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

Varenhorst, Christoph; James, Stefan; Erlinge, David LU ; Brandt, John T.; Braun, Oscar LU ; Man, Michael; Siegbahn, Agneta; Walker, Joseph; Wallentin, Lars and Winters, Kenneth J., et al. (2009) In European Heart Journal 30(14). p.1744-1752
Abstract
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. 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... (More)
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. 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 (TM) 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 (TM) 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. 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. (Less)
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published
subject
keywords
Cytochrome P450 enzymes, Clopidogrel, Prasugrel, CYP2C19, Pharmacogenetics
in
European Heart Journal
volume
30
issue
14
pages
1744 - 1752
publisher
Oxford University Press
external identifiers
  • wos:000268109600017
  • scopus:67649645191
ISSN
1522-9645
DOI
10.1093/eurheartj/ehp157
language
English
LU publication?
yes
id
7c5053f5-ce65-4fa0-a435-19917ddf2213 (old id 1461665)
date added to LUP
2009-08-31 11:05:38
date last changed
2017-08-27 04:46:19
@article{7c5053f5-ce65-4fa0-a435-19917ddf2213,
  abstract     = {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. 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 (TM) 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 (TM) P2Y(12) reaction unit (PRU) values were significantly higher (P &lt; 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. 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.},
  author       = {Varenhorst, Christoph and James, Stefan and Erlinge, David and Brandt, John T. and Braun, Oscar and Man, Michael and Siegbahn, Agneta and Walker, Joseph and Wallentin, Lars and Winters, Kenneth J. and Close, Sandra L.},
  issn         = {1522-9645},
  keyword      = {Cytochrome P450 enzymes,Clopidogrel,Prasugrel,CYP2C19,Pharmacogenetics},
  language     = {eng},
  number       = {14},
  pages        = {1744--1752},
  publisher    = {Oxford University Press},
  series       = {European Heart Journal},
  title        = {Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease},
  url          = {http://dx.doi.org/10.1093/eurheartj/ehp157},
  volume       = {30},
  year         = {2009},
}