A Randomized, 2-Period, Crossover Design Study to Assess the Effects of 1304 Dexlansoprazole, Lansoprazole, Esomeprazole, and Omeprazole on the Steady-State Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Volunteers
What is the impact of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel?
The authors performed a randomized, open-label, crossover study of 160 healthy subjects who were homozygous for CYP2C19 extensive metabolizer genotype. All subjects took clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or omeprazole 80 mg) daily. Omeprazole was used as a positive control. Pharmacokinetics and pharmacodynamics were assessed on day 9 or 10. Pharmacodynamic endpoints were vasodilator-stimulated phosphoprotein P2Y12 platelet reactivity index, maximal platelet aggregation to 5 and 20 µmol/L adenosine diphosphate, and VerifyNow P2Y12 platelet response units.
The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole (as well as omeprazole), but not with dexlansoprazole or lansoprazole. A significantly reduced effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index was seen with esomeprazole, but not dexlansoprazole or lansoprazole. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units.
There was a significant difference between various PPIs with respect to their interaction with and resulting in reduced bioavailability of clopidogrel.
This study elegantly demonstrates the difference in the potential of different PPIs to interact with clopidogrel. The clinical relevance of this, however, remains uncertain. The COGENT trial demonstrated no evidence of increased cardiovascular events in patients treated with clopidogrel compared with those treated with clopidogrel and omeprazole (Bhatt DL, et al., N Engl J Med 2010;363:1909-17), and it is hard to justify change in clinical practice based on the results of surrogate markers, as evaluated in this study.
Clinical Topics: Novel Agents
Keywords: Healthy Volunteers, Microfilament Proteins, Cross-Over Studies, Ticlopidine, Biological Availability, Proton Pump Inhibitors, Lansoprazole, Esomeprazole, Biological Markers, Dexlansoprazole, Platelet Aggregation, Phosphoproteins, Omeprazole, Cell Adhesion Molecules
< Back to Listings