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Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an

Stefan Willmann1, Kirstin Thelen1, Dagmar Kubitza1

  • 11Clinical Sciences, Bayer AG, Bayer AG, Aprather Weg 18a, Wuppertal, Germany.

Thrombosis Journal
|December 12, 2018
PubMed

Insights

A new pediatric physiologically based pharmacokinetic (PBPK) model for rivaroxaban effectively predicts drug exposure in children treated for venous thromboembolism (VTE). This model supports optimized dosing for pediatric VTE treatment.

Area of Science:

  • Pharmacology
  • Pediatric Medicine
  • Pharmacokinetics

Background:

  • The EINSTEIN-Jr program investigates rivaroxaban for pediatric venous thromboembolism (VTE).
  • A physiologically based pharmacokinetic (PBPK) model was developed for pediatric rivaroxaban dosing.
  • The model targets exposures similar to the adult 20 mg once-daily dose.

Purpose of the Study:

  • To quantitatively assess rivaroxaban pharmacokinetics (PK) in children.
  • To evaluate the applicability of the pediatric PBPK model.
  • To compare PBPK model predictions with population pharmacokinetic (PopPK) and non-compartmental analyses.

Main Methods:

  • Analysis of plasma concentration-time data from 59 children in the EINSTEIN-Jr phase I study.
  • Utilized population pharmacokinetic (PopPK) modeling and non-compartmental analysis.
  • Compared observed data with predictions from a pediatric rivaroxaban PBPK model.

Main Results:

  • Observed plasma concentration-time profiles were largely within the PBPK model's 90% prediction interval.
  • PopPK estimates and non-compartmental analysis results agreed well with PBPK predictions for children aged ≥6 years.
  • The PBPK model demonstrated applicability across different doses and formulations (tablet, oral suspension).

Conclusions:

  • The rivaroxaban pediatric PBPK model is applicable to children aged 0.5-18 years.
  • The validated PBPK model, combined with PopPK data, will guide future pediatric rivaroxaban dose selection.
  • This supports the ongoing EINSTEIN-Jr phase II and III studies for VTE treatment in children.
Abstract

Keywords:
PediatricPharmacokineticsPhysiologically based pharmacokinetic modellingRivaroxaban

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