Elvitegravir / Cobicistat

Clopidogrel

Use with caution.

No pharmaceutical opinion available for this interaction.

Mechanism

Elvitegravir / Cobicistat can inhibit the metabolism (CYP 3A4) and decrease the active metabolite formation of Clopidogrel.

Elvitegravir / Cobicistat

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Clopidogrel

Pharmacodynamic effects

Possible decrease of clinical efficacy.

Recommendations

Use with caution or choose an alternative.

Closely monitor clinical effectiveness.

See comments.

Alternative solution(s)

Prasugrel

Monitor

Tests

Pharmacokinetic parameters

Comment

Ref #3447 : A randomized crossover study evaluated the impact of boosted antiretrovirals on the pharmacokinetics of the active metabolites of clopidogrel and prasugrel and on their efficacy in HIV-positive patients. In patients receiving clopidogrel 300 mg concomitantly with a ritonavir or cobicistat containing regimen, there was a significant 69% decrease in AUC and Cmax of clopidogrel active metabolite compared to healthy patients receiving clopidogrel alone. Platelet inhibition was insufficient in 44% of patients taking ritonavir or cobicistat while it was adequate in all patients without ritonavir or cobicistat. For patients receiving prasugrel 60 mg with ritonavir or cobicistat, there was a 52% decrease in AUC and 41% in the Cmax of prasugrel active metabolite. On the other hand, all patients undergoing prasugrel show potent platelet inhibition. The authors conclude that prasugrel remains an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this setting, regardless of the metabolic interaction and inhibition of its bioactivation pathways.

Ref #3449 : Another study in healthy patients receiving clopidogrel (300 mg on the first day followed by 75 mg QD) and ritonavir (100 mg BID) showed a decrease in clopidogrel active metabolite AUC and Cmax of 52% and 49%, respectiveley. Mean and maximum platelet inhibition were reduced to 31% and 40%, respectively. The authors conclude that it is recommended to avoid the concomitant administration of clopidogrel with ritonavir-containing regimens.

Ref #3448 : Case report of a 45-year-old HIV-positive patient treated with darunavir/ritonavir and emtricitabine/ tenofovir. Following coronary intervention, the patient began double antiplatelet therapy with aspirin and clopidogrel while his antiretroviral therapy was maintained. Six months later, the patient presented with an episode of chest pain with electrocardiographic signs of acute anterior myocardial infarction and signs of thrombosis of the implanted stent. Following a new intervention, clopidogrel is replaced by prasugrel, while darunavir/ritonavir is maintained. No new episodes of thrombosis were observed.

Ref #3134 : Ketoconazole 400 mg decreased clopidogrel active metabolite AUC by 22-29% and platelet aggregation by 22–33% in healthy volunteers.

Ref #3162 : Case report of decreased responsiveness to clopidogrel in a HIV-positive patient receiving isoniazid (CYP2C19, 3A4 inhibitor) and darunavir/ritonavir QD suggesting decreased effect due to potential 3A4 inhibition.

In a study with erythromycin (CYP3A4 inhibitor), the following results were observed: baseline platelet aggregation of 93%, platelet aggregation of 42% with the addition of clopidogrel, and platelet aggregation of 55% when clopidogrel and erythromycin were administered together. The author concluded that the addition of a CYP3A4 inhibitor can potentially decrease the antiplatelet effect of clopidogrel. Moreover, although the findings vary from one study to another, several studies have also reported a loss of efficacy when atorvastatin (CYP3A4 inhibitor) is combined with clopidogrel.

Reference
  • 2641
    Clopidogrel (Plavix), Sanofi-Aventis, Québec, Canada, 8 février 2019.
  • 3447
    Marsousi N, Daali Y, Fontana P, Reny JL, Ancrenaz-Sirot V et al. Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Clin Pharmacokinet. 2018 Oct; 57(10): 1347-1354.
  • 3449
    Itkonen MK, Tornio A, Lapatto-Reiniluoto O, Neuvonen M, Neuvonen PJ et al. Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Clin Pharmacol Ther, 2018 Apr 26. doi: 10.1002/cpt.1099.
  • 3448
    Bravo I, Alvarez H, Marino A, Clotet B, Molto J. Recurrent coronary disease in HIV-infected patients: role of drug-drug interactions. Br J Clin Pharmacol. 2018 Jul;84(7):1617-1619.
  • 3134
    Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT, Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007 May; 81 (5): 735-741.
  • 3162
    Metzger NL, Momary KM. A patient with HIV and tuberculosis with diminished clopidogreal response. Int J STD & AIDS 2013; 25: 532-4.
  • 2642
    Ancrenazl Y, Daali P, Fontana M, et al. Impact of Genetic Polymorphisms and Drug–Drug Interactions on Clopidogrel and Prasugrel Response Variability. Current Drug Metabolism 2010; 11 (8): 677-677.
  • 2644
    Farid NA, Kurihara A, Wreighton SA. Metabolism and Disposition of the Thienopyridine Antiplatelet Drugs Ticlopidine, Clopidogrel, and Prasugrel in Humans. J Clin Pharmacol 2010; 50: 126-142.
  • 2645
    Nishiva Y, Hagihara K, et al. Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel. Drug Metab Dispos 2009; 37: 589-593.
  • 2684
    Bates ER, Lau WC, Angiolillo DJ. Clopidogrel – Drug interactions. Journal of the American College of Cardiology Vol. 57, No. 11, 2011.
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  • 2686
    De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: 196–203.
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    Mega JL, Close SL. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. N Engl J Med 2009; 360: 354-62.
  • 2688
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