The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response

  • Gladding P
  • Webster M
  • Zeng I
  • et al.
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Abstract

The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response: An Analysis From the PRINC (Plavix Response in Coronary Intervention) TrialPatrick Gladding, Mark Webster, Irene Zeng, Helen Farrell, Jim Stewart, Peter Ruygrok, John Ormiston, Seif El-Jack, Guy Armstrong, Patrick Kay, Douglas Scott, Arzu Gunes, Marja Liisa-DahlPharmacogenomics might explain the variability in clopidogrel response. Sixty patients undergoing elective percutaneous coronary intervention were genotyped for polymorphisms in CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes. CYP2C1911 carriers had greater platelet inhibition 2 h after a 600-mg dose than CYP2C192, 4, or17 carriers did. CYP2C192 or 4 carriers had greater platelet inhibition with a split 1,200-mg dose than with a 600-mg loading dose, and with a 150-mg compared with a 75-mg daily maintenance dosage. Those with CYP2C192 and 4 showed reduced platelet inhibition after clopidogrel 600 mg, but responded to higher loading and maintenance dose regimensObjectives This study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel.Background Variability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate–receptor P2Y12).Methods Sixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction–based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes.Results CYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers (9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042).Conclusions Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583)

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APA

Gladding, P., Webster, M., Zeng, I., Farrell, H., Stewart, J., Ruygrok, P., … Dahl, M.-L. (2008). The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response. JACC: Cardiovascular Interventions, 1(6), 620–627. https://doi.org/10.1016/j.jcin.2008.09.008

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