Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric-coated omeprazole and clopidogrel.
BACKGROUND
A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction.


RESULTS
A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 μM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype.


CONCLUSIONS
PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.
Sinai Center for Thrombosis Research, Baltimore, MD, USA. pgurbel@lifebridgehealth.org
Paul A
PA
Gurbel
Kevin P
KP
Bliden
John G
JG
Fort
Young-Hoon
YH
Jeong
Alan
A
Shuldiner
Sumbul
S
Chai
Tania
T
Gesheff
Mark
M
Antonino
Martin
M
Gesheff
Ying
Y
Zhang
Udaya S
US
Tantry
D000284:Administration, Oral; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000150:complications / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D013608:Tablets, Enteric-Coated; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D013608:Tablets, Enteric-Coated; D000077144:Clopidogrel; D009853:Omeprazole; D013988:Ticlopidine; D001241:Aspirin