Pharmacodynamic Effects of Concomitant Versus Staggered Clopidogrel and Omeprazole Intake

Abstract

Background-A drug interaction between clopidogrel and omeprazole resulting in impaired platelet inhibition has been reported. It has been suggested that staggering administration of clopidogrel and omeprazole may overcome this pharmacodynamic (PD) interaction. Methods and Results-This prospective, open-label, 3-period, randomized crossover study was performed in 20 healthy volunteers. Subjects were randomly selected to receive omeprazole (40 mg daily) concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy in a crossover fashion, with a 2-to 4-week washout period between treatments. After another 2-to 4-week washout period, all subjects were treated for 1 week with clopidogrel alone. Clopidogrel was administered as a 600-mg loading dose followed by a 75-mg maintenance dose during all phases. PD effects were assessed by vasodilator-stimulated phosphoprotein phosphorylation assay, VerifyNow P2Y 12 system, and light transmittance aggregometry at baseline, 24 hours, and 1 week.

Pharmacodynamic Evaluation of Pantoprazole Therapy on Clopidogrel Effects

“…[7][8][9] Although the clinical implications associated with the reduced pharmacodynamic effects in clopidogrel-treated patients as a cause of this drug interaction remain controversial, this has prompted drug-regulating authorities in the United States and in Europe to provide a box warning for the use of these drugs, administered either concomitantly or staggered. 13,14 In fact, the impact of any negative interaction between PPIs and clopidogrel is of particular concern because of the high frequency with which these two drugs are coprescribed.…”

“…This investigation expands on a recently reported study by our group evaluating the pharmacodynamic effects of the clopidogrel-omeprazole drug interaction and how this may be affected by timing of drug intake and presents the same study entry criteria. 8 The study design of the present investigation is illustrated in Figure 1. Subjects were randomly assigned in a 1:1 fashion to take pantoprazole concomitantly (CONC regimen) or staggered by 8 to 12 hours (STAG regimen) for 1 week on a background of clopidogrel therapy.…”

“…5,6 Among these, a drug interaction between proton pump inhibitors (PPIs), in particular omeprazole, and clopidogrel has recently emerged. [7][8][9] This drug interaction probably is due to the common metabolic pathway of these agents, which involves the cytochrome P450 (CYP) 2C19 enzyme. 10,11 The CYP2C19 isoenzyme is of particular importance because it is involved in both oxidation steps required for clopidogrel prodrug to generate its active metabolite.…”

“…[7][8][9] The concerns surrounding this interaction have prompted a box warning for the concomitant use of these drugs. 13,14 However, whether the clopidogrel-PPI interaction is a class effect or a drug-specific effect is still a matter of debate.…”

Role of Platelets and Antiplatelet Therapy in Cardiovascular Disease

“…Despite the fact that aspirin plus clopidogrel therapy resulted in a significant benefit, a considerable number of patients continued to experience cardiovascular events, which may in part be due to the substantial interindividual variation in platelet response to clopidogrel 29) . A large number of factors that may influence the response to clopidogrel have been identified, such as poor compliance, possible drug-drug interactions involving the cytochrome P450 system [30][31][32] , genetic polymorphisms 33) and several cellular factors 34,35) . The relatively slow onset of action and limited potency of clopidogrel in its approved regimen has stimulated a number of studies evaluating higher doses of clopidogrel that can act more rapidly and more effectively.…”