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

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Abstract

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.

Methods

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.

Results

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.

Conclusion

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.

ClinicalTrials.gov Identifier

NCT03126695.

EudraCT

2017-000371-93.

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Acknowledgements

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

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Authors and Affiliations

  1. Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca Gothenburg, Mölndal, Sweden

    Mohammad Niazi

  2. Global Medicines Development, AstraZeneca Gothenburg, Mölndal, Sweden

    Jenny Wissmar, Anders R. Berggren & Per Johanson

  3. Pharmaceutical Technology and Development, AstraZeneca Gothenburg, Mölndal, Sweden

    Christer Karlsson

Authors
  1. Mohammad Niazi
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  2. Jenny Wissmar
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  3. Anders R. Berggren
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  4. Christer Karlsson
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  5. Per Johanson
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Corresponding author

Correspondence to Mohammad Niazi.

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Funding

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 https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

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Niazi, M., Wissmar, J., Berggren, A.R. et al. Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor. Clin Drug Investig 39, 765–773 (2019). https://doi.org/10.1007/s40261-019-00800-w

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  • DOI: https://doi.org/10.1007/s40261-019-00800-w

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