OBJECTIVES: Our aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers. BACKGROUND: Clopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis. METHODS: Forty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 +/- 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms. RESULTS: Platelet inhibition increased over 1 week, mean +8.6 +/- 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 +/- 11%, p = 0.03) and reduction in platelet reactivity (mean -26 +/- 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04). CONCLUSIONS: Increasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment.
OBJECTIVES: Our aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers. BACKGROUND:Clopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis. METHODS: Forty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 +/- 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms. RESULTS: Platelet inhibition increased over 1 week, mean +8.6 +/- 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 +/- 11%, p = 0.03) and reduction in platelet reactivity (mean -26 +/- 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04). CONCLUSIONS: Increasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment.
Authors: Victoria M Pratt; Barbara Zehnbauer; Jean Amos Wilson; Ruth Baak; Nikolina Babic; Maria Bettinotti; Arlene Buller; Ken Butz; Matthew Campbell; Chris Civalier; Abdalla El-Badry; Daniel H Farkas; Elaine Lyon; Saptarshi Mandal; Jason McKinney; Kasinathan Muralidharan; LeAnne Noll; Tara Sander; Junaid Shabbeer; Chingying Smith; Milhan Telatar; Lorraine Toji; Anand Vairavan; Carlos Vance; Karen E Weck; Alan H B Wu; Kiang-Teck J Yeo; Markus Zeller; Lisa Kalman Journal: J Mol Diagn Date: 2010-10-01 Impact factor: 5.568
Authors: Jessica L Mega; Tabassome Simon; Jean-Philippe Collet; Jeffrey L Anderson; Elliott M Antman; Kevin Bliden; Christopher P Cannon; Nicolas Danchin; Betti Giusti; Paul Gurbel; Benjamin D Horne; Jean-Sebastian Hulot; Adnan Kastrati; Gilles Montalescot; Franz-Josef Neumann; Lei Shen; Dirk Sibbing; P Gabriel Steg; Dietmar Trenk; Stephen D Wiviott; Marc S Sabatine Journal: JAMA Date: 2010-10-27 Impact factor: 56.272
Authors: Victoria M Pratt; Robin E Everts; Praful Aggarwal; Brittany N Beyer; Ulrich Broeckel; Ruth Epstein-Baak; Paul Hujsak; Ruth Kornreich; Jun Liao; Rachel Lorier; Stuart A Scott; Chingying Huang Smith; Lorraine H Toji; Amy Turner; Lisa V Kalman Journal: J Mol Diagn Date: 2015-11-24 Impact factor: 5.568