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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 5/2012

01-05-2012 | Review Article

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile of the Oral Antiplatelet Agent Ticagrelor

Author: Dr Renli Teng

Published in: Clinical Pharmacokinetics | Issue 5/2012

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Abstract

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y12 receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y12 receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y12 receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3–2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y12 receptor. As well as exerting effects via platelet P2Y12 receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y12 receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes.
This article summarizes our current knowledge regarding the pharmacokinetic, pharmacodynamic and pharmacogenetic profile of ticagrelor.
Literature
1.
Kolansky DM. Acute coronary syndromes: morbidity, mortality, and pharmacoeconomic burden. Am J Manag Care 2009; 15(2 Suppl.): S36–41PubMed
2.
Turpie AG. Burden of disease: medical and economic impact of acute coronary syndromes. Am J Manag Care 2006; 12(16 Suppl.): S430–4PubMed
3.
Kumar A, Cannon CP. Acute coronary syndromes: diagnosis and management, part I. Mayo Clin Proc 2009; 84(10): 917–38PubMedCrossRef
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): 516–28PubMedCrossRef
5.
Munnix IC, Cosemans JM, Auger JM, et al. Platelet response heterogeneity in thrombus formation. Thromb Haemost 2009; 102(6): 1149–56PubMed
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): e148–304PubMedCrossRef
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). J Am Coll Cardiol 2004; 44(3): E1–211PubMedCrossRef
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): 1598–660PubMedCrossRef
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): 2909–45PubMedCrossRef
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): 494–502PubMedCrossRef
11.
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357(20): 2001–15PubMedCrossRef
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): 6013–8PubMedCrossRef
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): 1045–57PubMedCrossRef
14.
15.
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): 487–96PubMedCrossRef
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): 1514–21PubMedCrossRef
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): 1852–6PubMedCrossRef
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): 1038–47PubMedCrossRef
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): 65–77PubMedCrossRef
24.
Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment. J Clin Pharmacol 2011; 51(7): 978–87PubMedCrossRef
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): 1555–67PubMedCrossRef
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): 703–10PubMedCrossRef
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): e1099CrossRef
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): 87–97PubMedCrossRef
30.
31.
Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65(1): 64–73PubMedCrossRef
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): 485–94PubMed
33.
Eika C. The platelet aggregating effect of eight commercial heparins. Scand J Haematol 1972; 9(5): 480–2PubMed
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): 161–5PubMedCrossRef
35.
Schneider DJ, Tracy PB, Mann KG, et al. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; 96(9): 2877–83PubMedCrossRef
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): 1585–93PubMedCrossRef
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): 1556–65CrossRef
38.
Husted S, van Giezen JJ. Ticagrelor: The first reversibly binding oral P2Y receptor antagonist. Cardiovasc Ther 2009; 27(4): 259–74PubMedCrossRef
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): 565–71PubMedCrossRef
41.
van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost 2005; 31(2): 195–204PubMedCrossRef
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): 743–9PubMedCrossRef
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): 1179–88PubMedCrossRef
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): 187–92PubMedCrossRef
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): 1810–5PubMedCrossRef
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): 609–17PubMedCrossRef
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): 2577–85PubMedCrossRef
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): 1456–62PubMedCrossRef
52.
Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121(10): 1188–99PubMedCrossRef
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): 1844–51PubMedCrossRef
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): 264–71PubMedCrossRef
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): 2908–13PubMedCrossRef
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): 3171–5PubMedCrossRef
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): 783–7PubMed
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): 556–66PubMedCrossRef
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): 1320–8PubMedCrossRef
60.
Storey RF, Melissa TS, Lawrance R, et al. Ticagrelor yields consistent dose-dependent inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of genotypic variations in P2RY12, P2RY1, and ITGB3. Platelets 2009; 20(5): 341–8PubMedCrossRef
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): 491–7PubMedCrossRef
62.
Fontana P, Remones V, Reny JL, et al. P2Y1 gene polymorphism and ADP-induced platelet response. J Thromb Haemost 2005; 3(10): 2349–50PubMedCrossRef
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): 252–7PubMed
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): 250–8PubMedCrossRef
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): 199–204CrossRef
Metadata
Title
Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile of the Oral Antiplatelet Agent Ticagrelor
Author
Dr Renli Teng
Publication date
01-05-2012
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 5/2012
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/11630960-000000000-00000