title: Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease.
abstract: 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.
authors.affiliation: David Erlinge, Dept. of Cardiology, Lund University, Skane University Hospital, Lund; 221 85 Lund, Sweden, Tel: +46 46172597, Fax: +46 46157857, E-mail: david.erlinge@med.lu.se.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.forename: Stefan
authors.initials: S
authors.lastname: James
authors.forename: Suman
authors.initials: S
authors.lastname: Duvvuru
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Henrik
authors.initials: H
authors.lastname: Wagner
authors.forename: Christoph
authors.initials: C
authors.lastname: Varenhorst
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Brown
authors.forename: David
authors.initials: D
authors.lastname: Small
authors.forename: Brian A
authors.initials: BA
authors.lastname: Moser
authors.forename: Scott S
authors.initials: SS
authors.lastname: Sundseth
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Walker
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
mesh_terms: D000293:Adolescent; D000368:Aged; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D019095:Point-of-Care Systems; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: Genotyping techniques; clopidogrel; pharmacogenetics CYP2C19 polymorphisms; prasugrel