The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients.
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.


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.
Gurbel
P A
PA
Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, Baltimore, MD 21215, USA. pgurbel@lifebridgehealth.org
Bliden
K P
KP
Antonino
M J
MJ
Stephens
G
G
Gretler
D D
DD
Jurek
M M
MM
Pakyz
R E
RE
Shuldiner
A R
AR
Conley
P B
PB
Tantry
U S
US
D000244:Adenosine Diphosphate; D000284:Administration, Oral; D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000295:instrumentation; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D000077144:Clopidogrel; D003094:Collagen / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000628:therapy*; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D010641:Phenotype; D010750:Phosphoproteins / Q000097:blood; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D058919:Purinergic P2 Receptor Antagonists; D052999:Quinazolinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D015607:Stents; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013916:Thrombelastography; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D052999:Quinazolinones; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D013449:Sulfonamides; D000098662:Vasodilator-Stimulated Phosphoprotein; D000244:Adenosine Diphosphate; D003094:Collagen; C549473:elinogrel; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine; D001241:Aspirin