Pharmacodynamic Evaluation of Pantoprazole Therapy on Clopidogrel Effects: Results of a Prospective, Randomized, Crossover Study

Study Questions:

What is the impact of high-dose pantoprazole therapy, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects?

Methods:

This was a prospective, randomized, crossover study conducted in 20 healthy volunteers. Subjects were randomly assigned to receive pantoprazole (80 mg daily) administered concomitantly (CONC) or staggered by 8-12 hours (STAG) for 1 week on a background of clopidogrel therapy (600 mg loading dose followed by a 75 mg maintenance dose during all phases) in a crossover fashion with a 2- to 4-week washout period between treatments. All subjects had a 1-week treatment phase with a clopidogrel-only regimen, with a 2- to 4-week washout period from randomization sequence. Platelet function was assessed by flow cytometric analysis of the status of phosphorylation of the vasodilator-stimulated phosphoprotein, light transmittance aggregometry after adenosine diphosphate stimuli, and VerifyNow P2Y12 system at three time points: baseline, 24 hours after loading dose, and 1 week after maintenance dose. The primary endpoint was the comparison of P2Y12 reactivity index assessed by vasodilator-stimulated phosphoprotein at 1 week.

Results:

After 1 week, there were no significant difference in P2Y12 reactivity index between the CONC and STAG regimens (least-squares mean ± standard error of mean, 56.0 ± 3.9% vs. 56.1 ± 3.9%; p = 0.974), as well as when compared with the clopidogrel-only regimen (61.0 ± 3.9%; p = 0.100 vs. CONC and p = 0.107 vs. STAG). Further, no differences were observed at baseline and 24 hours between regimens. Concordant results were obtained by light transmittance aggregometry and VerifyNow P2Y12 assays.

Conclusions:

The authors concluded that pantoprazole therapy used at high doses is not associated with modulation of the pharmacodynamic effects of clopidogrel, irrespective of timing of drug administration.

Perspective:

This study demonstrates the lack of any significant impairment in clopidogrel-induced pharmacodynamic effects with pantoprazole administered either concomitantly or staggered. Pantoprazole is a proton pump inhibitor (PPI) with low potential to inhibit CYP2C19, and the study suggests that the pharmacodynamic interaction between clopidogrel and PPIs may be drug-specific rather than a class effect. This study had an open-label design, performed in healthy volunteers, and had a small sample size and, thus, should be considered hypothesis generating. Head-to-head investigations comparing the effects of PPIs with different effects on CYP2C19 activity (e.g., omeprazole vs. pantoprazole) would provide more insight on this interaction.

Clinical Topics: Novel Agents

Keywords: Microfilament Proteins, Phosphoproteins, 2-Pyridinylmethylsulfinylbenzimidazoles, Omeprazole, Cell Adhesion Molecules, Proton Pump Inhibitors


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