrel active metabolite (Pras-AM) and prasugrel's inactive thiolactone metabolite (Pras-thiolactone) were simultaneously fit to a multicompartmental model; a similar model adequately described clopidogrel's active metabolite (Clop-AM) PK. By linking to the PK model through the active metabolite concentrations, the PK/PD model characterized the irreversible inhibition of platelet aggregation through a sigmoidal Emax model. Although dose, sex, and weight were identified as significant covariates in the prasugrel PK model, only the effect of body weight produced significant changes in Pras-AM exposure. Generally, these factors resulted in only minor changes in Pras-AM exposures such that, overall, the change in the resulting maximal platelet aggregation (MPA) was predicted to be < or =10% points on average. The clopidogrel PK model included dose as a covariate indicating that a significantly less-than-proportional increase in Clop-AM exposure is expected over the dose range of 75-600 mg, thus, the model-predicted PD response is lower than might be anticipated given an 8-fold difference in dose and lower than that typically achieved following prasugrel 60 mg LD. The greater PD response with prasugrel compared with clopidogrel was accounted for by greater conversion of dose to active metabolite.

Abstract 3995: Comparison of the Effects of Prasugrel and High Dose Clopidogrel on In Vivo and In Vitro Platelet Activation: Results from PRINCIPLE-TIMI 44

In PRINCIPLE-TIMI 44, a randomized study in 201 patients undergoing cardiac catheterization for planned PCI, we reported that prasugrel resulted in greater inhibition of in vitro ADP-stimulated platelet aggregation than clopidogrel 600 mg loading dose (LD) and 150 mg maintenance dose (MD). Here we compare the effects of prasugrel and clopidogrel on in vivo and in vitro platelet activation. As prespecified end points of PRINCIPLE-TIMI 44, we measured circulating platelet-monocyte aggregates (PMA), circulating platelet-neutrophil aggregates (PNA), circulating P-selectin-positive platelets (PSPP), plasma soluble CD40 ligand (sCD40L) and (because activated platelets induce its release from leukocytes) myeloperoxidase (MPO). We also evaluated in vitro ADP-stimulated PMA, PNA and PSPP. At 6 h post LD, clopidogrel and prasugrel resulted in similar reductions in circulating PMA (Fig. A ), PNA and PSPP. In vitro ADP-stimulated PMA (Fig. B ), PNA and PSPP were inhibited to a greater degree by prasugrel than clopidogrel during the LD and MD phases. At 6 h post LD, clopidogrel- but not prasugrel-treated patients had elevated plasma MPO compared to pre-treatment (Fig. C ). Plasma sCD40L was unaffected by time or treatment. In this randomized study: Prasugrel, like clopidogrel, inhibited in vivo platelet activation. Prasugrel, to a greater degree than clopidogrel, inhibited ADP-stimulated PMA, PNA and PSPP – which may be mechanistically important, given the high local concentrations of ADP at sites of thrombus formation. Prasugrel, unlike clopidogrel, prevented the post-PCI-induced increase in the inflammatory marker MPO.

Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects

Prasugrel, a novel P2Y12 antagonist, achieves faster onset and greater inhibition of platelet aggregation than clopidogrel 300 and 600 mg loading doses (LD). We studied the safety, time course, and level of platelet inhibition when switching directly from clopidogrel 75 mg maintenance dose (MD) to a prasugrel 60 mg LD/10 mg MD or 10 mg MD regimen. Healthy subjects (n = 39) on aspirin (81 mg/d) received a clopidogrel 600 mg LD followed by 10 days of clopidogrel MD (75 mg/d). Subjects were then randomized without a washout period to prasugrel 60 mg LD (n = 16) followed by 10 days of prasugrel MD (10 mg/d) or to prasugrel MD (10 mg/d, n = 19) for 11 days. Maximal platelet aggregation (MPA) to 20 µM ADP was measured by turbidimetric aggregometry. In subjects on clopidogrel 75 mg MD, mean MPA decreased from 39 to 12% by 30 minutes, and to 5% by 1 hour after a prasugrel 60 mg LD (p < 0.001 for both) and from 37 to 28% (p < 0.001) by 1 hour after a prasugrel 10 mg MD. During prasugrel MD, a new pharmacodynamic steady state MPA of ∼24% (p < 0.01 vs. clopidogrel MD) occurred within four to five days of switching from clopidogrel. Changing from clopidogrel to prasugrel did not increase bleeding episodes or other adverse events. Switching directly from clopidogrel MD to either prasugrel LD or MD was well tolerated and resulted in significantly greater levels of platelet inhibition than a clopidogrel 75 mg MD.

A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry

Platelet inhibition as measured by vasodilator-stimulated phosphoprotein (VASP) and light transmission aggregometry (LTA) have shown concordance following dosing of clopidogrel. No reports have directly compared the VASP assay and LTA at the levels of P2Y(12) blockade after loading doses (LDs) of prasugrel or high dose clopidogrel (600 and 900 mg). The aim was to compare the VASP assay and LTA during the loading dose phase of a comparative study of prasugrel and clopidogrel. Prasugrel 60 mg LD/10 mg maintenance dose (MD) and clopidogrel 300 mg/75 mg and 600 mg/75 mg LD/MD regimens were compared in a 3-way crossover study in 41 healthy, aspirin-free subjects. Each LD was followed by seven daily MDs and a 14-day washout period. P2Y(12) receptor blockade was estimated using the VASP assay, expressed as platelet reactivity index (VASP-PRI). Platelet aggregation was assessed by light transmission aggregometry (20 and 5 microM ADP). Twenty-four hours after prasgurel 60 mg or clopidogrel 300 mg and 600 mg, respectively, VASP-PRI decreased from approximately 80% to 8.9%, 54.7%, and 39.0%, and maximal platelet aggregation (MPA) decreased from approximately 79% to 10.8%, 42.7%, and 31.2%, with an overall VASP:MPA correlation of 0.88 (p < 0.01). VASP assay responses after the clopidogrel LDs showed a wider range of values (300 mg: 0-93%; 600 mg: 0-80%) than prasugrel (0-13%); MPA responses followed a similar trend. Pearson's correlation suggested a strong agreement between VASP and LTA (20 microM ADP) for MPA (r = 0.86, p < 0.0001). VASP and LTA demonstrated concordance across the response range of P2Y(12) receptor blockade following thienopyridine LDs.

Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease

P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.