The effect of CYP2C19  gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease

Summary CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator- stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/* 17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VNPRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

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Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease

Thrombosis and Haemostasis ◽

10.1160/th13-09-0767 ◽

2014 ◽

Vol 111 (05) ◽

pp. 943-950 ◽

Cited By ~ 6

Author(s):

Stefan James ◽

Suman Duvvuru ◽

Joseph A. Jakubowski ◽

Henrik Wagner ◽

Christoph Varenhorst ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Active Metabolite ◽

Platelet Reactivity ◽

Point Of Care ◽

Stable Coronary Artery Disease ◽

Extensive Metabolisers ◽

Level Data ◽

Artery Disease ◽

High Degree

SummaryWe compared results obtained with the Nanosphere Verigene® System, a novel point-of-care (POC) genetic test capable of analysing 11 CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix™ DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17, *17/*17), reduced metabolisers (*1/*2, *1/*8, *2/*2, *2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel’s active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow® P2Y12 assay) and VASP PRI (PRI) were also assessed. There was a 99.9% overall concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI ≥50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.

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Abstract 2041: Low P2Y 12 -Specific Platelet Inhibition in Clopidogrel-Treated Patients with Coronary Artery Disease is Common and not Reliably Detected by Conventional Aggregation Tests

Circulation ◽

10.1161/circ.116.suppl_16.ii_442 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Andreas Schaefer ◽

Sarah Weinberger ◽

Martin Eigenthaler ◽

Georg Ertl ◽

Johann Bauersachs

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Real World ◽

Platelet Reactivity ◽

Reactivity Index ◽

Individual Response ◽

Specific Assay ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk ◽

Artery Disease

Background: Incomplete inhibition of P2Y 12 -mediated platelet activation during clopidogrel treatment has been associated with increased cardiovascular morbidity and mortality after percutaneous coronary intervention. This study aimed to investigate the incidence of impaired individual clopidogrel-responsiveness using a P2Y 12 -specific and pre-treatment-independent assay in a real world situation. Methods: 100 consecutive patients with coronary artery disease on clopidogrel treatment (> 5 days including a loading dose of at least 300 mg) were screened for response to ADP-induced platelet signalling. We assessed the vasodilator-stimulated phosphoprotein-based platelet reactivity index (PRI) as the only P2Y 12 -specific assay to determine clopidogrel responsiveness. Insufficient inhibition of P2Y 12 by clopidogrel was defined as a PRI >50% based on previous studies indicating increased risk of stent thrombosis under this condition. The results were compared with conventional assays to assess ADP-induced P-selectin surface-expression and conventional turbinometric platelet aggregation to several concentrations of ADP. Results: Clopidogrel significantly lowered functional platelet reactivity in patients with coronary artery disease compared to untreated patients. However, insufficient individual response to treatment predisposing for adverse events and therefore previously described as “non-response” was diagnosed in 69% of clopidogrel-treated patients using PRI. Conventional aggregation failed to detect insufficient P2Y 12 -inhibition in 1/3of patients with a PRI>50%. Conclusion: Using the PRI as the only P2Y 12 -specific assay to evaluate the treatment effect of clopidogrel in patients with coronary artery disease, insufficient P2Y 12 -inhibition was present in the majority of patients in a real-world scenario. Insufficient P2Y12-inhibition could not be reliably detected by conventional aggregation More prospective studies are needed to evaluate the influence of the high prevalence of incomplete clopidogrel responsiveness to major adverse cardiac events.

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