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Pharmacogenetic Testing for Clopidogrel Using the Rapid INFINITI Analyzer

A Dose-Escalation Study

Patrick Gladding, MBChB^_*,,_*, Harvey White, MBChB, DSc^_*, Jamie Voss, MBChB^_*, John Ormiston, MBChB^_*, Jim Stewart, MBChB^_*, Peter Ruygrok, MD, MBChB^_*, Badi Bvaldivia, Ruth Baak, PhD, Catherine White, MBChB^_*, Mark Webster, MBChB^_*

^_* Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
AutoGenomics, Carlsbad, California
Theranostics Lab (NZ) Ltd., Auckland, New Zealand

^_* Reprint requests and correspondence: Dr. Patrick Gladding, Auckland City Hospital, Green Lane Cardiovascular Service, Park Road, Grafton, Auckland, North Island 1061, Auckland, New Zealand (Email: patrickg{at}theranostics.co.nz).

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.

Key Words: clopidogrel • pharmacogenetics • personalized • platelets

Abbreviations and Acronyms   CI = confidence interval   PPI = proton pump inhibitor   PRU = platelet response unit

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