Skip to main content
SpringerLink
Log in

Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and objectives

Prasugrel and clopidogrel are inhibitors of the ADP-P2Y12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection.

Methods

In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial.

Results

A significantly lower exposure to clopidogrel AM [3.2-fold lower area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax)] and prasugrel AM (2.1-fold and 1.7-fold lower AUC and Cmax) were demonstrated in HIV-infected patients treated with boosted ARTs compared with healthy controls; however, a differential impact was observed on platelet inhibition between clopidogrel and prasugrel. Clopidogrel 300 mg induced adequate (although modest) platelet inhibition in all healthy subjects, while platelet inhibition was insufficient in 44% of HIV patients. On the contrary, prasugrel 60 mg induced a potent platelet inhibition in both healthy and HIV-infected subjects.

Conclusion

Prasugrel appears to remain 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006;34(4):600–7.

    Article  PubMed  CAS  Google Scholar 

  2. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373(9665):723–31.

    Article  PubMed  CAS  Google Scholar 

  3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.

    Article  PubMed  CAS  Google Scholar 

  4. Wiviott SD, Trenk D, Frelinger AL, O’Donoghue M, Neumann FJ, Michelson AD, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923–32.

    Article  PubMed  CAS  Google Scholar 

  5. Culm-Merdek KE, von Moltke LL, Gan L, Horan KA, Reynolds R, Harmatz JS, et al. Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther. 2006;79(3):243–54.

    Article  PubMed  CAS  Google Scholar 

  6. Greenblatt DJ, von Moltke LL, Harmatz JS, Durol AL, Daily JP, Graf JA, et al. Differential impairment of triazolam and zolpidem clearance by ritonavir. J Acquir Immune Defic Syndr. 2000;24(2):129–36.

    Article  PubMed  CAS  Google Scholar 

  7. Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr. 2006;42(1):52–60.

    PubMed  CAS  Google Scholar 

  8. Putcharoen O, Do T, Avihingsanon A, Ruxrungtham K. Rationale and clinical utility of the darunavir-cobicistat combination in the treatment of HIV/AIDS. Drug Des Devel Ther. 2015;9:5763–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  9. Tybost: EU summary of product characteristics. Gilead Sciences International Ltd. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002572/WC500153014.pdf. Accessed May 2017.

  10. Xu L, Liu H, Murray BP, Callebaut C, Lee MS, Hong A, et al. Cobicistat (GS-9350): a potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer. ACS Med Chem Lett. 2010;1(5):209–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Boccara F. Cardiovascular complications and atherosclerotic manifestations in the HIV-infected population: type, incidence and associated risk factors. AIDS. 2008;22(Suppl 3):S19–26.

    Article  PubMed  Google Scholar 

  12. Boccara F, Lang S, Meuleman C, Ederhy S, Mary-Krause M, Costagliola D, et al. HIV and coronary heart disease: time for a better understanding. J Am Coll Cardiol. 2013;61(5):511–23.

    Article  PubMed  Google Scholar 

  13. Hsue PY, Hunt PW, Schnell A, Kalapus SC, Hoh R, Ganz P, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS. 2009;23(9):1059–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Matetzky S, Domingo M, Kar S, Noc M, Shah PK, Kaul S, et al. Acute myocardial infarction in human immunodeficiency virus-infected patients. Arch Intern Med. 2003;163(4):457–60.

    Article  PubMed  Google Scholar 

  15. Curtis MJ, Bond RA, Spina D, Ahluwalia A, Alexander SP, Giembycz MA, et al. Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol. 2015;172(14):3461–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Godino C, Mendolicchio L, Figini F, Latib A, Sharp AS, Cosgrave J, et al. Comparison of VerifyNow-P2Y12 test and flow cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy? Thromb J. 2009;7:4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J. 2008;29(8):992–1000.

    Article  PubMed  Google Scholar 

  18. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation. 2009;119(2):237–42.

    Article  PubMed  Google Scholar 

  19. Cuisset T, Frere C, Poyet R, Quilici J, Gaborit B, Bali L, et al. Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting. Arch Cardiovasc Dis. 2010;103(1):39–45.

    Article  PubMed  Google Scholar 

  20. Leunissen TC, Peeters Weem SM, Urbanus RT, den Ruijter HM, Moll FL, Asselbergs FW, et al. High on-treatment platelet reactivity in peripheral arterial disease: a pilot study to find the optimal test and cut off values. Eur J Vasc Endovasc Surg. 2016;52(2):198–204.

    Article  PubMed  CAS  Google Scholar 

  21. Daali Y, Ancrenaz V, Bosilkovska M, Dayer P, Desmeules J. Ritonavir inhibits the two main prasugrel bioactivation pathways in vitro: a potential drug-drug interaction in HIV patients. Metabolism. 2011;60(11):1584–9.

    Article  PubMed  CAS  Google Scholar 

  22. Ancrenaz V, Deglon J, Samer C, Staub C, Dayer P, Daali Y, et al. Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers. Basic Clin Pharmacol Toxicol. 2013;112(2):132–7.

    Article  PubMed  CAS  Google Scholar 

  23. Hauguel-Moreau M, Boccara F, Boyd A, Salem JE, Brugier D, Curjol A, et al. Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study. Eur Heart J. 2017;38(21):1676–86.

    PubMed  Google Scholar 

  24. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, et al. A phenotype–genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther. 2010;87(6):735–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Fukushima K, Kobuchi S, Mizuhara K, Aoyama H, Takada K, Sugioka N. Time-dependent interaction of ritonavir in chronic use: the power balance between inhibition and induction of P-glycoprotein and cytochrome P450 3A. J Pharm Sci. 2013;102(6):2044–55.

    Article  PubMed  CAS  Google Scholar 

  26. Kageyama M, Namiki H, Fukushima H, Terasaka S, Togawa T, Tanaka A, et al. Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats. Biol Pharm Bull. 2005;28(1):130–7.

    Article  PubMed  CAS  Google Scholar 

  27. Perloff MD, von Moltke LL, Greenblatt DJ. Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in rats. Xenobiotica. 2004;34(2):133–50.

    Article  PubMed  CAS  Google Scholar 

  28. Park J, Vousden M, Brittain C, McConn DJ, Iavarone L, Ascher J, et al. Dose-related reduction in bupropion plasma concentrations by ritonavir. J Clin Pharmacol. 2010;50(10):1180–7.

    Article  PubMed  CAS  Google Scholar 

  29. Kakuda TN, DeMasi R, van Delft Y, Mohammed P. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. HIV Med. 2013;14(7):421–9.

    Article  PubMed  CAS  Google Scholar 

  30. Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS 2nd, Brandt JT, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81(5):735–41.

    Article  PubMed  CAS  Google Scholar 

  31. Riesmeyer JS, Salazar DE, Weerakkody GJ, Ni L, Wrishko RE, Ernest CS 2nd, et al. Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy. J Clin Pharmacol. 2012;52(6):789–97.

    Article  PubMed  CAS  Google Scholar 

  32. Efient: product information. Parsippany, NJ: Daiichi Sankyo, Inc. and Eli Lilly and Company. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000984/WC500021971.pdf. Accessed May 2017.

  33. Gurbel PA, Erlinge D, Ohman EM, Neely B, Neely M, Goodman SG, et al. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA. 2012;308(17):1785–94.

    Article  PubMed  CAS  Google Scholar 

  34. Gurbel PA, deFilippi CR, Bliden KP, Tantry US. HIV infection, ACS, PCI and high platelet reactivity: ingredients for a perfect thrombotic storm. Eur Heart J. 2017;38(21):1687–9.

    PubMed  Google Scholar 

  35. Marsousi N, Samer CF, Fontana P, Reny JL, Rudaz S, Desmeules JA, et al. Coadministration of ticagrelor and ritonavir: toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach. Clin Pharmacol Ther. 2016;100(3):295–304.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This clinical study was supported by the Swiss National Science Foundation (FNRS 32003B-156471). The authors wish to thank Dr. Thanh D. Lecompte and Dr. Olivier Nawej Tshikung for their valuable contribution in patient recruitment, as well as the Clinical Research Centre of Geneva University Hospitals, Mrs. Severine Nolli and Mr. Michel Muster for their contribution in the VerifyNow® instruments disposition and platelet reactivity analysis.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil 4, 1211, Geneva, Switzerland

    Niloufar Marsousi, Youssef Daali, Virginie Ancrenaz-Sirot, Jules Alexandre Desmeules & Caroline Flora Samer

  2. School of Pharmaceutical Sciences, Geneva and Lausanne Universities, Geneva, Switzerland

    Niloufar Marsousi, Youssef Daali, Serge Rudaz & Jules Alexandre Desmeules

  3. Swiss Center for Applied Human Toxicology (SCAHT), Basel, Switzerland

    Youssef Daali, Serge Rudaz, Jules Alexandre Desmeules & Caroline Flora Samer

  4. Faculty of Medicine, Geneva University, Geneva, Switzerland

    Pierre Fontana, Jules Alexandre Desmeules & Caroline Flora Samer

  5. Division of Angiology and Haemostasis, Geneva University Hospitals, Geneva, Switzerland

    Pierre Fontana

  6. Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Pierre Fontana & Jean-Luc Reny

  7. Department of General Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland

    Jean-Luc Reny

  8. Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland

    Alexandra Calmy

Authors
  1. Niloufar Marsousi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Youssef Daali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Fontana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Luc Reny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Virginie Ancrenaz-Sirot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexandra Calmy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Serge Rudaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jules Alexandre Desmeules
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caroline Flora Samer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caroline Flora Samer.

Ethics declarations

Conflict of Interest

Niloufar Marsousi, Youssef Daali, Pierre Fontana, Jean-Luc Reny, Virginie Ancrenaz-Sirot, Alexandra Calmy, Serge Rudaz, Jules Alexandre Desmeules and Caroline Flora Samer declare no conflicts of interest relevant to the content of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 79 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marsousi, N., Daali, Y., Fontana, P. et al. Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites. Clin Pharmacokinet 57, 1347–1354 (2018). https://doi.org/10.1007/s40262-018-0637-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-018-0637-6

Search

Navigation