Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor
- 65 Downloads
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.
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.
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.
All subjects provided written informed consent.
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.
- 6.Brilinta® (ticagrelor) prescribing information. AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA. http://www.azpicentral.com/brilinta/brilinta.pdf. Accessed 14 Jan 2018.
- 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
- 11.European Medicines Agency. Guideline on pharmaceutical development of medicines for paediatric use. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/06/WC500107908.pdf. Accessed 15 Jun 2018.
- 12.Solid oral pharmaceutical compositions comprising ticagrelor or salt thereof. Patent application. https://patents.google.com/patent/WO2015110952A1/fi. Accessed 23 May 2019.
- 15.AstraZeneca’s policy on bioethics. https://www.astrazeneca.com/content/dam/az/our-company/Documents/Bioethics%20policy%207.0.pdf. Accessed 23 May 2019.
- 17.European Medicines Agency. Guideline on the investigation of bioequivalence. 2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed 19 Jun 2018.
- 18.US Food and Drug Administration. Statistical approaches to establishing bioequivalence. 2001. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070244.pdf. Accessed 19 Jun 2018.