Liverpool HEP Interactions

Do Not Coadminister

Ombitasvir/Paritaprevir/r + Dasabuvir

Clopidogrel

Summary:

Coadministration of clopidogrel and ritonavir-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. The interaction between clopidogrel (300 mg loading dose followed by 75 mg once daily) and ritonavir (100 mg twice daily) was investigated in 12 HCV-negative subjects in the presence of dasabuvir (250 mg single dose). Dasabuvir AUC increased by 289% and Cmax increased by 82% in the presence of clopidogrel and ritonavir when compared to ritonavir alone. The AUC and Cmax of clopidogrel’s active metabolite decreased by 51% and 48% in the presence of ritonavir, with the average inhibition of platelet aggregation decreasing from 51% in the clopidogrel/dasabuvir phase to 31% in the clopidogrel/dasabuvir/ritonavir phase. 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). Subjects showed a comparable decrease in prasugrel’s active metabolite AUC (52% decrease), however this decrease did not impair prasugrel’s antiplatelet effect. Given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of ritonavir-boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered. [Note, the European SmPC for clopidogrel contraindicates its use in severe hepatic impairment but the US Prescribing Information states no dose alteration.]

Description:

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) all in the presence of dasabuvir (250 mg single dose). Dasabuvir AUC increased by 289% and Cmax increased by 82% in the presence of clopidogrel and ritonavir when compared to ritonavir alone. 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.

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 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.

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