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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.MethodsThis was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.ResultsFifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.ConclusionsBodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.Trial registrationClinicalTrials.gov number, NCT01145859.
Highlights
In adults, rivaroxaban is associated with similar efficacy and a significantly lower rate of major bleeding compared with low molecular weight heparin (LMWH) followed by dose-adjusted vitamin K antagonist [VKA] therapy) in patients with acute venous thromboembolism (VTE) [1]
In these in vitro spiking experiments, the prothrombin time (PT) and activated partial thromboplastin time, which have been frequently used in adults to describe the PD properties of rivaroxaban and their relationship to plasma concentrations, were assessed to establish whether they displayed similar properties in children [3, 4]
Pharmacodynamics Prothrombin time and rivaroxaban plasma concentrations In all age groups, PT changes from baseline showed a linear relationship versus rivaroxaban plasma concentrations (Fig. 2), and the data were similar to those of healthy adult volunteers receiving a single dose of rivaroxaban 10 mg or 20 mg
Summary
Rivaroxaban is associated with similar efficacy and a significantly lower rate of major bleeding compared with low molecular weight heparin (LMWH) followed by dose-adjusted vitamin K antagonist [VKA] therapy) in patients with acute venous thromboembolism (VTE) [1]. adult data are the basis for planning pediatric trials, it is important to assess potential differences between children and adults in terms of both pharmacokinetics (PK) and pharmacodynamics (PD), because these may affect pediatric dosing algorithms. It is important to understand whether rivaroxaban treatment results in different PD responses in children, compared with adults To address this question, previous in vitro spiking experiments were performed in plasma obtained from children and neonates, with the results suggesting that PD responses to rivaroxaban across a range of age groups were similar to those in adults [3, 4]. Previous in vitro spiking experiments were performed in plasma obtained from children and neonates, with the results suggesting that PD responses to rivaroxaban across a range of age groups were similar to those in adults [3, 4] In these in vitro spiking experiments, the prothrombin time (PT) and activated partial thromboplastin time (aPTT), which have been frequently used in adults to describe the PD properties of rivaroxaban and their relationship to plasma concentrations, were assessed to establish whether they displayed similar properties in children [3, 4]. 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
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