Abstract
BackgroundThe EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed.MethodsWe quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE.ResultsPK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions.ConclusionsThese results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies.Trial registrationClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.
Highlights
International guidelines recommend the use of unfractionated heparin, low molecular weight heparin and vitamin K antagonists for the treatment of venous thromboembolism (VTE) in children [1]
All subjects were valid for PK analyses and contributed 206 plasma concentrations, of which seven were excluded because they were below the Lower limit of quantification (LLOQ)
Observed plasma concentration–time data and physiologically based pharmacokinetic (PBPK) model predictions The observed plasma concentration–time data of the four age groups receiving the rivaroxaban 10 mg-equivalent and 20 mg-equivalent doses of rivaroxaban are shown in Fig. 3 in comparison with the PBPK model predictions
Summary
International guidelines recommend the use of unfractionated heparin, low molecular weight heparin and vitamin K antagonists for the treatment of venous thromboembolism (VTE) in children [1]. Based pharmacokinetic (PBPK) modelling is increasingly being used as a tool to guide dosing in. Rivaroxaban is approved in adults for the treatment of VTE [14, 15], but data in children are lacking. The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of VTE, aiming for a rivaroxaban exposure in children similar to the exposure observed in adult patients with VTE who have received rivaroxaban 20 mg. The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed
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