Key result
In vitro and clinical evidence suggest clopidogrel is primarily a CYP3A substrate, explaining why concomitant administration of CYP2C19 inhibitors like PPIs does not increase MACE.
Why the study?
Does concomitant administration of proton pump inhibitors (PPIs) with clopidogrel increase major adverse cardiovascular events?
Does concomitant administration of proton pump inhibitors (PPIs) with clopidogrel increase major adverse cardiovascular events?
Evidence suggests clopidogrel is primarily a CYP3A substrate, challenging the basis of the FDA black box warning regarding its interaction with CYP2C19 inhibitors like PPIs.
Answers are grounded in this paper and cite their sources.
May not warrant PPI avoidance with clopidogrel on CYP2C19 grounds; challenges FDA warning and leaves open CYP3A-focused trials.
It has been presumed that CYP2C19 has a major role in the metabolism of clopidogrel. This presumption has been based on in vitro drug metabolism studies using microsomes from baculovirus infected insect cells (BD-Supersomes™). If clopidogrel were primarily a CYP2C19 substrate, a drug/drug interaction with CYP2C19 inhibitors, such as proton pump inhibitors (PPIs), for example, omeprazole and lansoprazole would be anticipated. Several ex vivo studies, using ADP stimulated platelet aggregation, suggested that there was such an interaction. The data from these studies served as a basis for FDA to provide a "Black Box" warning for the clopidogrel label in March of 2010. However, a prospective clinical study, COGENT, and several large meta-analyses have failed to demonstrate a negative effect on major adverse cardiovascular events (MACE), with concomitant administration of clopidogrel and PPIs. The in vitro work using "Supersomes" was revisited. In vitro metabolism using hepatosomes, which resemble the native cytochrome P-450 enzyme expression, has confirmed the earlier work that clopidogrel is primarily a CYP3A substrate. This result correlates better with clinical findings. The absence of an increase in MACE by concomitant administration of PPIs, which are CYP2C19 inhibitors, to a regimen including clopidogrel, is therefore not surprising. A hypothesis is offered to explain why subjects, who carry two reduced function alleles of CYP2C19, may have more reactive platelets.
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Ford et al. (2013) conducted a review in Clopidogrel metabolism and drug interactions. Concomitant administration of clopidogrel and proton pump inhibitors was evaluated on Major adverse cardiovascular events (MACE). In vitro and clinical evidence suggest clopidogrel is primarily a CYP3A substrate, explaining why concomitant administration of CYP2C19 inhibitors like PPIs does not increase MACE.
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