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

Clin Pharmacokinet. 2019 Oct;58(10):1295-1307. doi: 10.1007/s40262-019-00758-0.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anemia, Sickle Cell* / blood
  • Anemia, Sickle Cell* / drug therapy
  • Anemia, Sickle Cell* / metabolism
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Models, Biological*
  • Platelet Aggregation Inhibitors / blood
  • Platelet Aggregation Inhibitors / pharmacokinetics*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Purinergic P2Y Receptor Antagonists / blood
  • Purinergic P2Y Receptor Antagonists / pharmacokinetics*
  • Purinergic P2Y Receptor Antagonists / pharmacology*
  • Ticagrelor / blood
  • Ticagrelor / pharmacokinetics*
  • Ticagrelor / pharmacology*

Substances

  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Ticagrelor

Associated data

  • ClinicalTrials.gov/NCT02214121