Pharmacodynamic Evaluation of Pantoprazole Therapy on Clopidogrel Effects: Results of a Prospective, Randomized, Crossover Study
What is the impact of high-dose pantoprazole therapy, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects?
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.
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.
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.
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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