Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor

Clinical Pharmacokinetics

Volumn 51, Issue 5, 2012, Pages 305-318

  Teng, Renli ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Acute coronary syndromes; Antiplatelets; Pharmacogenetics; Pharmacokinetics; Pharmacology; Ticagrelor

Indexed keywords

ATORVASTATIN; CLOPIDOGREL; PURINERGIC P2Y12 RECEPTOR; SIMVASTATIN; TICAGRELOR; URIC ACID;

ACUTE CORONARY SYNDROME; ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG TOLERABILITY; HUMAN; NONHUMAN; PHARMACODYNAMICS; PHARMACOGENETICS; PRIORITY JOURNAL; REVIEW; THROMBOCYTE AGGREGATION INHIBITION;

ACUTE CORONARY SYNDROME; ADENOSINE; ADMINISTRATION, ORAL; ANIMALS; ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; DRUG INTERACTIONS; HUMANS; PHARMACOGENETICS; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS;

EID: 84859524326     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11630960-000000000-00000     Document Type: Review

References (65)

1. Kolansky DM. Acute coronary syndromes: morbidity, mortality, and pharmacoeconomic burden. Am J Manag Care 2009; 15 (2 Suppl.): S36-41
2. Turpie AG. Burden of disease: medical and economic impact of acute coronary syndromes. Am J Manag Care 2006; 12 (16 Suppl.): S430-4 (Pubitemid 46053401)
3. Kumar A, Cannon CP. Acute coronary syndromes: diagnosis and management, part I. Mayo Clin Proc 2009; 84 (10): 917-38
4. Gharacholou SM, Lopes RD, Washam JB, et al. Antithrombotic therapy in acute coronary syndromes: guidelines translated for the clinician. J Thromb Thrombolysis 2010; 29 (4): 516-28
5. Munnix IC, Cosemans JM, Auger JM, et al. Platelet response heterogeneity in thrombus formation. Thromb Haemost 2009; 102 (6): 1149-56
6. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the 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): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007; 116 (7): e148-304
7. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). JAmColl Cardiol 2004; 44 (3): E1-211
8. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28 (13): 1598-660
9. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29 (23): 2909-45
10. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345 (7): 494-502 (Pubitemid 32758501)
11. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl JMed 2007; 357 (20): 2001-15 (Pubitemid 350106708)
12. Springthorpe B, Bailey A, Barton P, et al. From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg Med Chem Lett 2007; 17 (21): 6013-8 (Pubitemid 47446193)
13. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11): 1045-57
14. Ticagrelor (Brilinta). Full prescribing information. 2011 [online]. Available from URL: http://www1.astrazeneca-us.com/pi/brilinta.pdf [Accessed 2012 Mar 14]
15. Ticagrelor (Brilique). Summary of product characteristics. 2010 [online]. Available from URL: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR- Product-Information/human/001241/WC500100494.pdf [Accessed 2012 Mar 14]
16. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 2010; 66 (5): 487-96
17. Teng R, Oliver S, Hayes MA, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38 (9): 1514-21
18. Storey RF, Husted S, Harrington RA, et al. 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 2007; 50 (19): 1852-6 (Pubitemid 350017792)
19. Husted SE, Gurbel P, Storey RF. Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease [abstract no. 5494]. Circulation 2009; 120 Suppl.: S1102
20. Husted S, Emanuelsson H, Heptinstall S, et al. 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 2006; 27 (9): 1038-47
21. Butler K, Mitchell PD, Teng R. No significant food effect on the pharmacokinetics of ticagrelor (AZD6140), the first reversibly binding oral P2Y12 receptor antagonist, in healthy subjects. American Society for Clinical Pharmacology and Therapeutics; 2009 Mar 18-21; Washington, DC
22. Teng R, Mitchell PD, Butler K. Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers. J Clin Pharm Ther. Epub 2011 Oct 4
23. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 2010; 70 (1): 65-77
24. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment. J Clin Pharmacol 2011; 51 (7): 978-87
25. Li Y, Landqvist C, Grimm SW. Disposition and metabolism of ticagrelor, a novel P2Y12 receptor antagonist, in mice, rats, and marmosets. Drug Metab Dispos 2011; 39 (9): 1555-67
26. Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics. Drug Metab Dispos 2011; 39 (4): 703-10
27. Husted S, James S, Becker RC, et al. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial [abstract]. J Am Coll Cardiol 2011; 57 (14 Suppl. 1): e1099
28. Butler K, Teng R. Pharmacokinetics, pharmacodynamics and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol. Epub 2011 Sep 29
29. Li H, Butler K, Yang L, et al. Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese volunteers: an open-label, sequential, two-cohort, single-centre study. Clin Drug Investig 2012; 32 (2): 87-97
30. European Medicines Agency. Assessment report for Brilique. 2011 [online]. Available from URL: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR- Public-assessment-report/human/001241/WC500100492.pdf [Accessed 2012 Mar 14]
31. Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65 (1): 64-73 (Pubitemid 10214332)
32. Thomson C, Forbes CD, Prentice CR. The potentiation of platelet aggregation and adhesion by heparin in vitro and in vivo. Clin Sci Mol Med 1973; 45 (4): 485-94
33. Eika C. The platelet aggregating effect of eight commercial heparins. Scand J Haematol 1972; 9 (5): 480-2
34. Aggarwal A, Sobel BE, Schneider DJ. Decreased platelet reactivity in blood anticoagulated with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary intervention. J Thromb Thrombolysis 2002; 13 (3): 161-5 (Pubitemid 35282634)
35. Schneider DJ, Tracy PB, Mann KG, et al. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; 96 (9): 2877-83 (Pubitemid 27500085)
36. Butler K, Teng R. Effect of ticagrelor on the pharmacokinetics of ethinyl oestradiol and levonorgestrel in healthy volunteers. Curr Med Res Opin 2011; 27 (8): 1585-93
37. van Giezen JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7 (9): 1556-65
38. Husted S, van Giezen JJ. Ticagrelor: The first reversibly binding oral P2Y receptor antagonist. Cardiovasc Ther 2009; 27 (4): 259-74
39. Patil SB, Norman KE, Robins SJ, et al. Inhibition of thrombosis by AZD6140 via selective blockade of the P2Y12 receptor in a murine laser-injury model [abstract]. J Thromb Haemost 2007; 5 Suppl. 1: P-W-632
40. van Giezen JJ, Berntsson P, Zachrisson H, et al. Comparison of ticagrelor and thienopyridine P2Y(12) binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis. Thromb Res 2009; 124 (5): 565-71
41. van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 31 (2): 195-204 (Pubitemid 40605194)
42. Guthikonda S, Alviar CL, Vaduganathan M, et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008; 52 (9): 743-9
43. Kuijpers MJE, Megens RTA, Nikookhesal E, et al. Role of newly formed platelets in thrombus formation after clopidogrel treatment: comparison to the reversibly binding P2Y12 antagonist ticagrelor. Thromb Haemost 2011; 106 (6): 1179-88
44. Hogberg C, Svensson H, Gustafsson R, et al. The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol 2010; 142 (2): 187-92
45. Wihlborg AK, Wang L, Braun OO, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004; 24 (10): 1810-5 (Pubitemid 39350296)
46. Wang K, Zhou X, Huang Y, et al. Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model. Thromb Haemost 2010; 104 (3): 609-17
47. van Giezen JJ, Sidaway J, Glaves P, et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. Epub 2011 Jun 22
48. Gan LM, Wittfeldt A, Emanuelsson H, et al. TCT-162: Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans: a randomised, double-blind, placebo-controlled, crossover, single centre study using transthoracic color Doppler echocardiography [abstract no. TCT-162]. J Am Coll Cardiol 2011; 58: B43
49. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120 (25): 2577-85
50. Storey RF, Bliden KP, Patil SB, et al. Earlier recovery of platelet function after treatment cessation in ticagrelor-treated patients compared to clopidogrel high responders [abstract no. P2313]. Eur Heart J 2010; 31 Suppl. 1: 389
51. Storey RF, Angiolillo DJ, Patil SB, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010; 56 (18): 1456-62
52. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: theRESPOND study. Circulation 2010; 121 (10): 1188-99
53. Cannon CP, Husted S, Harrington RA, et al. 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 2007; 50 (19): 1844-51 (Pubitemid 350007959)
54. Butler K, Teng R. Evaluation and characterization of the ticagrelor effects on serum and urinary uric acid in healthy volunteers. Clin Pharmacol Ther 2012; 91 (2): 264-71
55. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107 (23): 2908-13 (Pubitemid 36736631)
56. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109 (25): 3171-5
57. Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89 (5): 783-7 (Pubitemid 36603418)
58. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet 2010; 3 (6): 556-66
59. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376 (9749): 1320-8
60. Storey RF, Melissa TS, Lawrance R, et al. Ticagrelor yields consistent dosedependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3. Platelets 2009; 20 (5): 341-8
61. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res 2005; 116 (6): 491-7 (Pubitemid 41330814)
62. Fontana P, Remones V, Reny JL, et al. P2Y1 gene polymorphism and ADPinduced platelet response. J Thromb Haemost 2005; 3 (10): 2349-50 (Pubitemid 41727218)
63. Hetherington SL, Singh RK, Lodwick D, et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol 2005; 25 (1): 252-7 (Pubitemid 40054285)
64. Smith SM, Judge HM, Peters G, et al. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets 2006; 17 (4): 250-8 (Pubitemid 43890796)
65. von Beckerath N, von Beckerath O, Koch W, et al. P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose. Blood Coagul Fibrinolysis 2005; 16 (3): 199-204 (Pubitemid 40547275)