Drug Interactions between cobicistat and Plavix

MONITOR CLOSELY: Coadministration with cobicistat or ritonavir may reduce the efficacy of clopidogrel, whose antiplatelet effect is dependent in part on bioactivation to a pharmacologically active metabolite via various CYP450 isoenzymes including CYP450 2C19 and 3A4/5, as well as CYP450 1A2 and 2B6 to a lesser extent. Since cobicistat and ritonavir are potent inhibitors of CYP450 3A4 used primarily as pharmacokinetic boosters, they may interfere with the formation of the active metabolite of clopidogrel. In a study consisting of 9 HIV-infected male subjects receiving cobicistat or ritonavir boosted antiretroviral therapy and 12 healthy male subjects receiving no background medications, mean peak plasma concentration (Cmax) and systemic exposure (AUC) of the active metabolite following a single 300 mg dose of clopidogrel were 3.2-fold lower in HIV subjects compared to healthy subjects. In addition, platelet inhibition was considered insufficient (i.e., platelet reactivity units above cut-off value at 4 hours post-dose) in 44% of HIV subjects, while adequate platelet inhibition was demonstrated in all healthy subjects. Overall, there was a general consistency between platelet inhibition and the AUC of the active metabolite of clopidogrel. In the same study, a 60 mg dose of prasugrel led to almost complete platelet inhibition in all HIV and healthy subjects, despite a 1.7- and 2.1-fold lower Cmax and AUC of its active metabolite, respectively, in the HIV subjects. In another study conducted in 12 healthy volunteers, investigators reported that coadministration of ritonavir (100 mg twice daily on days 1 to 5) and clopidogrel (300 mg on day 3, followed by 75 mg on days 4 and 5) decreased the Cmax and AUC of the active metabolite of clopidogrel by 48% and 51%, respectively, compared to clopidogrel administered alone. The average inhibition of platelet aggregation was 31% with ritonavir and 51% without ritonavir, and the maximal platelet inhibition by clopidogrel was 40% versus 60% with and without ritonavir. A case report has also been published describing clopidogrel resistance in a patient with HIV, latent tuberculosis, and cardiovascular disease due to a suspected interaction with isoniazid and ritonavir.

MANAGEMENT: The potential for reduced efficacy of clopidogrel should be considered in patients receiving cobicistat or ritonavir boosted pharmacologic regimens. This may be particularly relevant in populations that may rely more on CYP450 3A4 for bioactivation of clopidogrel, such as patients with genetic polymorphisms of CYP450 2C19 and/or 3A5 resulting in reduced or absent activity of those isoenzymes or taking concomitant drugs that inhibit those isoenzymes. Close clinical and laboratory monitoring for evidence of diminished antiplatelet effects is recommended, or consider using alternative antiplatelet agents.