Clinical Drug Investigation

, Volume 39, Issue 8, pp 765–773 | Cite as

Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor

  • Mohammad NiaziEmail author
  • Jenny Wissmar
  • Anders R. Berggren
  • Christer Karlsson
  • Per Johanson
Original Research Article


Background and Objective

Ticagrelor is a P2Y12 receptor inhibitor approved as an antiplatelet drug for patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also being investigated for the reduction of vaso-occlusive crises in pediatric patients with sickle cell disease. A pediatric formulation suitable for this age range was developed; the development strategy is described. Primary objectives were determining the relative bioavailability of ticagrelor pediatric tablets and granules for oral suspension to the adult immediate-release tablet, and the pediatric tablets taken whole and dispersed/suspended in water to the granules for oral suspension. Bioequivalence between the pediatric tablet taken whole or suspended in water was also assessed. Secondary objectives were comparing the formulations’ safety and tolerability.


We conducted a randomized, four-period, cross-over, single-dose study. Pharmacokinetic parameters were assessed for ticagrelor and its active metabolite AR-C124910XX. Bioequivalence was concluded if the 90% confidence intervals of the maximum plasma concentration and area under the plasma concentration–time curve ratios were contained completely within the 80.00–125.00% limits for ticagrelor/AR-C124910XX.


Forty-four healthy adults (95% white; 57% male) were included. Similar bioavailability of ticagrelor (and AR-C124910XX) was demonstrated for all comparisons tested. Ticagrelor pediatric tablets taken whole were bioequivalent to pediatric tablets suspended in water. The plasma concentration–time profiles for ticagrelor and AR-C124910XX were similar, showing rapid ticagrelor absorption and AR-C124910XX formation. All formulations were well tolerated.


Similar bioavailability of a new pediatric dispersible tablet formulation of ticagrelor for use across a wide age range of pediatric patients was demonstrated compared with other oral ticagrelor formulations. Identifier






Medical writing assistance, funded by AstraZeneca, was provided by Steven Tresker of Cactus Communications.

Compliance with Ethical Standards


This study was funded by AstraZeneca.

Conflict of interest

All authors are current employees of AstraZeneca.

Ethical approval

All procedure performed in this study were in accordance with the ethical standards of the institution and/or national research committee and were in compliance with the 1964 Declaration of Helsinki and its later amendments. The local institutional review board or independent ethics committee approved the final protocol and amendment.

Informed consent

All subjects provided written informed consent.

Data availability

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at

Supplementary material

40261_2019_800_MOESM1_ESM.docx (435 kb)
Supplementary material 1 (DOCX 435 kb)


  1. 1.
    Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27:259–74.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    van Giezen JJJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost. 2009;7:1556–65.CrossRefGoogle Scholar
  3. 3.
    Armstrong D, Summers C, Ewart L, et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther. 2014;19:209–19.CrossRefPubMedGoogle Scholar
  4. 4.
    Nylander S, Femia EA, Scavone M, et al. Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. J Thromb Haemost. 2013;11:1867–76.PubMedGoogle Scholar
  5. 5.
    Nylander S, Schulz R. Effects of P2Y12 receptor antagonists beyond platelet inhibition—comparison of ticagrelor with thienopyridines. Br J Pharmacol. 2016;173:1163–78.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Brilinta® (ticagrelor) prescribing information. AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA. Accessed 14 Jan 2018.
  7. 7.
    Hsu LL, Sarnaik S, Williams S, et al. A dose-ranging study of ticagrelor in children aged 3–17 years with sickle cell disease: a 2-part phase 2 study. Am J Hematol. 2018;93:1493–500.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kanter J, Abboud MR, Kaya B, et al. Ticagrelor does not impact patient-reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study. Br J Haematol. 2019;184:269–78.CrossRefPubMedGoogle Scholar
  9. 9.
    Heeney MM, Abboud MR, Amilon C, et al. Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3). In: Poster presented at the 23rd European Hematology Association Congress, 16 June, 2018; abstract PS1460.Google Scholar
  10. 10.
    Liu F, Ranmal S, Batchelor HK, et al. Patient-centred pharmaceutical design to improve acceptability of medicines: similarities and differences in paediatric and geriatric populations. Drugs. 2014;74:1871–89.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    European Medicines Agency. Guideline on pharmaceutical development of medicines for paediatric use. 2011. Accessed 15 Jun 2018.
  12. 12.
    Solid oral pharmaceutical compositions comprising ticagrelor or salt thereof. Patent application. Accessed 23 May 2019.
  13. 13.
    Hansen DL, Tulinius D, Hansen EH. Adolescents’ struggles with swallowing tablets: barriers, strategies and learning. Pharm World Sci. 2008;30:65–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Steffensen GK, Pachai A, Pedersen SE. Peroral drug administration to children: are there any problems? [Article in Danish]. Ugeskr Laeger. 1998;160:2249–52.PubMedGoogle Scholar
  15. 15.
  16. 16.
    Sillen H, Cook M, Davis P. Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:2299–306.CrossRefPubMedGoogle Scholar
  17. 17.
    European Medicines Agency. Guideline on the investigation of bioequivalence. 2010. Accessed 19 Jun 2018.
  18. 18.
    US Food and Drug Administration. Statistical approaches to establishing bioequivalence. 2001. Accessed 19 Jun 2018.
  19. 19.
    Baguley D, Lim E, Bevan A, Pallet A, Faust SN. Prescribing for children—taste and palatability affect adherence to antibiotics: a review. Arch Dis Child. 2012;97:293–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Mennella JA, Roberts KM, Mathew PS, Reed DR. Children’s perceptions about medicines: individual differences and taste. BMC Pediatr. 2015;15:130.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Steele RW, Thomas MP, Begue RE. Compliance issues related to the selection of antibiotic suspensions for children. Pediatr Infect Dis J. 2001;20:1–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Quantitative Clinical Pharmacology, Early Clinical DevelopmentAstraZeneca GothenburgMölndalSweden
  2. 2.Global Medicines DevelopmentAstraZeneca GothenburgMölndalSweden
  3. 3.Pharmaceutical Technology and DevelopmentAstraZeneca GothenburgMölndalSweden

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