Thienopyridine–proton pump inhibitor drug interaction

Issue: November 10, 2009

ByStephanie Inverso Polli, PharmD

Clopidogrel is a prodrug that undergoes hepatic metabolism to an active metabolite, which inhibits platelet function via the irreversible binding to the adenosine 5-diphosphate P2Y12 receptor on platelets.

The metabolism of clopidogrel is complex: Approximately 85% of a dose is metabolized to an inactive metabolite via esterases, and the remaining 15% undergoes two separate oxidative hepatic processes via cytochrome P450 (CYP) isoenzymes. The first CYP–oxidative process is mediated by isoenzymes CYP1A2, CYP2C19 and CYP2B6 and yields an inactive metabolite. The inactive metabolite then undergoes a second CYP–oxidative process mediated by CYP3A4/CYP3A5, CYP2C9, CYP2C19 and CYP2B6, yielding the active metabolite that is responsible for inhibiting platelet function.

Stephanie Inverso Polli, PharmD
Stephanie Inverso Polli

Genetic mutations resulting in decreased CYP2C19 function have been associated with attenuated platelet inhibition and higher rates of cardiovascular events in patients treated with clopidogrel. Drug–drug interactions with medications that compete for or inhibit CYP2C19 function, such as proton pump inhibitors, may lead to similar outcomes.

The mechanism for the drug–drug interaction between clopidogrel and PPIs is believed to be mediated through the PPI inhibition of CYP2C19. When the CYP–oxidative metabolism of clopidogrel is decreased, it diverts metabolism away from the CYP metabolic process to the esterase metabolic process. This pushes the small amount of clopidogrel that would have become the active metabolite into the inactive pathway, thus attenuating platelet inhibition by clopidogrel.

All six currently available PPIs — dexlansoprazole (Kapidex, Takeda), esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole — are metabolized hepatically via CYP enzymes. In all cases, CYP2C19 plays a significant role in the metabolism. Thus, the potential for the interaction exists with all PPIs.

Current practice

Results of several studies have shown decreased platelet inhibitory effect of clopidogrel in patients assigned to concomitant therapy with a PPI. Similarly, findings from some retrospective studies have indicated an association between adverse cardiovascular outcomes in patients assigned clopidogrel and a PPI, whereas others have not suggested the same outcomes.

There is currently no consensus for the management of the interaction between clopidogrel and a PPI. Pantoprazole was initially recommended as the PPI of choice in patients administered clopidogrel because the increase in cardiovascular events was not seen with this agent. However, a subsequent study has yielded conflicting results. It was suggested that prophylactic use of PPIs be avoided in patients administered clopidogrel and PPIs be reserved for patients with a clear indication. Histamine₂ (H₂) receptor antagonists may be an alternative for some patients. The Society for Cardiovascular Angiography and Intervention recommends H₂ receptor antagonists or antacids. It also suggests contacting the patient’s gastroenterologist or primary care physician to discuss alternatives.

Prasugrel

Prasugrel (Effient, Lilly), the recently approved thienopyridine, also requires transformation to an active metabolite to exert the desired platelet inhibition, although the metabolism of prasugrel is less complex than clopidogrel. Prasugrel first undergoes metabolism by esterases into an inactive metabolite. That metabolite then undergoes a single CYP–oxidative process mediated by CYP3A4, CYP2B6, CYP2C9 and CYP2C19, yielding the active metabolite that is responsible for inhibiting platelet function. Genetic mutations resulting in decreased CYP2C19 activity do not appear to negatively affect platelet inhibition or clinical outcomes in patients assigned prasugrel. In vitro, CYP3A4 and CYP2B6 appear to be primarily responsible for metabolism of prasugrel, with CYP2C9 and CYP2C19 contributing to a lesser extent.

A report from the PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trials, presented at the European Society of Cardiology Congress 2009 in Barcelona, Spain, and simultaneously published online in The Lancet, indicated concomitant use of a PPI and either clopidogrel or prasugrel resulted in lower mean platelet inhibition than clopidogrel or prasugrel alone. However, in TRITON-TIMI 38, in which researchers measured long-term outcomes, this reduction in platelet inhibition did not translate to an increased risk for adverse cardiovascular outcomes (adjusted HR=0.94; 95% CI, 0.80-1.11 for clopidogrel and HR=1.00; 95% CI, 0.84-1.20 for prasugrel).

Although these new data suggest it may not be necessary to avoid concomitant use of PPIs (in patients who have a clear indication for them) and either clopidogrel or prasugrel, at this time, it is prudent to consider alternative agents when possible until additional, more definitive interaction data are available.

For more information:

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Society of Cardiovascular Angiography and Interventions. A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: the Clopidogrel Medco Outcomes Study. SCAI website. scai.org/drlt1.aspx?PAGE_ID=5870. Accessed Sept. 17, 2009.

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