Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina

Piotr Niezgoda; Joanna Sikora; Malwina Barańska; Adam Sikora; Katarzyna Buszko; Emilia Siemińska; Michał Piotr Marszałł; Jolanta M. Siller-Matula; Bernd Jilma; Dimitrios Alexopoulos; Tomasz Fabiszak; Jacek Kubica

doi:10.1160/TH16-08-0670

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(04): 718-726
DOI: 10.1160/TH16-08-0670

Cellular Haemostasis and Platelets

Schattauer GmbH

Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina

A pharmacokinetic/pharmacodynamic study

Piotr Niezgoda^*

¹Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Joanna Sikora^*

²Department of Pharmacology and Therapy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Malwina Barańska

¹Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Adam Sikora

³Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Katarzyna Buszko

⁴Department of Theoretical Foundations of Biomedical Science and Medical Informatics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Emilia Siemińska

¹Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Michał Piotr Marszałł

³Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Jolanta M. Siller-Matula

⁵Department of Cardiology, Medical University of Vienna, Vienna, Austria

,

Bernd Jilma

⁶Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

,

Dimitrios Alexopoulos

⁷Department of Cardiology, Patras University Hospital, Rion, Patras, Greece

,

Tomasz Fabiszak

¹Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

,

Jacek Kubica

¹Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

› Author Affiliations

Abstract

Summary

Oral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina. Ticagrelor and its metabolite AR-C124900XX plasma concentration was evaluated in nine time points (time frame of 6 hours) using liquid chromatography coupled with mass spectrometry; platelet reactivity was evaluated using multiple electrode aggregometry. The area under the plasma concentration-time curve for ticagrelor and AR-C124900XX was significantly higher in patients treated with crushed tablets given orally compared with crushed tablets given sublingually only within the first hour after loading dose (936.9 ± 898.0 vs 368.0 ± 422.4, p=0.042 and 103.4 ± 120.8 vs 31.3 ± 43.9, p=0.031, respectively). Moreover, we showed significantly stronger platelet inhibition in patients receiving crushed ticagrelor orally vs. sublingually at 30 and 45 min after the loading dose (p=0.024 and p=0.016, respectively). Therefore, the administration strategy of ticagrelor determines the pharmacokinetic and pharmacodynamic profile of both ticagrelor and its active metabolite AR-C124900XX.

Keywords

Ticagrelor - crushed ticagrelor administration - sublingual - platelets - unstable angina

Full Text

References

References
1 Montalescot G, van’t Hof AW, Lapostolle F. et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014; 11: 1016-1027
2 Alexopoulos D, Xanthopoulou I, Gkizas V. et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2012; 5: 797-804
3 Parodi G, Valenti R, Bellandi B. et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013; 61: 1601-1606
4 Kubica J, Adamski P, Ostrowska M. et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 2016; 37: 245-252
5 Silvain J, Storey RF, Cayla G. et al. P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction. The PRIVATE-ATLANTIC study. Thromb Haemost 2015; 116: 369-378
6 Parodi G, Bellandi B, Valenti R. 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: 909-914
7 Parodi G, Bellandi B, Xanthopoulou I. 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 2015; 8: e001593
8 Alexopoulos D, Gkizas V, Patsilinakos S. 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: 940-941
9 Franchi F, Rollini F, Cho JR. et al. Impact of morphine on pharmacokinetic and pharmacodynamic profiles of ticagrelor in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 2015; 65: 10S
10 Hobl EL, Reiter B, Schoergenhofer C. et al. Morphine Decreases Ticagrelor Concentrations but not its Antiplatelet Effects: A Randomized Trial in Healthy Volunteers. Eur J Clin Invest 2016; 46: 7-14
11 Parodi G, Xanthopoulou I, Bellandi B. et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J Am Coll Cardiol 2015; 65: 511-512
12 Alexopoulos D, Barampoutis N, Gkizas V. et al. Crushed Versus Integral Tablets of Ticagrelor in ST-Segment Elevation Myocardial Infarction Patients: A Randomized Pharmacokinetic/Pharmacodynamic Study. Clin Pharmacokinet 2016; 55: 359-367
13 Kubica J, Kubica A, Jilma B. et al. Impact of morphine on antiplatelet effects of oral P2Y12 receptor inhibitors. Int J Cardiol 2016; 215: 201-208
14 Siller-Matula JM, Specht S, Kubica J. et al. Abciximab as a bridging strategy to overcome morphine-prasugrel interaction in STEMI patients. Br J Clin Pharmacol 2016 Epub ahead of print
15 Meine TJ, Roe MT, Chen AY. et al. Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005; 149: 1043-1049
16 Niezgoda P, Sikora J, Baranska M. et al. Impact of ticagrelor administration strategy on its pharmacokinetics and pharmacodynamics in patients with unstable angina pectoris: a protocol of a randomized study. Med Res J 2016; 1: 10-14
17 Remko M, Remkova A, Broer R. A comperative study of molecular structure, pKa, lipophilicity, solubility, absorption and polar surface area of some antiplatelet drugs. Int J Mol Sci 2016; 17: 388
18 Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery. Clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 2002; 41: 661-680
19 Crean B, Finnie C, Crosby A. Evaluation of crushed ticagrelor tablet doses: recovery following crushing and nasogastric tube passage ex vivo. Drugs R D. 2013; 13: 153-157
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: 182-189
21 Tilemann LM, Stiepak J, Zelniker T. et al. Efficacy of enteral ticagrelor in hypothermic patients after out-of-hospital cardiac arrest. Clin Res Cardiol 2016; 105: 332-340
22 Zafar MU, Farkouh ME, Fuster V. et al. Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets. J Interv Cardiol 2009; 22: 385-389
23 Rollini F, Franchi F, Hu J. et al. Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study. J Am Coll Cardiol 2016; 67: 1994-2004