Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 3/2016

01-03-2016 | Original Research Article

Crushed Versus Integral Tablets of Ticagrelor in ST-Segment Elevation Myocardial Infarction Patients: A Randomized Pharmacokinetic/Pharmacodynamic Study

Authors: Dimitrios Alexopoulos, Nikolaos Barampoutis, Vasileios Gkizas, Chrysoula Vogiatzi, Grigorios Tsigkas, Nikolaos Koutsogiannis, Periklis Davlouros, George Hahalis, Sven Nylander, Guido Parodi, Ioanna Xanthopoulou

Published in: Clinical Pharmacokinetics | Issue 3/2016

Login to get access

Abstract

Objective

The objective of this study was to assess the pharmacokinetic and pharmacodynamic behavior of ticagrelor administered either as crushed (in the semi-upright sitting position) or as integral (in the supine position) tablets in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).

Methods

We randomized 20 patients to ticagrelor 180 mg either as 2 integral tablets administered in the supine position (standard administration) or as 2 tablets crushed and dispersed, administered in the semi-upright sitting position. Blood samples were drawn for pharmacokinetic and pharmacodynamic assessment at randomization (0 h) and at 0.5, 1, 2, and 4 h.

Results

At 1 h, ticagrelor plasma exposure and area under the plasma concentration–time curve from time zero to 1 h (AUC1) (co-primary endpoints) were higher in the crushed versus integral tablets group (median 586 vs. 70.1 ng/mL and 234 vs. 24.4 ng·h/mL, respectively), with a ratio of adjusted geometric means (95 % confidence interval [CI]) of 12.67 (2.34–68.51) [p = 0.005] and 19.28 (3.51–106.06) [p = 0.002], respectively. Time to maximum plasma concentration was shorter in the crushed versus integral tablets group (median 2 vs. 4 h), with a ratio of adjusted geometric means (95 % CI) of 0.69 (0.49–0.97) [p = 0.035]. Parallel findings were observed with AR-C124910XX (active metabolite). Platelet reactivity (VerifyNow®) at 1 h was lower with crushed versus standard administration with least squares estimates mean difference (95 % CI) of 92 (−158.4 to 26.6) P2Y12 reaction units (p = 0.009).

Conclusions

In patients with STEMI undergoing primary PCI, ticagrelor crushed tablets administered in the semi-upright sitting position seems to lead to a faster—compared with standard administration—absorption, with stronger antiplatelet activity within the first hour.
Trial registration: ClinicalTrials.gov identifier: NCT02046486.
Appendix
Available only for authorised users
Literature
1.
Alexopoulos D, Xanthopoulou I, Goudevenos J. Effects of P2Y12 receptor inhibition in patients with ST-segment elevation myocardial infarction. Am J Cardiol. 2014;113:2064–9.CrossRefPubMed
2.
Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569–619.CrossRef
3.
American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions, O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78–140.
4.
Heestermans AA, van Werkum JW, Taubert D, Seesing TH, von Beckerath N, Hackeng CM, et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res. 2008;122:776–81.CrossRefPubMed
5.
Valgimigli M, Tebaldi M, Campo G, Gambetti S, Bristot L, Monti M, et al. FABOLUS PRO Investigators. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. J Am Coll Cardiol Interv. 2012;5:268–77.CrossRef
6.
Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST elevation myocardial infarction. Circ Cardiovasc Interv. 2012;5:797–804.CrossRefPubMed
7.
Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI study. J Am Coll Cardiol. 2013;61:1601–6.CrossRefPubMed
8.
Alexopoulos D, Gkizas V, Patsilinakos S, Xanthopoulou I, Angelidis C, Anthopoulos P, et al. Double versus standard loading dose of ticagrelor: onset of antiplatelet action in patients with STEMI undergoing primary PCI. J Am Coll Cardiol. 2013;62:940–1.CrossRefPubMed
9.
Parodi G, Bellandi B, Valenti R, Migliorini A, Marcucci R, Carrabba N, et al. Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: the Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study. Am Heart J. 2014;167:909–14.CrossRefPubMed
10.
Alexopoulos D, Makris G, Xanthopoulou I, Patsilinakos S, Deftereos S, Gkizas V, et al. Onset of antiplatelet action with high (100 mg) versus standard (60 mg) loading dose of prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: pharmacodynamic study. Circ Cardiovasc Interv. 2014;7:233–9.CrossRefPubMed
11.
Parodi G, Xanthopoulou I, Bellandi B, Gkizas V, Valenti R, Karanikas S, et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol. 2015;10(65):511–2.CrossRef
12.
Zhang X, Xiang X, Tu L, Xie X, Hou X. Esophageal motility in the supine and upright positions for liquid and solid swallows through high-resolution manometry. J Neurogastroenterol Motil. 2013;19:467–72.PubMedCentralCrossRefPubMed
13.
Crean B, Finnie C, Crosby A. Evaluation of crushed ticagrelor tablet doses: recovery following crushing and naso-gastric tube passage ex vivo. Drugs. 2013;13:153–7.
14.
Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, et al. Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to ADP associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62:2261–73.CrossRefPubMed
15.
Sillén H, Cook M, Davis P. Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2010;878:2299–306.CrossRef
16.
Husted SE, Storey RF, Bliden K, Tantry US, Høimark L, Butler K, et al. Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET–OFFSET and RESPOND studies. Clin Pharmacokinet. 2012;51:397–409.CrossRefPubMed
17.
Zafar MU, Farkouh ME, Fuster V, Chesebro JH. Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets. J Interv Cardiol. 2009;22:385–9.CrossRefPubMed
18.
Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, 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;50:1852–6.CrossRefPubMed
19.
Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, 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;120:2577–85.CrossRefPubMed
20.
Teng R, Carlson G, Hsia J. An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers. Int J Clin Pharmacol Ther. 2015;53:183–9.CrossRef
21.
Montalescot G, van’t Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, et al. ATLANTIC Investigators. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371:1016–27.CrossRefPubMed
22.
Parodi G, Alexopoulos D. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371:2337–8.CrossRefPubMed
23.
Akers WS, Oh JJ, Oestreich JH, Ferraris S, Wethington M, Steinhubl SR. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol. 2010;50:27–35.CrossRefPubMed
24.
Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, et al. CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303–13.CrossRefPubMed
25.
Parodi G, Bellandi B, Xanthopoulou I, Capranzano P, Capodanno D, Valenti R, et al. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv. 2014;8(1):e001593. doi:10.​1161/​CIRCINTERVENTION​S.​114.​001593.CrossRefPubMed
26.
Alexopoulos D. OraL crushed and dIspersed ticagrelor 180mg compared to whole tablets of eQUal dose in STEMI patients unDergoing primary PCI: a pharmacokinetic/pharmacodynamic study (the LIQUID Study) [ClinicalTrials.gov identifier NCT02046486]. US National Institutes of Health, ClinicalTrials.gov. https://​www.​clinicaltrials.​gov. Accessed 6 Aug 2015.
Metadata
Title
Crushed Versus Integral Tablets of Ticagrelor in ST-Segment Elevation Myocardial Infarction Patients: A Randomized Pharmacokinetic/Pharmacodynamic Study
Authors
Dimitrios Alexopoulos
Nikolaos Barampoutis
Vasileios Gkizas
Chrysoula Vogiatzi
Grigorios Tsigkas
Nikolaos Koutsogiannis
Periklis Davlouros
George Hahalis
Sven Nylander
Guido Parodi
Ioanna Xanthopoulou
Publication date
01-03-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 3/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0320-0

Other articles of this Issue 3/2016

Clinical Pharmacokinetics 3/2016 Go to the issue

Original Research Article

Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug–Drug Interactions

Review Article

Pharmacokinetic Properties of Anticancer Agents for the Treatment of Central Nervous System Tumors: Update of the Literature

Review Article

A Qualitative Review on the Pharmacokinetics of Antibiotics in Saliva: Implications on Clinical Pharmacokinetic Monitoring in Humans

Erratum

Erratum to: Enzalutamide: A Step Towards Pharmacokinetic-Based Dosing in Men with Metastatic Castration-Resistant Prostate Cancer

Original Research Article

Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies

Original Research Article

Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy