Progress in pharmacokinetics, pharmacodynamics and pharmacogenetics of the antiplatelet drug ticagrelor

Abstract

Abstract: Ticagrelor is a recently approved oral antiplatelet agent that belongs to a new chemical class, the cyclopentyltriazolopyrimidines (CPTP). Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.5 hours. The new drug possesses advantages compared with other P2Y12 receptor antagonists such as clopidogrel and prasugrel in that it acts more quickly with no necessity of metabolic activation, bonds to P2Y12 receptor reversibly and therefore the platelet function can recover rapidly after drug withdrawal. Furthermore, ticagrelor may confer additional pharmacological effect via inhibition of non-platelet P2Y12 receptors. The pharmacokinetic characteristics of ticagrelor are not influenced by age, gender, diet, or clopidogrel responsiveness. Ticagrelor is primarily metabolized by cytochrome P450 (CYP) 3A4, rapidly produces plasma concentration-dependent IPA and can overcome non-responsiveness in patients previously treated with clopidogrel. What's more, CYP2C19 and ABCB1 genotypes show no effects on the pharmacodynamic profile of ticagrelor. This review summarized recent progress in pharmacokinetics, pharmacodynamics and pharmacogenetics of ticagrelor.

Key words: ticagrelor, pharmacokinetics, pharmacodynamics, pharmacogenetics

CLC Number:

R969.1

LI Mu-peng, XIONG Yan, CHEN Xiao-ping. Progress in pharmacokinetics, pharmacodynamics and pharmacogenetics of the antiplatelet drug ticagrelor[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(2): 214-222.

References

[1] Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC)[J].Eur Heart J,2011,32(23): 2999-3054.
[2] Arora RR, Rai F. Antiplatelet intervention in acute coronary syndrome[J].Am J Ther,2009,16(5): e29-e40.
[3] Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes[J].N Engl J Med,2007,357(20): 2001-2015.
[4] Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist[J].Cardiovasc Ther,2009,27(4): 259-274.
[5] Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes[J].N Engl J Med,2009,361(11): 1045-1057.
[6] Brilinta (ticagrelor) Tablets: A P2Y(12) platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS)[J].P T, 2012,37(4 section 2): 4-18.
[7] 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[J].Eur J Clin Pharmacol,2010,66(5): 487-496.
[8] Teng R, Oliver S, Hayes MA, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects[J] Drug Metab Dispos,2010,38(9): 1514-1521.
[9] 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].J Am Coll Cardiol,2007,50(19): 1852-1856.
[10] 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[J].Eur Heart J,2006,27(9): 1038-1047.
[11] Teng R, Mitchell PD, Butler K. Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers[J].J Clin Pharm Ther,2012,37(4): 464-468.
[12] Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers[J].Br J Clin Pharmacol,2010,70(1): 65-77.
[13] Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment[J].J Clin Pharmacol,2011,51(7): 978-987.
[14] Li Y, Landqvist C, Grimm SW. Disposition and metabolism of ticagrelor, a novel P2Y12 receptor antagonist, in mice, rats, and marmosets[J].Drug Metab Dispos,2011,39(9): 1555-1567.
[15] 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[J].Drug Metab Dispos,2011,39(4): 703-710.
[16] Teng R, Mitchell P, Butler K. Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals[J].Eur J Clin Pharmacol,2012,68(8): 1175-1182.
[17] Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment[J].J Clin Pharmacol,2012,52(9): 1388-1398.
[18] Brilinta (ticagrelor): Summary of product characteristics[EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001241/WC500100494.pdf, 2013-03.
[19] Li H, Butler K, Yang L, et al. Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single-centre study[J].Clin Drug Investig,2012,32(2): 87-97.
[20] European Medicines Agency: Assessment report for Brilique.[EB/OL]. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001241/WC500100492.pdf,2013-03.
[21] Husted SE, Storey RF, Bliden K, et al. Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies[J].Clin Pharmacokinet,2012,51(6): 397-409.
[22] Teng R, Mitchell P, Butler K. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects[J].Eur J Clin Pharmacol,2013,69(4): 877-883.
[23] Holmberg MT, Tornio A, Joutsi-Korhonen L, et al. Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects[J].Br J Clin Pharmacol,2013,75(6): 1488-1496.
[24] Teng R, Mitchell PD, Butler KA. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers[J].Eur J Clin Pharmacol,2013,69(3): 477-487.
[25] Butler K, Teng R. Effect of ticagrelor on the pharmacokinetics of ethinyl oestradiol and levonorgestrel in healthy volunteers[J].Curr Med Res Opin,2011,27(8): 1585-1593.
[26] Teng R, Mitchell P, Butler K. Evaluation of the pharmacokinetic interaction between ticagrelor and tolbutamide, a cytochrome P450 2C9 substrate, in healthy volunteers[J].Int J Clin Pharmacol Ther,2013,51(4): 305-312.
[27] 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].J Thromb Haemost,2009,7(9): 1556-1565.
[28] 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[J].Thromb Res,2009,124(5): 565-571.
[29] van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists[J].Semin Thromb Hemost,2005,31(2): 195-204.
[30] Kuijpers MJ, Megens RT, Nikookhesal E, et al. Role of newly formed platelets in thrombus formation in rat after clopidogrel treatment: comparison to the reversible binding P2Y(1)(2) antagonist ticagrelor[J].Thromb Haemost,2011,106(6): 1179-1188.
[31] Hogberg C, Svensson H, Gustafsson R, et al. The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature[J].Int J Cardiol,2010,142(2): 187-192.
[32] 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[J].Arterioscler Thromb Vasc Biol,2004,24(10): 1810-1815.
[33] Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells[J].Biochem Biophys Res Commun,2012,418(4): 754-758.
[34] 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].J Cardiovasc Pharmacol Ther,2012,17(2): 164-172.
[35] Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans[J].J Am Coll Cardiol,2013,61(7): 723-727.
[36] 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[J].Circulation,2009,120(25): 2577-2585.
[37] Storey RF, Bliden KP, Ecob R, et al. Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared with clopidogrel in patients with high antiplatelet responses[J].J Thromb Haemost,2011,9(9): 1730-1737.
[38] Storey RF, Angiolillo DJ, Patil S B, 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].J Am Coll Cardiol, 2010,56(18): 1456-1462.
[39] Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study[J].Circulation, 2010,121(10): 1188-1199.
[40] 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].J Am Coll Cardiol,2007,50(19): 1844-1851.
[41] Butler K, Teng R. Evaluation and characterization of the effects of ticagrelor on serum and urinary uric acid in healthy volunteers[J].Clin Pharmacol Ther,2012,91(2): 264-271.
[42] Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story[J].Circulation,2004,109(25): 3064-3067.
[43] 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[J].Circulation,2004,109(25): 3171-3175.
[44] 贺春晖,胡琴,邹建军,等. 氯吡格雷抵抗的基因多态性探讨[J]. 中国临床药理学与治疗学,2010,15(11): 1288-1293.
[45] 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[J].Circ Cardiovasc Genet,2010,3(6): 556-566.
[46] 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[J].Lancet,2010,376(9749): 1320-1328.
[47] 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[J].Platelets,2009,20(5): 341-348.
[48] Bonello L, Bonello-Palot N, Armero S, et al. Impact of P2Y12-ADP receptor polymorphism on the efficacy of clopidogrel dose-adjustment according to platelet reactivity monitoring in coronary artery disease patients[J].Thromb Res,2010,125(4): e167-e170.
[49] Sibbing D, von Beckerath O, Schomig A, et al. P2Y1 gene A1622G dimorphism is not associated with adenosine diphosphate-induced platelet activation and aggregation after administration of a single high dose of clopidogrel[J].J Thromb Haemost,2006,4(4): 912-914.
[50] Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events[J].N Engl J Med, 2009,360(4): 363-375.