Liverpool HIV Interactions

No Interaction Expected

Darunavir/cobicistat (DRV/c)

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration of prasugrel with a pharmacoenhancer has been evaluated in a clinical study. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6. In HIV-positive subjects, the presence of a pharmacoenhancer (ritonavir n=8; cobicistat n=1) decreased the AUC and Cmax of prasugrel’s active metabolite by 52% and 43% when compared to values obtained in HIV-negative subjects (n=12). However this decrease did not impair prasugrel’s antiplatelet effect. Conversely, this same study showed that ritonavir or cobicistat significantly reduced both clopidogrel’s active metabolite exposure and inhibitory effect on platelet aggregation. These data are in line with clinical observations as early thrombosis of a coronary stent was reported in a patient treated with darunavir/ritonavir concomitantly with clopidogrel while subsequent replacement of clopidogrel by prasugrel did not lead to novel stent thrombosis episodes. Given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of ritonavir or cobicistat boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered.

Description:

Coadministration is expected not to affect concentrations of the prasugrel active metabolite. No dose adjustment is needed when prasugrel is coadministered with darunavir/cobicistat.

Prezcobix US Prescribing Information, Janssen Pharmaceuticals Inc, March 2023.

The impact of boosted antiretroviral therapies on the pharmacokinetics of clopidogrel and prasugrel active metabolites (AM) and on the efficacy of prasugrel and clopidogrel were evaluated in a randomized crossover study. A significantly lower exposure of clopidogrel AM (69% decrease) and prasugrel AM (52% decrease) were demonstrated in HIV-infected patients treated sequentially with a loading dose of clopidogrel (300 mg) and prasugrel (60 mg) while on a ritonavir- or cobicistat- containing antiretroviral regimen compared to healthy volunteers receiving only the corresponding antiplatelet agent. Of interest, the coadministration with ritonavir or cobicistat had a differential impact on clopidogrel and prasugrel pharmacodynamics effect. Treatment with clopidogrel resulted in adequate platelet inhibition in all healthy volunteers (no coadministration of ritonavir- or cobicistat-boosted regimens) while 44% of HIV-infected patients were shown to have insufficient platelet inhibition (coadministration with ritonavir- or cobicistat-boosted regimens). On the contrary, treatment with prasugrel resulted in a potent platelet inhibition in both healthy and HIV-infected subjects. The authors conclude that prasugrel remains an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.

Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Marsousi N, Daali Y, Fontana P, et al. Clin Pharmacokinet, 2018, 57(10):1347-1354.

A 45-year-old HIV infected patient treated with darunavir/ritonavir plus emtricitabine/tenofovir. The patient underwent coronary stenting as he presented a significant stenosis of the coronary artery. The patient was subsequently started on dual antiplatelet therapy with aspirin and clopidogrel while his actual antiretroviral treatment was maintained. Six month later, the patient presented an episode of chest pain with electrocardiographic signs of acute anterior myocardial infarction, and evidence of thrombosis of the implanted stent. He underwent thromboaspiration and implantation of a novel stent. Clopidogrel was replaced by prasugrel while the darunavir/ritonavir regimens was maintained. No novel stent thrombosis episodes occurred while on prasugrel.

Recurrent coronary disease in HIV-infected patients: role of drug-drug interactions. Bravo I, Alvarez H, Marino A, Clotet B, Molto J. Br J Clin Pharmacol 2019, 105(1):219-228.

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