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Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects.

Methods

In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of 0.1–100 mg or placebo (n = 25) and 30–400 mg or placebo (n = 13).

Results

Absorption of ticagrelor was rapid [median time to peak plasma concentration (tmax) 1.3–2 h], as was the formation of its main (active) metabolite, AR-C124910XX (tmax 1.5–3 h). For both ticagrelor and AR-C124910XX, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (\( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \)) increased in an apparently dose-proportional manner over the dose range studied, indicating linear pharmacokinetics. The mean terminal-phase half-life (t½) was approximately 7–8.5 h for ticagrelor and 8.5–10 h for AR-C124910XX; AR-C124910XX exposure was approximately one third that of ticagrelor. Inhibition of platelet aggregation (IPA) was dose related and was nearly complete at 2 h (mean 88–95%; final extent, with 20 µM adenosine diphosphate ADP) at doses of 100–400 mg.

Conclusion

Linear and predictable pharmacokinetics of ticagrelor and AR-C124910XX were observed. A consistent and high IPA was maintained over 2–12 h, gradually decreasing with declining plasma concentration starting around 12 h post-dose, indicating that the IPA is reversible. Ticagrelor was well tolerated, with no serious or dose-related adverse events or notable changes in laboratory values observed.

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References

  1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502

    Article  CAS  PubMed  Google Scholar 

  2. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ, CREDO Investigators (2002) Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–2420 [published correction appears in JAMA 289:987 (2003)]

    Google Scholar 

  3. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH (2005) Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179–1189

    Article  CAS  PubMed  Google Scholar 

  4. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E, Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators (2005) Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 294:1224–1232

    Article  CAS  PubMed  Google Scholar 

  5. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B, American College of Cardiology, American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction), American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association of Cardiovascular and Pulmonary Rehabilitation, Society for Academic Emergency Medicine (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. Circulation 116:803–877

    Article  Google Scholar 

  6. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W, for the Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology (2007) Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 28:1598–1660

    Article  CAS  PubMed  Google Scholar 

  7. Gurbel PA, Bliden KP (2003) Durability of platelet inhibition by clopidogrel. Am J Cardiol 91:1123–1125

    Article  CAS  PubMed  Google Scholar 

  8. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H (2004) Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 109:3171–3175

    Article  CAS  PubMed  Google Scholar 

  9. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ (2005) Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 45:246–251

    Article  CAS  PubMed  Google Scholar 

  10. Geisler T, Langer H, Wydymus M, Göhring K, Zürn C, Bigalke B, Stellos K, May AE, Gawaz M (2006) Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 27:2420–2425

    Article  CAS  PubMed  Google Scholar 

  11. Gurbel PA, Tantry US (2006) Drug insight: clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 3:387–395

    Article  CAS  PubMed  Google Scholar 

  12. Heptinstall S (2006) Variable therapeutic effectiveness of clopidogrel in acute coronary syndromes. J Thromb Haemost 4:539–541

    Article  CAS  PubMed  Google Scholar 

  13. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA (2007) Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49:1505–1516

    Article  CAS  PubMed  Google Scholar 

  14. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA (2007) Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention. Is the current antiplatelet therapy adequate? J Am Coll Cardiol 49:657–666

    Article  CAS  PubMed  Google Scholar 

  15. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D (2007) Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 49:2312–2317

    Article  CAS  PubMed  Google Scholar 

  16. Thebault JJ, Keiffer G, Lowe GD, Nimmo WS, Cariou R (1999) Repeated-dose pharmacodynamics of clopidogrel in healthy subjects. Semin Thromb Hemost 25[suppl 2]:9–14

    CAS  PubMed  Google Scholar 

  17. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakubowski JA, Naganuma H, Winters KJ (2007) A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153:66.e9–16

    Article  Google Scholar 

  18. Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L (2006) Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 27:1166–1173

    Article  CAS  PubMed  Google Scholar 

  19. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015

    Article  CAS  PubMed  Google Scholar 

  20. van Giezen JJJ, Humphries RG (2005) Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 31:195–204

    Article  PubMed  Google Scholar 

  21. Springthorpe B, Bailey A, Barton P, Birkinshaw TN, Bonnert RV, Brown RC, Chapman D, Dixon J, Guile SD, Humphries RG, Hunt SF, Ince F, Ingall AH, Kirk IP, Leeson PD, Leff P, Lewis RJ, Martin BP, McGinnity DF, Mortimore MP, Paine SW, Pairaudeau G, Patel A, Rigby AJ, Riley RJ, Teobald BJ, Tomlinson W, Webborn PJ, Willis PA (2007) From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 17:6013–6018

    Article  CAS  PubMed  Google Scholar 

  22. Data on file. AstraZeneca Pharmaceuticals LP, Wilmington, DE

  23. Butler K, Oliver S, Teng R (2008) A mass balance study of major excretory routes and metabolic profile following an oral [14C] dose of AZD6140, the first reversible oral platelet P2Y12 receptor antagonist, in healthy male subjects. Curr Drug Metab Suppl 3:204–205

  24. van Giezen JJJ, Berntsson P, Wissing B-M (2008) Direct oral P2Y12 receptor antagonist AZD6140 potently and reversibly binds to the rh-P2Y12 receptor expressed on CHO-K1 cells (abstract P207). Arterioscler Thromb Vasc Biol 28:e72

    Google Scholar 

  25. Peters G, Robbie G (2004) Single dose pharmacokinetics and pharmacodynamics of AZD6140. Haematologica 89[suppl 7]:14–15

    Google Scholar 

  26. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G (2006) Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 27:1038–1047

    Article  CAS  PubMed  Google Scholar 

  27. Nilsson L, van Giezen JJJ, Greasley PJ (2006) Evidence for distinct ligand binding sites on recombinant P2Y12 receptors (abstract 1313). Circulation 114[Suppl II]:II-248

    Google Scholar 

  28. van Giezen JJJ, Nilsson L (2008) AZD6140 binds to the rh-P2Y12 receptor expressed on CHO-K1 cells at a site distinct from the ADP binding site but antagonizes ADP-induced signaling (abstract P393). Arterioscler Thromb Vasc Biol 28:e104

    Google Scholar 

  29. van Giezen JJJ, Berntsson P (2008) AZD6140 displays over 100-fold higher affinity for the P2Y12 receptor vs AZ11702105, a compound indistinguishable from the active metabolite of prasugrel, and is a more potent inhibitor of ADP-induced platelet aggregation (abstract P584). Arterioscler Thromb Vasc Biol 28:e139–140

    Google Scholar 

  30. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, for the PLATO investigators (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057

    Article  CAS  PubMed  Google Scholar 

  31. Cardinal DC, Flower RJ (1980) The electronic aggregometer: a novel device for assessing platelet behavior in blood. J Pharmacol Methods 3:135–158

    Article  CAS  PubMed  Google Scholar 

  32. Ingerman-Wojenski CM, Silver MJ (1984) A quick method for screening platelet dysfunctions using the whole blood lumi-aggregometer. Thromb Haemost 51:154–156

    CAS  PubMed  Google Scholar 

  33. Zeidan AM, Kouides PA, Tara MA, Fricke WA (2007) Platelet function testing: state of the art. Expert Rev Cardiovasc Ther 5:955–967

    Article  PubMed  Google Scholar 

  34. Teng R, Butler K (2008) AZD6140, the first reversible oral platelet P2Y12 receptor antagonist, has linear pharmacokinetics and provides near complete inhibition of platelet aggregation, with reversibility of effect, in healthy subjects (abstract 9). Can J Clin Pharmacol 5:e26

    Google Scholar 

  35. Husted S, van Giezen JJ (2009) Ticarelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 27(4):259–274

    Google Scholar 

  36. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF, DISPERSE-2 Investigators (2007) Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 50:1844–1851 [published correction appears in J Am Coll Cardiol 50:2196 (2007)]

    Google Scholar 

  37. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP (2007) Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 50:1852–1856

    Article  CAS  PubMed  Google Scholar 

  38. Gachet C (2008) P2 receptors, platelet function and pharmacological implications. Thromb Haemost 99:466–472

    CAS  PubMed  Google Scholar 

  39. Labarthe J, Théroux P, Angioï M, Ghitescu M (2005) Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 46:638–645

    Article  CAS  PubMed  Google Scholar 

  40. van Giezen JJJ, Zachrisson H, Björkman JA (2008) Reduced bleeding time prolongation for the reversible P2Y12 antagonist AZD6140 compared with clopidogrel and AZ11703072, a chemical compound indistinguishable from prasugrel, in both a rat and a dog model of combined thrombosis and hemostatis (abstract P585). Arterioscler Thromb Vasc Biol 28:e140

    Google Scholar 

  41. James SK, Åkerblom A, Cannon CP (2009) Comparison of ticagrelor, the first reversible P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 157:599–605

    Article  CAS  PubMed  Google Scholar 

  42. Tantry US, Bliden KP, Gurbel PA (2005) Resistance to antiplatelet drugs: current status and future research. Expert Opin Pharmacother 6:2027–2045

    Article  CAS  PubMed  Google Scholar 

  43. Tantry US, Bliden KP, Gurbel PA (2007) AZD6140. Expert Opin Invest Drugs 16:225–229

    Article  CAS  Google Scholar 

  44. van Giezen JJJ (2008) Optimizing platelet inhibition. Eur Heart J Suppl 10[Suppl D]:D23–D29

    Article  Google Scholar 

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Acknowledgements

The authors wish to thank Dr. Tony Verco and his team for conducting the studies and Dr. Gary Peters for his medical contributions. We also thank Joe Hirsch from BioScience Communications, and Jackie Phillipson from Gardiner Communications, who provided medical writing support funded by AstraZeneca.

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  1. Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA

    Renli Teng & Kathleen Butler

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  1. Renli Teng
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Correspondence to Renli Teng.

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Teng, R., Butler, K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 66, 487–496 (2010). https://doi.org/10.1007/s00228-009-0778-5

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