Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban

Stefan Willmann, Corina Becker, Rolf Burghaus, Katrin Coboeken, Andrea Edginton, Jörg Lippert, Hans-Ulrich Siegmund, Kirstin Thelen, Wolfgang Mück, Stefan Willmann, Corina Becker, Rolf Burghaus, Katrin Coboeken, Andrea Edginton, Jörg Lippert, Hans-Ulrich Siegmund, Kirstin Thelen, Wolfgang Mück

Abstract

Background: Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population.

Objective: The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0-18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients.

Methods: Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration-time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations.

Results: Simulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However, pharmacokinetic values in infants and preschool children (body weight <40 kg) were lower than the 90 % confidence interval threshold of the adult reference model and, therefore, indicated that doses in these groups may need to be increased to achieve the same plasma levels as in adults. For children with body weight between 40 and 70 kg, simulated plasma pharmacokinetic parameters (C max, C 24h and AUC) overlapped with the values obtained in the corresponding adult reference simulation, indicating that body weight-related exposure was similar between these children and adults. In adolescents of >70 kg body weight, the simulated 90 % prediction interval values of AUC and C 24h were much higher than the 90 % confidence interval of the adult reference population, owing to the weight-based simulation approach, but for these patients rivaroxaban would be administered at adult fixed doses of 10 and 20 mg.

Conclusion: The paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients.

Trial registration: ClinicalTrials.gov NCT01145859.

Figures

Fig. 1
Fig. 1
Generic workflow for the PBPK-based scaling of rivaroxaban pharmacokinetics from adults to children. ADME processes processes that involve absorption, distribution, metabolism and excretion of a drug, IV intravenous, PK pharmacokinetic, PBPK physiologically based pharmacokinetic
Fig. 2
Fig. 2
Individually observed (dots) and simulated (lines) plasma concentration–time profiles for rivaroxaban after a 30-min intravenous infusion of 1 mg rivaroxaban in healthy adults depicted as a linear (main graph) and semi-log plot (inset). Simulated data are represented as geometric means (black line), 90 % prediction interval (grey shaded area) and minimum and maximum values (dotted lines)
Fig. 3
Fig. 3
Individually observed (dots) and simulated (lines) plasma concentration–time profiles for rivaroxaban after oral administration of an immediate-release tablet to healthy adults depicted as a linear (main graph) and semi-log plot (inset). Simulated data are represented as geometric means (black line), 90 % prediction interval (grey shaded area) and minimum and maximum values (dotted lines). The graphs show concentration–time profiles of 10 mg (a, c) and 20 mg (b, d) rivaroxaban, under fasting (a, b) and fed (c, d) conditions
Fig. 4
Fig. 4
Gender-pooled paediatric simulations for maximum (peak) plasma drug concentration (Cmax) (a, b), area under the plasma concentration–time curve (AUC) (c, d) and concentration in plasma after 24 h (C24h) (e, f) versus body weight for two different doses of rivaroxaban: 0.143 mg/kg body weight (a, c, e) and 0.286 mg/kg body weight (b, d, f), simulated as oral suspension formulation compared with the adult reference population. Simulated data of the paediatric population are represented as geometric means (blue line) and 90 % prediction interval (grey shaded area). Simulated data of the adult reference population are represented as geometric means (thick red line) and 90 % confidence interval (red shaded area in the background of the graph). Expected body weight ranges for infants, preschool children, children and adolescents are indicated

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