Functional variability of platelet response to clopidogrel correlates with P2Y(12) receptor occupancy.
Interindividual variability of response to clopidogrel is currently a subject of much interest. We tested the hypothesis that functional variability in the platelet response to clopidogrel correlates with occupancy of the platelet P2Y(12) receptor by clopidogrel active metabolite. Healthy subjects were screened after seven days' treatment with clopidogrel 75 mg/day to select three clopidogrel-response groups (n = 12/group), defined as 'average' (40-60% inhibition of platelet aggregation [IPA]), 'low' (<10% IPA) or 'high' (>80% IPA) responders. After a two- to six-week wash-out period, subjects were randomized (double-blind) to clopidogrel 75 mg/day (n = 10/group) for 10 days, followed by clopidogrel 300 mg on day 11, or placebo (n = 2/group). IPA induced by adenosine diphosphate (ADP), and P2Y(12) receptor occupancy were measured repeatedly. The incidence of low responders was 3.7%, and low responses to clopidogrel were maintained during the randomized evaluation phase. Treatment with clopidogrel for 10 days induced a significant increase in P2Y(12) receptor occupancy in each group of responders versus placebo; receptor affinity was unchanged. This reduction correlated with IPA response (r = 0.54). The additional 300 mg dose of clopidogrel on top of 75 mg chronic treatment increased IPA and P2Y(12) receptor occupancy in all groups, but relatively more in low responders. Variability in the response to clopidogrel appears to be linked to differences in P2Y(12) receptor occupancy. An additional 300 mg dose of clopidogrel improves both IPA and P2Y(12) receptor occupancy mostly in the subset of 'low' responders.
Bal Dit Sollier
Claire
C
IVS, Hôpital Lariboisière, Paris, France.
Berge
Natacha
N
Boval
Bernadette
B
Hovsepian
Lionel
L
Drouet
Ludovic
L
D000244:Adenosine Diphosphate; D000293:Adolescent; D000328:Adult; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D004311:Double-Blind Method; D004351:Drug Resistance; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D010979:Platelet Function Tests; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000097:blood; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D055815:Young Adult
C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine