Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers

International Journal of Clinical Pharmacology and Therapeutics

Volumn 51, Issue 10, 2013, Pages 795-806

  Teng, Renli ^a   Butler, Kathleen ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Antiplatelet therapy; Bleeding time; Maximum tolerated dose; Phar macokinetics; Ticagrelor

Indexed keywords

DERMATOLOGICAL AGENT; DRUG METABOLITE; PARACETAMOL; PLACEBO; TICAGRELOR;

ABDOMINAL CRAMP; ADULT; AREA UNDER THE CURVE; ARTICLE; ATRIOVENTRICULAR BLOCK; BLEEDING; BLEEDING TIME; CONTACT DERMATITIS; CONTROLLED STUDY; DIAPHORESIS; DISEASE SEVERITY; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSE INCREASE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPNEA; FAINTNESS; FEMALE; FLATULENCE; GASTROINTESTINAL SYMPTOM; GASTROINTESTINAL TOXICITY; HEART ARRHYTHMIA; HEART RATE; HUMAN; HUMAN EXPERIMENT; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; NORMAL HUMAN; PHARMACODYNAMICS; PHARMACOKINETICS; RANDOMIZED CONTROLLED TRIAL; RESPIRATORY TRACT PARAMETERS; RESTLESSNESS; SIDE EFFECT; SINGLE DRUG DOSE; SINUS ARREST; STOMACH DISEASE; TIME TO MAXIMUM PLASMA CONCENTRATION; VOLUNTEER; VOMITING; YAWNING;

ABSORPTION; ADENOSINE; ADULT; AREA UNDER CURVE; BLEEDING TIME; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; FEMALE; HEALTHY VOLUNTEERS; HUMANS; MALE; YOUNG ADULT;

EID: 84885062087     PISSN: 09461965     EISSN: None     Source Type: Journal    
DOI: 10.5414/CP201903     Document Type: Article

References (24)

1. Wallentin L, Becker RC, Budaj A, Cannon C P, Emanuelsson H, Held C., Horrow J, Husted S, James S., Katus H, Mahaffey K W, Scirica BM, Skene A, Steg P.G., Storey R F, Harrington RA, Freij A, Thorsén M; PLATO Investigators. Ti-cagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361: 1045-1057.
2. Teng R, Butler K. Pharmacokinetics, pharmaco-dynamics, 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: 487-496.
3. Butler K, Teng R. Pharmacokinetics, pharmacody-namics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010; 70: 65-77.
4. Teng R, Oliver S, Hayes M.A., Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010; 38: 1514-1521.
5. 12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006; 27: 1038-1047.
6. AstraZeneca FDA Advisory Committee Briefing Document. 23 June 2010. Ticagrelor Briefing Document for Cardiovascular and Renal Drugs Advisory Committee Meeting NDA 22-433. http://www.fda.gov/downloads/AdvisoryCommit- teesMeetingMaterials/Drugs/Cardiovascularan-dRenalDrugsAdvisoryCommittee/ UCM220197.pdf. Accessed September 30, 2012.
7. 12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007; 50: 1852-1856. (Pubitemid 350017792)
8. Cannon C.P., Husted S, Harrington R.A., Scirica BM, Emanuelsson H, Peters G, Storey RF; DISPERSE-2 Investigators. Safety, tolerability, and initial effi-cacy of AZD6140, the first reversible oral adenos-ine 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: 1844-1851. (Pubitemid 350007959)
9. Storey R.F., Bliden K P, Patil SB, Karunakaran A, Ecob R., Butler K, Teng R, We i C, Tantry US, Gurbel PA; ONSET/OFFSET Investigators. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010; 56: 185-193.
10. ICH 2005 International Conference on Harmonization. Guidance for Industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proar-rhythmic Potential for Non-Antiarrhythmic Drugs. http://www.fda.gov/downloads/ RegulatoryInfor-mation/Guidances/ucm129357.pdf. Accessed January 16, 2013.
11. Sillén H., Cook M, Davis P. Determination of ti-cagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2299-2306.
12. Surgicutt® package insert. ITC April 2008.
13. Brilique (ticagrelor) Summary of Product Characteristics. Astra Zeneca. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/ human/001241/WC500100494.pdf. Accessed January 16, 2013.
14. van Giezen J.J., Sidaway J, Glaves P., Kirk I, Björkman JA. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyper-emia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012; 17: 164-172.
15. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, Gan LM Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013; 61: 723-727.
16. Wittfeldt A, Emanuelsson H, Nylander S., Jonasson J, Gan LM Adenosine may mediate ticagrelor-induced dyspnea. J Am Coll Cardiol. 2012; 59 (Suppl S): E344.
17. Shen WK, Kurachi Y. Mechanisms of adenosine-mediated actions on cellular and clinical cardiac electrophysiology. Mayo Clin Proc. 1995; 70: 274-291.
18. Storey R.F., Becker RC, Harrington R.A., Husted S., James SK, Cools F, Steg PG, Khurmi N.S., Emanuelsson H, Cooper A, Cairns R., Cannon C P, Wallentin L. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopido-grel and its association with clinical outcomes. Eur Heart J. 2011; 32: 2945-2953.
19. Serebruany VL, Stebbing J, Atar D. Dyspnoea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract. 2007; 61: 529-533.
20. Burki NK, Dale WJ, Lee LY Intravenous adenos-ine and dyspnea in humans. J Appl Physiol. 2005; 98: 180-185.
21. Storey R.F., Becker RC, Harrington R.A., Husted S., James SK, Cools F, Steg PG, Khurmi N.S., Emanuelsson H, Lim ST, Cannon C.P., Katus HA, Wallentin L. Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (the PLATelet inhibition and patient Outcomes (PLATO) pulmonary function substudy). Am J Cardiol. 2011; 108: 1542-1546.
22. Butler K, Teng R. Evaluation and characterization of the effects of ticagrelor on serum and urinary uric acid in healthy volunteers. Clin Pharmacol Ther. 2012; 91: 264-271.
23. Butler K, We i C, Teng R. Single-dose ticagrelor does not prolong the QT interval in healthy subjects. Int J Clin Pharmacol Ther. 2010; 48: 643-651.
24. Brilinta™, US full prescribing information, July 2011. AstraZeneca. http://www.accessdata.fda.gov/drugsatfda-docs/label/2011/022433s000lbl.pdf. Accessed April 30, 2013.