Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Abstract

Background: 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.

Methods: We 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.

Results: PK 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.

Conclusions: These 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 registration: ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.

Keywords: Pediatric; Pharmacokinetics; Physiologically based pharmacokinetic modelling; Rivaroxaban.

Conflict of interest statement

The protocol was approved by the Institutional Review Board or Ethics Committee of each participating center, if required, and de-identified data was retrieved.Not applicable.All authors are employees of Bayer AG.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

a Staggered approach and sampling strategy for collecting PK/PD and safety data in pediatric cohorts in this phase I study. PK/PD and safety data available for at least four subjects before starting next cohort; blue arrows indicate data monitoring committee agreement to progress to the next planned step of the phase I study, i.e. data collection for the next cohort. b Sampling windows per age group eq., equivalent, PD pharmacodynamics, PK pharmacokinetics.

Fig. 2

Schematic diagram of the integration of modelling and simulation approaches into the pediatric development process of rivaroxaban. Dashed arrows denote work in progress; outcomes of this work will be described in future publications eq., equivalent; PBPK, physiologically based pharmacokinetic; PopPK, population pharmacokinetic.

Fig. 3

Plasma concentration–time curves in children aged a 12–18 years given 10 mg-equivalent rivaroxaban, b 12–18 years given 20 mg-equivalent rivaroxaban, c 6–12 years given 10 mg-equivalent rivaroxaban, d 6–12 years given 20 mg-equivalent rivaroxaban, e 2–6 years given 10 mg-equivalent rivaroxaban, f 2–6 years given 20 mg-equivalent rivaroxaban, g 0.5–2 years given 10 mg-equivalent rivaroxaban and h 0.5–2 years given 20 mg-equivalent rivaroxaban. The solid black line shows the geometric mean of the population prediction, the dark grey shaded area denotes the 90% prediction interval of the PBPK model. The light grey shading denotes the enlarged expected concentration range representing 0.5-times the 5th percentile and 1.5-times the 95th percentile of the PBPK prediction. Data points represent clinically observed data from individual subjects (blue: tablet formulation, orange: undiluted suspension, green: diluted suspension). The inset panels show the same data as the respective main panel on a semi-logarithmic concentration scale eq., equivalent; PBPK, physiologically based pharmacokinetic.

Fig. 4

Range plots comparing PK parameters for children aged 0.5–18 years derived from the PopPK analysis or NCA (aged ≥6 years) with the corresponding PBPK model predictions: a AUC0–24, b Cmax and c C_24h for rivaroxaban 10 mg-equivalent doses, and d AUC0–24, e Cmax and f C_24h for rivaroxaban 20 mg-equivalent doses. The solid black line shows the geometric mean of the population prediction and the light grey shaded area denotes the 90% prediction interval of the PBPK model. The dark grey shading denotes the enlarged expected concentration range representing 0.5-times the 5th percentile and 1.5-times the 95th percentile of the PBPK prediction. Data points show PK parameters of individual subjects derived by NCA (closed symbols) or PopPK analysis (open symbols). The corresponding distributions of PK parameters observed via PopPK modelling from an adult reference population (N = 203 adult VTE patients aged 18–45 years) is also shown as box-whisker plot indicating the percentiles 5, 25, 50, 75 and 95 AUC0–24, area under the plasma concentration–time curve from time 0–24 h; C_24h, plasma concentration 24 h after rivaroxaban administration; Cmax, maximal plasma concentration; eq., equivalent; NCA, non-compartmental analysis; PBPK, physiologically based pharmacokinetics; PK, pharmacokinetics; PopPK, population pharmacokinetic; VTE, venous thromboembolism.