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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 10/2019

01-10-2019 | Ticagrelor | Original Research Article

Population Pharmacokinetics/Pharmacodynamics of Ticagrelor in Children with Sickle Cell Disease

Authors: Carl Amilon, Mohammad Niazi, Anders Berggren, Magnus Åstrand, Bengt Hamrén

Published in: Clinical Pharmacokinetics | Issue 10/2019

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Abstract

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.

Methods

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.

Results

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.

Conclusions

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.
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Metadata
Title
Population Pharmacokinetics/Pharmacodynamics of Ticagrelor in Children with Sickle Cell Disease
Authors
Carl Amilon
Mohammad Niazi
Anders Berggren
Magnus Åstrand
Bengt Hamrén
Publication date
01-10-2019
Publisher
Springer International Publishing
Keyword
Ticagrelor
Published in
Clinical Pharmacokinetics / Issue 10/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-019-00758-0

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