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

Abstract

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 P2Y(12) 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 clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.

Figure 1

Comparison of prasugrel 60 mg and clopidogrel 600 mg loading dose exposure of active metabolite by CYP2C19 genetic classification. Box represents median, 25th, and 75th percentiles and whiskers represent the most extreme values within 1.5 times inter-quartile range of the box. AUC, area under the concentration–time curve; EM, extensive metabolizer; RM, reduced metabolizer.

Figure 2

Ratio RM/EM or difference (EM − RM) for pharmacokinetics and pharmacodynamic responses for CYP2C19, CYP2B6, CYP2C9, and CYP3A5. Mean and 95% confidence interval for ratio (AUC at LD) or difference (VASP–PRI at 24 h post-LD and MD Day 14 and Day 29) is derived from a linear model and is plotted for each CYP gene. AUC, area under the concentration–time curve; EM, extensive metabolizer; LD, loading dose; MD, maintenance dose; RM, reduced metabolizer; VASP, vasodilator-stimulated phosphoprotein; PRI, platelet reactivity index.

Figure 3

Relationship between pharmacodynamic responses and CYP2C19 genetic classification measured by VASP assay (A) and VerifyNow™ P2Y12 device (B). EM, extensive metabolizer; RM, reduced metabolizer; VASP, vasodilator-stimulated phosphoprotein; PRI, platelet reactivity index; PRU, P2Y₁₂ reaction unit.