Development of a Paediatric Population-Based Model of the Pharmacokinetics of Rivaroxaban

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...

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Bibliographic Details
Published in:Clinical pharmacokinetics 2014-01, Vol.53 (1), p.89-102
Main Authors: Willmann, Stefan, Becker, Corina, Burghaus, Rolf, Coboeken, Katrin, Edginton, Andrea, Lippert, Jörg, Siegmund, Hans-Ulrich, Thelen, Kirstin, Mück, Wolfgang
Format: Article
Language:English
Subjects:
Adolescent
Adult
Anticoagulants - blood
Anticoagulants - pharmacokinetics
Biological and medical sciences
Child
Child, Preschool
Female
General pharmacology
Humans
Infant
Infant, Newborn
Internal Medicine
Male
Medical sciences
Medicine
Medicine & Public Health
Models, Biological
Morpholines - blood
Morpholines - pharmacokinetics
Original
Original Research Article
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pharmacotherapy
Rivaroxaban
Thiophenes - blood
Thiophenes - pharmacokinetics
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Summary: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
ISSN:0312-5963
1179-1926
DOI:10.1007/s40262-013-0090-5