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Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study
Patrick Gladding1, Harvey White, Jamie Voss
1Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand. patrickg@theranostics.co.nz
JACC. Cardiovascular Interventions
|November 21, 2009
Summary
Increasing clopidogrel dosage enhances antiplatelet effects in patients with CYP2C19*2 gene variants. Personalized pharmacogenomic dosing may optimize clopidogrel treatment for these individuals.
Area of Science:
- Pharmacogenomics
- Cardiovascular Pharmacology
- Clinical Trial Design
Background:
- Clopidogrel is a prodrug metabolized by cytochrome P450 enzymes, including CYP2C19.
- The CYP2C19*2 loss-of-function variant is linked to reduced clopidogrel efficacy and increased stent thrombosis risk.
- Understanding genetic influences on drug metabolism is crucial for personalized medicine.
Purpose of the Study:
- To evaluate if a higher clopidogrel maintenance dose improves antiplatelet response in CYP2C19*2 allele carriers.
- To compare the antiplatelet effects of increased clopidogrel dosage between CYP2C19*2 carriers and non-carriers.
- To investigate the role of pharmacogenomics in optimizing clopidogrel therapy.
Main Methods:
- A dose-escalation study involving 40 patients on standard clopidogrel maintenance dosage.
- Platelet function assessed using VerifyNow analyzer at baseline and after 1 week of 150 mg daily clopidogrel.
- Genomic DNA analysis for CYP2C19 (*2, *4, *17) and CYP2C9 (*2, *3) polymorphisms using microarray.
Main Results:
- Platelet inhibition significantly increased by 8.6% after 1 week of dose escalation (p=0.0003).
- CYP2C19*2 carriers exhibited significantly lower platelet inhibition at baseline and after dose increase compared to wild-type.
- Higher clopidogrel dose (150 mg) led to increased platelet inhibition (9%, p=0.03) and reduced reactivity (-26 PRU, p=0.04) in CYP2C19*2 carriers.
- Combined CYP2C19*2 and CYP2C9*3 carriers showed a greater increase in platelet inhibition with 150 mg daily compared to wild-type.
Conclusions:
- Elevating clopidogrel dosage can enhance antiplatelet response in patients with non-responder polymorphisms.
- Personalized clopidogrel dosing guided by pharmacogenomic data offers a promising strategy for treatment optimization.
- Pharmacogenomic testing can identify patients who may benefit from adjusted clopidogrel regimens.
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