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Intravenous Clopidogrel (MDCO-157) Compared with Oral Clopidogrel: The Randomized Cross-Over AMPHORE Study

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American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background

The extent of P2Y12 inhibition during coronary intervention is an important determinant of ischemic complications. The currently available oral P2Y12 inhibitors are limited by a relatively slow onset of action and variable on-treatment response.

Objective

Our objective was to determine the pharmacodynamic (PD) dose–antiplatelet response relationship and the pharmacokinetics of MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, and to identify the dose level of MDCO-157 that matches the PD effect of oral clopidogrel 300 mg.

Methodology

A randomized open-label crossover study was performed in 33 healthy adult volunteers to determine the pharmacokinetic (clopidogrel and clopidogrel H4 thiol active metabolite) and the PD (vasodilator-stimulated phosphoprotein [VASP]) effects of MDCO-157 at doses of 75, 150, and 300 mg and of oral clopidogrel 300 mg.

Results

Data are presented as %, mean (standard deviation). The maximum effect of P2Y12 receptor inhibition assessed by flow cytometry using VASP was 70.42 (6.7), 69.45 (7.1), and 65.58 (12.6) for intravenous MDCO-157 at doses of 75, 150, and 300 mg, respectively, compared with 56.6 (17.5) with oral clopidogrel 300 mg administration (p < 0.0001). Intravenous administration of MDCO-157 led to a stepwise increase in plasma exposure of clopidogrel, higher than with administration of an oral dose of 300 mg (p < 0.0001). Plasma exposure of H4-thiol also increased with intravenous dose (3.6 ± 2.6, 6.9 ± 4.6, and 12.4 ± 9.1 h·ng/ml for intravenous 75, 150, and 300 mg, respectively) but was lower than with oral administration of a 300-mg dose (34.0 ± 16.0 h.ng/ml; pairwise p < 0.0001).

Conclusions

MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, did not show significant platelet inhibition when administered at doses up to 300 mg. Higher doses with longer infusion may be needed to reach a sufficient threshold of active metabolite generation.

Trial Registration: ClinicalTrials.gov identifier: NCT01860105.

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References

  1. Savi P, Labouret C, Delesque N, Guette F, Lupker J, Herbert JM. P2Y(12), a new platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Commun. 2001;283:379–83.

    Article  PubMed  CAS  Google Scholar 

  2. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000;84:891–6.

    PubMed  CAS  Google Scholar 

  3. Collet J-P, Hulot J-S, Anzaha G, et al. High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). JACC Cardiovasc Interv. 2011;4:392–402.

    Article  PubMed  Google Scholar 

  4. Bellemain-Appaix A, O’Connor SA, Silvain J, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA. 2012;308:2507–16.

    Article  PubMed  CAS  Google Scholar 

  5. Bellemain-Appaix A, Brieger D, Beygui F, et al. New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis. J Am Coll Cardiol. 2010;56(19):1542–51.

    Article  PubMed  CAS  Google Scholar 

  6. Montalescot G, Wiviott SD, Braunwald E, 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 

  7. Steg PG, James S, Harrington RA, et al. Ticagrelor versus clopidogrel in patients with st-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a platelet inhibition and patient outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122(21):2131–41.

    Article  PubMed  Google Scholar 

  8. Montalescot G, van’t Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371:1016–27.

    Article  PubMed  CAS  Google Scholar 

  9. Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012;5:797–804.

    Article  PubMed  CAS  Google Scholar 

  10. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol. 2015;12:30–47.

    Article  PubMed  CAS  Google Scholar 

  11. Steg PG, Bhatt DL, Hamm CW, et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet. 2013;382:1981–92.

    Article  PubMed  CAS  Google Scholar 

  12. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003773/WC500180855.pdf. 2015.

  13. Anon. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm.

  14. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303–13.

    Article  PubMed  CAS  Google Scholar 

  15. Rollini F, Franchi F, Tello-Montoliu A, et al. Pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in prasugrel-treated patients. JACC Cardiovasc Interv. 2014;7:426–34.

    Article  PubMed  Google Scholar 

  16. Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis. 2012;34:44–55.

    Article  PubMed  CAS  Google Scholar 

  17. Schneider DJ, Agarwal Z, Seecheran N, Keating FK, Gogo P. Pharmacodynamic effects during the transition between cangrelor and ticagrelor. JACC Cardiovasc Interv. 2014;7:435–42.

    Article  PubMed  Google Scholar 

  18. Schneider DJ, Seecheran N, Raza SS, Keating FK, Gogo P. Pharmacodynamic effects during the transition between cangrelor and prasugrel. Coron Artery Dis. 2015;26:42–8.

    Article  PubMed  Google Scholar 

  19. Cushing DJ, Souney PF, Cooper WD, et al. Pharmacokinetics and platelet aggregation inhibitory effects of a novel intravenous formulation of clopidogrel in humans: effects of intravenous clopidogrel. Clin Exp Pharmacol Physiol. 2012;39:3–8.

    Article  PubMed  CAS  Google Scholar 

  20. Williams EJ. Experimental designs balanced for the estimation of residual effects of treatments. Aust J Sci Res 1949;2(3):149–168

    Google Scholar 

  21. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol. 2006;48:931–8.

    Article  PubMed  CAS  Google Scholar 

  22. Collet JP, Silvain J, Landivier A, et al. Dose-effect of clopidogrel re-loading in patients already on 75 mg maintenance dose: the RELOAD study. Circulation. 2008;118:1225–33.

    Article  PubMed  CAS  Google Scholar 

  23. Simon N, Finzi J, Cayla G, Montalescot G, Collet JP, Hulot JS. Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients. Eur J Clin Pharmacol 2015;71(9):1059–66

    Article  PubMed  CAS  Google Scholar 

  24. Pena A, Collet JP, Hulot JS, et al. Can we override clopidogrel resistance? Circulation. 2009;119(21):2854–8.

    Article  PubMed  Google Scholar 

  25. Hulot JS, Collet JP, Cayla G, et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011;4:422–8.

    Article  PubMed  CAS  Google Scholar 

  26. Frelinger AL 3rd, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61:872–9.

    Article  PubMed  CAS  Google Scholar 

  27. Windecker S, Alfonso F, Collet J-P, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the ESC/EACTS Developed with the special contribution of the EAPCI. Eur Heart J. 2014;35:2541–619.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France

    Jean-Philippe Collet, Jean-Sébastien Hulot, Johanne Silvain, Vanessa Gallois, Delphine Brugier, Ghalia Anzaha, Sophie Galier & Gilles Montalescot

  2. ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l’Hôpital, 75013, Paris, France

    Jean-Philippe Collet, Jean-Sébastien Hulot, Johanne Silvain, Vanessa Gallois, Delphine Brugier, Ghalia Anzaha, Sophie Galier & Gilles Montalescot

  3. Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France

    Christian Funck-Brentano, Joe-Elie Salem, Jean-Sébastien Hulot, Edith Guilloux & Nathalie Nicolas

  4. INSERM, CIC-1421 and UMR ICAN 1166, Paris, France

    Christian Funck-Brentano, Joe-Elie Salem, Jean-Sébastien Hulot, Edith Guilloux & Nathalie Nicolas

  5. Faculty of Medicine, Department of Pharmacology and UMR ICAN 1166, Sorbonne Universités, UPMC Univ Paris 06, Paris, France

    Christian Funck-Brentano, Joe-Elie Salem, Jean-Sébastien Hulot & Nathalie Nicolas

  6. The Medicine Company, Parsippany, NJ, USA

    Jayne Prats & Ming-yi Hu

  7. Biotranex LLC, Monmouth Junction, NJ, USA

    Kan He

Authors
  1. Jean-Philippe Collet
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  2. Christian Funck-Brentano
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  3. Jayne Prats
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  4. Joe-Elie Salem
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  5. Jean-Sébastien Hulot
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  6. Edith Guilloux
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  7. Ming-yi Hu
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  8. Kan He
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  9. Johanne Silvain
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  10. Vanessa Gallois
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  11. Delphine Brugier
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  12. Ghalia Anzaha
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  13. Sophie Galier
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  14. Nathalie Nicolas
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  15. Gilles Montalescot
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Corresponding author

Correspondence to Gilles Montalescot.

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Conflict of interest

Dr. Montalescot reports receiving consulting fees from Acuitude, Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers-Squibb, Brigham Women’s Hospital, Cardiovascular Research Foundation, CME resources, Conway, Daiichi-Sankyo, Eli-Lilly, Europa, Evidera, GLG, Hopitaux Universitaires Genève, Lead-Up, McKinsey & Company, Medcon International, Menarini, Medtronic, MSD, Pfizer, Sanofi-Aventis, Stentys, The Medicines Company, TIMI Study Group, Universität Basel, WebMD, Williams & Connolly, and Zoll Medical; and grant support from ADIR, Amgen, AstraZeneca, Bristol-Myers-Squibb, Celladon, Daiichi-Sankyo, Eli-Lilly, Fédération Française de Cardiologie, Gilead, ICAN, Janssen-Cilag, Pfizer, Recor, Sanofi-Aventis, Stentys. Dr. Silvain reports receiving research grants to the institution from Boehringer-Ingelheim, Daiichi-Sankyo, Eli Lilly, BRAHMS, and Sanofi-Aventis, Fédération Française de Cardiologie and Société Française de Cardiologie, INSERM; consultant fees from Daiichi-Sankyo, Eli Lilly, AstraZeneca, and The Medicines Company; and lecture fees from AstraZeneca, Cordis, Daiichi-Sankyo, Eli Lilly, Iroko Cardio, and STENTYS. Jayne Prats is an employee of The Medicines Company; Ming-yi Hu and Kan He were employees of The Medicines Company. Dr. Collet has received research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie, and Société Française de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly. Dr. Hulot discloses the following relationships: Data Monitoring Committees: Assistance Publique Hôpitaux de Paris; Honoraria: American College of Cardiology Foundation (Lecturer), Eli Lilly (Steering Committee), Servier (Lecturer); Consulting fees: Daiichi Sankyo (consultant), Imaxio (consultant); Research Grants: Bayer Pharma, Celladon, Cellectis Stem Cells, French Ministry of Health (AOM09191), Institute for Cardiometabolism and Nutrition Foundation, NIH/NHLBI (R01 HL113497), NIH/NGRI (1U01HG006380). The other authors declare no conflicts of interest.

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N. Nicolas: Deceased.

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Collet, JP., Funck-Brentano, C., Prats, J. et al. Intravenous Clopidogrel (MDCO-157) Compared with Oral Clopidogrel: The Randomized Cross-Over AMPHORE Study. Am J Cardiovasc Drugs 16, 43–53 (2016). https://doi.org/10.1007/s40256-015-0145-0

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