Kenneth J. Winters

Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel

Summary.  Background: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y12 adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized.

Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

BACKGROUND The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Randomized Comparison of Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y12 Antagonist, With Clopidogrel in Percutaneous Coronary Intervention Results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)–TIMI 26 Trial

Background—Despite the current standard antiplatelet regimen of aspirin and clopidogrel (with or without glycoprotein IIb/IIIa inhibitors) in percutaneous coronary intervention patients, periprocedural and postprocedural ischemic events continue to occur. Prasugrel (CS-747, LY640315), a novel potent thienopyridine P2Y12 receptor antagonist, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than currently approved doses of clopidogrel. Methods and Results—Joint Utilization of Medications to Block Platelets Optimally–Thrombolysis In Myocardial Infarction 26 (JUMBO-TIMI 26) was a phase 2, randomized, dose-ranging, double-blind safety trial of prasugrel versus clopidogrel in 904 patients undergoing elective or urgent percutaneous coronary intervention. Patients were randomized to either standard dosing with clopidogrel or 1 of 3 prasugrel regimens. Subjects were monitored for 30 days for bleeding and clinical events. The primary end point of the trial was clinically significant (TIMI major plus minor) non–CABG-related bleeding events in prasugrel- versus clopidogrel-treated patients. Hemorrhagic complications were infrequent, with no significant difference between patients treated with prasugrel or clopidogrel in the rate of significant bleeding (1.7% versus 1.2%; hazard ratio, 1.42; 95% CI, 0.40, 5.08). In prasugrel-treated patients, there were numerically lower incidences of the primary efficacy composite end point (30-day major adverse cardiac events) and of the secondary end points myocardial infarction, recurrent ischemia, and clinical target vessel thrombosis. Conclusions—In this phase 2 study, which was designed to assess safety when administered at the time of percutaneous coronary intervention, prasugrel and clopidogrel both resulted in low rates of bleeding. The results of this trial serve as a foundation for the large phase 3 clinical trial designed to assess both efficacy and safety.

Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel

Prasugrel and clopidogrel, thienopyridine prodrugs, are each metabolized to an active metabolite that inhibits the platelet P2Y12 ADP receptor. In this open‐label, 4‐period crossover study, the effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel were assessed in healthy subjects given single doses of prasugrel 60 mg and clopidogrel 300 mg with and without concurrent lansoprazole 30 mg qd. Cmax and AUC0‐tlast of prasugrels active metabolite, R‐138727, and clopidogrels inactive carboxylic acid metabolite, SR26334, were assessed. Inhibition of platelet aggregation (IPA) was measured by turbidimetric aggregometry 4 to 24 hours after each treatment. Lansoprazole (1) decreased R‐138727 AUC0‐tlast and Cmax by 13% and 29%, respectively, but did not affect IPA after the prasugrel dose, and (2) did not affect SR62334 exposure but tended to lower IPA after a clopidogrel dose. A retrospective tertile analysis showed in subjects with high IPA after a clopidogrel dose alone that lansoprazole decreased IPA, whereas IPA was unaffected in these same subjects after a prasugrel dose. The overall data suggest that a prasugrel dose adjustment is not likely warranted in an individual taking prasugrel with a proton pump inhibitor such as lansoprazole.

Cytochrome P450 3A Inhibition by Ketoconazole Affects Prasugrel and Clopidogrel Pharmacokinetics and Pharmacodynamics Differently

Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrels active metabolite (R‐138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrels activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2‐week washout between periods. Ketoconazole decreased R‐138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34–61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R‐138727 exposure or prasugrels inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrels active metabolite AUC0–24 (area under the concentration–time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrels but not prasugrels active metabolite. The decreased formation of clopidogrels active metabolite is associated with reduced IPA.

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

Aims The 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 results Ninety-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. Conclusion Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrels active metabolite and a corresponding reduction in P2Y12 inhibition, but has no significant influence on the response to prasugrel.

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

OBJECTIVES We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes. BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel.

Prasugrel pharmacodynamics and pharmacokinetics after a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MD) were compared in a 3-way crossover study to clopidogrel 600-mg/75-mg and 300-mg/75-mg LD/MD in 41 healthy, aspirin-free subjects. Each LD was followed by 7 days of daily MD and a 14-day washout period. Inhibition of platelet aggregation (IPA) was assessed by turbidometric aggregometry (20 and 5 μM ADP). Prasugrel 60-mg achieved higher mean IPA (54%) 30 minutes post-LD than clopidogrel 300-mg (3%) or 600-mg (6%) (P < 0.001) and greater IPA by 1 hour (82%) and 2 hours (91%) than the 6-hour IPA for clopidogrel 300-mg (51%) or 600-mg (69%) (P < 0.01). During MD, IPA for prasugrel 10-mg (78%) exceeded that of clopidogrel (300-mg/75-mg, 56%; 600-mg/75-mg, 52%; P < 0.001). Active metabolite area under the concentration-time curve (AUC0-tlast) after prasugrel 60-mg (594 ng·hr/mL) was 2.2 times that after clopidogrel 600-mg. Prasugrel active metabolite AUC0-tlast was consistent with dose-proportionality from 10-mg to 60-mg, while clopidogrel active metabolite AUC0-tlast exhibited saturable absorption and/or metabolism. In conclusion, greater exposure to prasugrels active metabolite results in faster onset, higher levels, and less variability of platelet inhibition compared with high-dose clopidogrel in healthy subjects.

The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration

Variability in response to antiplatelet agents has prompted the development of point-of-care (POC) technology. In this study, we compared the VerifyNow P2Y12 (VN-P2Y12) POC device with light transmission aggregometry (LTA) in subjects switched directly from clopidogrel to prasugrel. Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose (LD) followed by a 75 mg/d maintenance dose (MD) for 10 days. Subjects were then switched to a prasugrel 60 mg LD and then 10 mg/d MD for 10 days (n = 16), or to a prasugrel 10 mg/d MD for 11 days (n = 19). Platelet function was measured by LTA and VN-P2Y12 at baseline and after dosing. Clopidogrel 600 mg LD/75 mg MD treatment led to a reduction in P2Y(12) reaction units (PRU) from baseline. A switch from clopidogrel MD to prasugrel 60 mg LD/10 mg MD produced an immediate decrease in PRU, while a switch to prasugrel 10 mg MD resulted in a more gradual decline. Consistent with the reduction in PRU, device-reported percent inhibition increased during both clopidogrel and prasugrel regimens. Inhibition of platelet aggregation as measured by LTA showed a very similar pattern to that found with VN-P2Y12 measurement, irrespective of treatment regimens. The dynamic range of VN-P2Y12 appeared to be narrower than that of LTA. With two different thienopyridines, the VN-P2Y12 device, within a somewhat more limited range, reflected the overall magnitude of change in aggregation response determined by LTA. The determination of the clinical utility of such POC devices will require their use in clinical outcome studies.

Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A single ascending dose study in healthy humans

We assessed the tolerability, pharmacodynamics as measured by inhibition of platelet aggregation (IPA), and pharmacokinetics of prasugrel (CS-747, LY640315), a novel thienopyridine antiplatelet agent in healthy volunteers. Twenty-four subjects were randomized into four groups of six in a double-blind, placebo-controlled trial. One subject in each group received placebo and five subjects received prasugrel orally at single doses of 2.5, 10, 30, or 75 mg. The IPA, assessed using 5 and 20 µM ADP, was periodically measured over a 7-day period by light transmission aggregometry. Plasma concentrations for three major metabolites, R-95913, R-106583, and R-100932, were measured. There were no serious adverse events and no clinically significant changes noted in any laboratory or clinical evaluations in any subject. At 1 h after prasugrel 30 and 75 mg, platelet aggregation induced by 20 µM ADP was inhibited by 43.5 ± 7.8 and 43.2 ± 15.7%, respectively, and this inhibition was significantly greater than that following placebo (5.9 ± 3.5%) (P < 0.05 for both doses). The degree of inhibition observed at 2 h was slightly higher with both prasugrel 30 and 75 mg (59.8 ± 9.9 and 57.0 ± 7.2%) and was maintained through the subsequent 22 h. At 24 h, maximal platelet aggregation induced by 20 µM ADP was reduced to ≤39% in all subjects receiving prasugrel 30 mg and to ≤38% in subjects receiving prasugrel 75 mg. Full recovery of platelet aggregation occurred between 48 h and 7 days suggesting irreversible inhibition by prasugrel and/or its metabolites. With prasugrel 2.5 and 10 mg, there was no measurable effect on platelet aggregation throughout the study (P > 0.05 for 2.5 and 10 mg prasugrel vs. placebo). With prasugrel 75 mg at 4 h postdose, there was a significant increase in the mean bleeding time compared to placebo (682 vs. 161 s; P < 0.05). Prasugrel metabolites obeyed linear pharmacokinetics and the three metabolites appeared in the plasma soon after administration, reaching maximum levels at approximately 1 h. In conclusion, prasugrel 30 and 75 mg were well tolerated and achieved a consistently high level of platelet inhibition with a fast onset of action. Errors appear in the original version of this article. These errors have since been rectified, and a corrected PDF is available here