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Pharmacokinetic Modelling and Simulation Support the Age and Body-Weight-Adjusted Dosing of Dabigatran Etexilate in Paediatric Patients with Venous Thromboembolism

1Pharmetheus AB, Uppsala, Sweden, 2Boehringer Ingelheim Pharmaceuticals, Inc., Translational Medicine and Clinical Pharmacology, Ridgefield, United States, 3University Children's Hospital, Hematology Department, Zürich, Switzerland, 4Texas Children's Cancer Center, Baylor College of Medicine, Department of Pediatrics, Houston, United States, 5Royal Hospital for Children, Glasgow, United Kingdom, 6Pediatric Hospital Bambino Gesù, Pediatric Hematology/Oncology Department, Rome, Italy, 7University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, Canada, 8University of Alberta, Edmonton, Canada, 9Boehringer Ingelheim International GmbH, Therapeutic Area Cardiovascular Medicine, Ingelheim, Germany, 10Boehringer Ingelheim International GmbH, Therapeutic Area Inflammation Medicine, Ingelheim, Germany, 11Boehringer Ingelheim Pharmaceuticals, Inc., Therapeutic Area Cardiovascular Medicine, Ridgefield, United States, 12University of Toronto, The Hospital for Sick Children, Toronto, Canada

Abstract Number: PB1271

Meeting: ISTH 2020 Congress

Theme: Pediatrics » Thrombosis in Neonates and Children

Background: Dabigatran etexilate (DE), a direct oral thrombin inhibitor effective for the treatment of venous thromboembolism (VTE) in adults, is currently being evaluated for the treatment of VTE in children using several formulations across the age spectrum from birth to < 18 years.

Aims: This study evaluated the pharmacokinetics (PK) of dabigatran in paediatric patients with VTE following administration of DE as oral solution, coated granules, or capsules. The appropriateness of a dabigatran paediatric dosing algorithm was assessed using simulations based on a population PK model.

Methods: Paediatric data from three phase IIa and two phase IIb/III paediatric studies (N=392) as well as data from 32 healthy males (< 40 years old), were used for the analysis (consent obtained, ethics committee approved). A population PK model was fitted to the data, using non-linear mixed-effects modelling. The potential influence of co-variates, such as age, body weight and renal function, was evaluated using a stepwise co-variate model-building procedure. The final population PK model was used for evaluating the performance of the dabigatran paediatric dosing algorithm by comparing the simulated paediatric trough exposure with adult reference exposure.

Results: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and first-order absorption. All the disposition parameters increased with increasing body weight in accordance with allometric scaling. The apparent clearance increased with increasing age and decreased with decreasing renal function. The original paediatric dosing algorithms for DE, based on body weight and age, were confirmed by simulations. The impact of dose titration was minimal.

Conclusions: A population PK model of dabigatran for paediatric patients with VTE was developed. Simulation demonstrated that the final dosing algorithms for DE were appropriate for all formulations. No dose titration is needed when DE is administered to paediatric patients as oral solution, coated granules, or capsules (Figure).


[Figure: Plasma levels of dabigatran following administration to paediatric patients as oral solution, coated granules, or capsules.]

To cite this abstract in AMA style:

Roeshammar D, Huang F, Albisetti M, Bomgaars L, Chalmers E, Luciani M, Halton J, Mitchell L, Joseph D, Tartakovsky I, Gropper S, Reilly P, Brueckmann M, Brandão L, on Behalf of the Study Investigators . Pharmacokinetic Modelling and Simulation Support the Age and Body-Weight-Adjusted Dosing of Dabigatran Etexilate in Paediatric Patients with Venous Thromboembolism [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/pharmacokinetic-modelling-and-simulation-support-the-age-and-body-weight-adjusted-dosing-of-dabigatran-etexilate-in-paediatric-patients-with-venous-thromboembolism/. Accessed December 2, 2022.

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