Population Pharmacokinetics/Pharmacodynamics of Ticagrelor in Children with Sickle Cell Disease
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Background and Objective
Ticagrelor, a reversible P2Y12 platelet inhibitor, is under investigation as a sickle cell disease (SCD) therapy in children. HESTIA1 (NCT02214121) was the first ticagrelor study generating pharmacokinetic (PK), pharmacodynamic (PD, P2Y12 reactivity units [PRU]), and safety data in 45 pediatric SCD patients. Population PK and PK/PD relationships for ticagrelor were quantified using a PK approach.
An adult population PK model was refined to describe ticagrelor and AR–C124910XX (active metabolite) plasma concentration and time data over a wide range of single/repeated ticagrelor doses (0.125–2.25 mg/kg). Population PK/PD modeling was used to describe the time course and extent of platelet inhibition. Demographic covariate relationships were investigated.
The final population PK model adequately described ticagrelor and AR-C124910XX plasma concentrations over time. An allometric body weight relationship between ticagrelor and AR-C124910XX clearances and volumes of distribution was used. Significant covariates for ticagrelor were sex (relative bioavailability) and cholecystectomy (central volume of distribution). Estimated oral clearances (35 kg patient; median bodyweight) were 22.8 L/h (ticagrelor) and 9.97 L/h (AR-C124910XX). The final population PK/PD model well-described the time course and extent of platelet inhibition. Estimated baseline PRU was 283, maximum PRU effect was fixed at 1, and the ticagrelor concentration for half-maximum PRU effect was 233 nmol/L.
These analyses offer the first quantitative characterization of the dose-exposure-response relationship for ticagrelor in pediatric SCD patients. This model-based approach may be used to inform dose selection and design of subsequent studies that aim to define ticagrelor safety and efficacy in pediatric SCD patients.
The authors would like to acknowledge Jessica Persson (AstraZeneca, Gothenburg, Sweden) for dataset programming support, and also Jackie Phillipson from Zoetic Science (Macclesfield, UK), who provided medical writing support (outline, all drafts, assembling tables and figures, collating author comments, grammatical editing and referencing); this support was funded by AstraZeneca.
Compliance with Ethical Standards
Conflicts of interest
Carl Amilon, Mohammad Niazi, Anders Berggren, Magnus Åstrand, and Bengt Hamrén are employees of AstraZeneca and also hold stocks/shares in AstraZeneca.
Prior to the start of any study-related procedures, signed informed consent was obtained from the parent(s)/legal guardian, and assent/consent was obtained from each child/adolescent. The final study protocol, amendments, and informed consent documentation were approved by an Ethics Committee and/or Institutional Review Board. HESTIA1 was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice Guidelines, and followed applicable regulatory requirements and the AstraZeneca policy on bioethics.
This study and analyses were funded by AstraZeneca.
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