Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin.
OBJECTIVE
This double-blind, parallel-group study was conducted to assess the pharmacodynamics, pharmacokinetics, and safety of AZD6140, the first oral, reversible adenosine diphosphate (ADP) receptor antagonist.


RESULTS
Patients (n = 200) with atherosclerosis were randomized to receive AZD6140 50, 100, or 200 mg twice daily (bid) or 400 mg daily (qd) or clopidogrel 75 mg qd for 28 days. All groups received aspirin 75-100 mg qd. AZD6140 (100 and 200 mg bid, 400 mg qd) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at day 28. On day 1, peak final-extent inhibition of platelet aggregation (IPA) was observed 2-4 h post-dose with AZD6140, whereas clopidogrel minimally inhibited platelet aggregation (mean percentage IPA < 20%, all time points). Four hour post-dose at steady state, the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA (approximately 90-95%), which exceeded that with AZD6140 50 mg bid or clopidogrel (approximately 60%). AZD6140 was generally well tolerated. All bleeding events, except one in a patient receiving 400 mg qd, were minor and of mild-to-moderate severity.


CONCLUSIONS
AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.
Department of Medicine and Cardiology, Arhus University Hospital, Denmark. steen.husted@as.aaa.dk
Steen
S
Husted
Håkan
H
Emanuelsson
Stan
S
Heptinstall
Per Morten
PM
Sandset
Mark
M
Wickens
Gary
G
Peters
D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy*; D001760:Bleeding Time; D000077144:Clopidogrel; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D017698:Postmenopause; D000077486:Ticagrelor; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine; D001241:Aspirin