| 1. |
- Braun, Oscar, et al.
(author)
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Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways
- 2013
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 110:6, s. 1223-1231
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Journal article (peer-reviewed)abstract
- Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow (R) P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PR!) after 14 days of maintenance dosing. Clopi-, dogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but notABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.
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| 2. |
- Erlinge, David, et al.
(author)
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Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease
- 2014
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In: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 111:5, s. 943-950
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Journal article (peer-reviewed)abstract
- We compared results obtained with the Nanosphere Verigene (R) 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 (TM) 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 (R) 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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| 3. |
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| 4. |
- Gurbel, Paul A., et al.
(author)
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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
- 2014
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In: Thrombosis and Haemostasis. - : Schattauer. - 0340-6245 .- 2567-689X. ; 112:3, s. 589-597
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Journal article (peer-reviewed)abstract
- 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 [Cl]: 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 VN-PRU, 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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