Drug Interactions between clopidogrel and modafinil

MONITOR: Coadministration with inhibitors of CYP450 2C19 may reduce the efficacy of clopidogrel, whose antiplatelet effect is dependent in part on bioactivation by the isoenzyme to a pharmacologically active metabolite. This is consistent with studies that reported decreased effectiveness of clopidogrel and poorer clinical outcome in patients who have common genetic polymorphisms of CYP450 2C19 resulting in reduced or absent enzyme activity. The interaction has been studied with omeprazole, a potent CYP450 2C19 inhibitor. In 72 healthy subjects administered clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg) simultaneously for 5 days, systemic exposure to the active metabolite of clopidogrel decreased by 46% (Day 1) and 42% (Day 5) during coadministration with omeprazole, while mean inhibition of platelet aggregation (IPA) diminished by 47% (24 hours) and 30% (Day 5). Similar results were reported when the same doses of clopidogrel and omeprazole were administered 12 hours apart in another study. Data are not available for less potent inhibitors of CYP450 2C19. However, ineffective inhibition of platelet aggregation has been reported in association with a potential interaction with amiodarone, whose active metabolite, desethylamiodarone, has been shown to inhibit CYP450 2C19 in vitro.

MANAGEMENT: Based on existing data, it may be advisable to closely monitor the therapeutic efficacy of clopidogrel during concomitant treatment with CYP450 2C19 inhibitors.