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

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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.

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Authors and Affiliations

  1. Department of Cardiology, Patras University Hospital, Rion, 26500, Patras, Greece

    Dimitrios Alexopoulos, Nikolaos Barampoutis, Vasileios Gkizas, Chrysoula Vogiatzi, Grigorios Tsigkas, Nikolaos Koutsogiannis, Periklis Davlouros, George Hahalis & Ioanna Xanthopoulou

  2. AstraZeneca R&D, Mölndal, Sweden

    Sven Nylander

  3. Cardiovascular and Thoracic Department, Careggi Hospital, Florence, Italy

    Guido Parodi

Authors
  1. Dimitrios Alexopoulos
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  2. Nikolaos Barampoutis
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  3. Vasileios Gkizas
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  6. Nikolaos Koutsogiannis
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  11. Ioanna Xanthopoulou
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Corresponding author

Correspondence to Dimitrios Alexopoulos.

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Disclosures

This study was supported by the Research Committee of the Patras University Medical School. Dr Alexopoulos has received speaker honoraria from AstraZeneca and Advisory Board fees from AstraZeneca, Boeringer Ingelheim, Bayer, and the Medicines Company. Dr Nylander is an employee of AstraZeneca. Dr Parodi has received consulting fees from Daiichi Sankyo, Eli Lilly, AstraZeneca, Bayer, and the Medicines Company and lecture fees from Daiichi Sankyo, Eli Lilly, and AstraZeneca. Nikolaos Barampoutis, Vasileios Gkizas, Chrysoula Vogiatzi, Grigorios Tsigkas, Nikolaos Koutsogiannis, Periklis Davlouros, George Hahalis, Sven Nylander, and Ioanna Xanthopoulou have nothing to disclose.

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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 55, 359–367 (2016). https://doi.org/10.1007/s40262-015-0320-0

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