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The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response

An Analysis From the PRINC (Plavix Response in Coronary Intervention) Trial

Patrick Gladding, FRACP^_*,_*, Mark Webster, FRACP^_*, Irene Zeng, MSc^_*, Helen Farrell, BHSc^_*, Jim Stewart, FRACP^_*, Peter Ruygrok, FRACP^_*, John Ormiston, FRACP^_*, Seif El-Jack, FRACP^_*, Guy Armstrong, FRACP^_*, Patrick Kay, FRACP^_*, Douglas Scott, FRACP^_*, Arzu Gunes, MD, PhD, Marja-Liisa Dahl, MD, PhD

^_* Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden

^_* Reprint requests and correspondence: Dr. Patrick Gladding, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92 024, Auckland 1030, New Zealand (Email: patrickg{at}adhb.govt.nz).

Objectives: 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)

Key Words: clopidogrel • pharmacogenetics • antiplatelets

Abbreviations and Acronyms   CYP = cytochrome P450   i = intronic   PCI = percutaneous coronary intervention   SNP = single nucleotide polymorphism

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