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Do Not Coadminister

Darunavir/Cobicistat/ Emtricitabine/Tenofovir alafenamide (DRV/c/FTC/TAF)

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration of clopidogrel and boosted regimens has been evaluated in clinical studies. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. In HIV-positive subjects, the presence of a pharmacoenhancer (ritonavir n=8; cobicistat n=1) decreased the AUC and Cmax of clopidogrel’s active metabolite both by 69% when compared to values obtained in HIV-negative subjects (n=12). In HIV-negative subjects (n=12), coadministration of clopidogrel and ritonavir (100 mg twice daily) decreased the AUC and Cmax of clopidogrel’s active metabolite by 51% and 48%. Importantly, the decrease in clopidogrel’s active metabolite lead to insufficient inhibition of platelet aggregation in 44% of the patients treated with clopidogrel and ritonavir or cobicistat. Consistently, the study in HIV-negative subjects showed that the average inhibition of platelet aggregation was decreased from 51% (clopidogrel alone) to 31% (clopidogrel + ritonavir). Of interest, the study with HIV-infected patients showed a comparable decrease in prasugrel’s active metabolite AUC (52% decrease), however this decrease did not impair prasugrel’s antiplatelet effect. The differential impact on clopidogrel and prasugrel pharmacodynamics effect is in line with clinical observations. 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. Taken together these data suggest that given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Description:

Based on theoretical considerations co administration of Symtuza with clopidogrel is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel. Co administration of Symtuza with clopidogrel is not recommended. Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.

Symtuza Summary of Product Characteristics, Janssen-Cilag Ltd, June 2023.

Co-administration is expected to decrease concentrations of the clopidogrel active metabolite. Co-administration of Symtuza and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel.

Symtuza US Prescribing Information, Janssen Products, 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.

The impact of ritonavir on the pharmacokinetics of clopidogrel active metabolite (AM) and the pharmacodynamic effect was evaluated in a randomized, placebo-controlled, crossover study in 12 healthy volunteers. Subjects ingested either placebo or clopidogrel (300 mg followed by 75 mg the two following days) alone and together with ritonavir (100 mg twice daily). Ritonavir significantly decreased the exposure of clopidogrel AM by 51% and average platelet inhibition significantly decreased from 51% without ritonavir to 31% with ritonavir (mean difference 90% CI -27% to -12%). The maximal platelet inhibition by clopidogrel was also reduced from 60% to 40% during concurrent ritonavir (mean difference 90% CI -29% to -11%). The authors conclude that patients receiving ritonavir are at risk for diminished clopidogrel response and consequently increased risk for atherothrombotic events if the two drugs are used concurrently. The authors recommend to avoid concomitant administration of clopidogrel with ritonavir.

Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Itkonen MK, Tornio A, Lapatto-Reiniluoto O, et al. Clin Pharmacol Ther, 2019, 105(1):219-228.

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 2018, 84(7):1617-1619.

A 64-year-old man presented with increasing shortness of breath, fatigue and chest pain radiating to his left shoulder and neck. His home medications included darunavir, ritonavir, emtricitabine-tenofovir, isoniazid, pyridoxine, clopidogrel, aspirin, carvedilol, rosuvastatin, valsartan, sertraline, tamsulosin and esomeprazole. Potential drug-drug interactions between isoniazid and clopidogrel, and ritonavir and clopidogrel were identified that could interfere with clopidogrel activation. Based on this, platelet function testing was completed and impaired clopidogrel response was seen on two platelet function tests. There was no genetic cause (i.e., CYP2C19 genotype) for the impaired clopidogrel response.

A patient with HIV and tuberculosis with diminished clopidogrel response. Metzger NL, Momary KN. Int J STD AIDS, 2013, 25(7): 532-534.