A randomized, 2-Period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers
Background
The co-administration of proton pump inhibitors (PPI) with clopidogrel reduces the risk of gastrointestinal (GI) bleeding associated with the antiplatelet effects of clopidogrel. There are conflicting data as to whether PPIs have the potential to reduce the effectiveness of clopidogrel. The metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19 – PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel.
Aim of the study
To determine the effects of four different PPIs (dexlansoprazole, lansoprazole, omeprazole, and esomeprazole) on the steady-state pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel.
Methods
This is a randomized, open-label, two-period crossover study of 160 healthy subjects, homozygousfor CYP2C19 extensive metabolizer genotype.
Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for nine days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 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.
Results
Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. 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.
Conclusions
Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the co-administration of dexlansoprazole or lansoprazole with clopidogrel than by the co-administration of esomeprazole or omeprazole.
Perspective – Clinical impact
The results of this investigation are important and have clinical implications, suggesting that the potential of PPIs to attenuate clopidogrel efficacy could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole.
All tested PPIs significantly decreased peak plasma concentrations of clopidogrel, but esomeprazole and omeprazole did so to a greater degree than lansoprazole and dexlansoprazole.
This study’s randomized, two-period crossover design was a strength, as were the enrollment criteria that eliminated variables known to influence clopidogrel and/or PPI metabolism, including CYP2C19 polymorphisms – providing a uniform study population.
Subjects were confined and received a standardized restricted diet, eliminating potential confounding factors (including smoking, concurrent medications and noncompliance with drug administration).
Regarding limitations, the results for omeprazole 80 mg do not necessarily apply to the more commonly-used doses of 20 and 40 mg. Also, this study was conducted in confined healthy volunteers and not patients, the reason being that this enabled authors to use a randomized, crossover design while controlling for concurrent medications, diet, smoking, exercise and other factors. Finally, for uniformity, this study included only homozygous CYP2C19 wt/wt extensive metabolizers. Consequently, these conclusions are limited to this population.
Citation: J Am Coll Cardiol 2012; 59:1304–11