1. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients.
- Author
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Gurbel PA, Bliden KP, Antonino MJ, Stephens G, Gretler DD, Jurek MM, Pakyz RE, Shuldiner AR, Conley PB, and Tantry US
- Subjects
- Adenosine Diphosphate, Administration, Oral, Aged, Angioplasty, Balloon, Coronary instrumentation, Aryl Hydrocarbon Hydroxylases metabolism, Blood Coagulation drug effects, Blood Platelets metabolism, Cell Adhesion Molecules blood, Clopidogrel, Collagen therapeutic use, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP3A genetics, Drug Therapy, Combination, Female, Gene Frequency, Genotype, Humans, Male, Microfilament Proteins blood, Middle Aged, Phenotype, Phosphoproteins blood, Phosphorylation, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors administration & dosage, Platelet Aggregation Inhibitors pharmacokinetics, Quinazolinones administration & dosage, Quinazolinones pharmacokinetics, Receptors, Purinergic P2 metabolism, Receptors, Purinergic P2Y12, Stents, Sulfonamides administration & dosage, Sulfonamides pharmacokinetics, Thrombelastography, Ticlopidine therapeutic use, Vasodilator-Stimulated Phosphoprotein, Aryl Hydrocarbon Hydroxylases genetics, Aspirin therapeutic use, Blood Platelets drug effects, Coronary Artery Disease therapy, Platelet Aggregation Inhibitors therapeutic use, Polymorphism, Genetic, Purinergic P2 Receptor Antagonists, Quinazolinones therapeutic use, Sulfonamides therapeutic use, Ticlopidine analogs & derivatives
- Abstract
Unlabelled: To study the effect of a new direct acting reversible P2Y(12) inhibitor, elinogrel (PRT060128), and the relation to cytochrome P450 (CYP) polymorphisms in patients with high platelet reactivity (HPR) on standard dual antiplatelet therapy., Methods and Results: We studied the pharmacodynamic and pharmacokinetic effects of a single 60-mg oral dose of elinogrel in 20 of 45 previously stented stable patients with HPR. We also genotyped for CYP2C19*2,3,5,17 and CYP3A5*3. Platelet reactivity fell within 4 h of dosing, the earliest time point evaluated as measured by the following assays: maximum 5 and 10 microM ADP LTA (P < 0.001 for both vs. predosing); maximum 20 microM ADP LTA (P < 0.05); VerifyNow (P < 0.001); thrombelastography (P < 0.05); VASP phosphorylation (P < 0.01); and perfusion chamber assay (P < 0.05); this was reversible within 24 h in these same assays (P = ns vs. predosing for all assays). CYP2C19*2 was present in 44% of all patients but was more frequent in HPR patients (77% vs. 16%, P = 0.0004)., Conclusions: HPR is reversibly overcome by a single 60-mg oral dose of elinogrel, a drug now being investigated in a phase 2 trial. CYP2C19*2 was associated with HPR during conventional dual antiplatelet therapy.
- Published
- 2010
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