Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease

David Erlinge; Stefan James; Suman Duvvuru; Joseph A. Jakubowski; Henrik Wagner; Christoph Varenhorst; Udaya S. Tantry; Patricia B. Brown; David Small; Brian A. Moser; Scott S. Sundseth; Joseph R. Walker; Kenneth J. Winters; Paul A. Gurbel

doi:10.1160/TH13-09-0767

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(05): 943-950
DOI: 10.1160/TH13-09-0767

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease

David Erlinge

¹Department of Cardiology, Lund University, Lund, Sweden

,

Stefan James

²Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Sweden

,

Suman Duvvuru

³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

,

Joseph A. Jakubowski

³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

,

Henrik Wagner

¹Department of Cardiology, Lund University, Lund, Sweden

,

Christoph Varenhorst

²Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Sweden

,

Udaya S. Tantry

⁴Sinai Center for Thrombosis Research, Baltimore, MD, USA

,

Patricia B. Brown

³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

,

David Small

³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

,

Brian A. Moser

³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

,

Scott S. Sundseth

⁵Cabernet Pharmaceuticals Durham, NC, USA

,

Joseph R. Walker

⁶Daiichi Sankyo Pharma Development, Edison, NJ, USA

,

Kenneth J. Winters

³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

,

Paul A. Gurbel

⁴Sinai Center for Thrombosis Research, Baltimore, MD, USA

› Author Affiliations

Abstract

Summary

We compared results obtained with the Nanosphere Verigene^® System, a novel point-of-care (POC) genetic test capable of analysing 11 CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix™ DMET⁺; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17, *17/*17), reduced metabolisers (*1/*2, *1/*8, *2/*2, *2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel’s active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow^® P2Y12 assay) and VASP PRI (PRI) were also assessed. There was a 99.9% overall concordance of marker-level data between the Nanosphere Verigene and DMET⁺ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI ≥50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.

Keywords

Genotyping techniques - clopidogrel - prasugrel - pharmacogenetics CYP2C19 polymorphisms

Full Text

References

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