Pharmacokinetic-Pharmacodynamic Relationship between Dabigatran Plasma Concentrations and Coagulation Laboratory Parameters in Paediatric Patients with Venous Thromboembolism

L. Mitchell¹, D. Roeshammar², F. Huang³, M. Albisetti⁴, L. Brandão⁵, L. Bomgaars⁶, E. Chalmers⁷, J. Halton⁸, M. Luciani⁹, D. Joseph³, I. Tartakovsky¹⁰, S. Gropper¹¹, P. Reilly¹², M. Brueckmann¹⁰, J. Stangier¹³, on Behalf of the Study Investigators

¹University of Alberta, Edmonton, Canada, ²Pharmetheus AB, Uppsala, Sweden, ³Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, United States, ⁴University Children's Hospital, Hematology Department, Zürich, Switzerland, ⁵The Hospital for Sick Children, University of Toronto, Toronto, Canada, ⁶Texas Children's Cancer Center, Baylor College of Medicine, Department of Pediatrics, Houston, United States, ⁷Royal Hospital for Children, Glasgow, United Kingdom, ⁸Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada, ⁹Pediatric Hospital Bambino Gesù, Pediatric Hematology/Oncology Department, Rome, Italy, ¹⁰Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany, ¹¹Therapeutic Area Inflammation Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany, ¹²Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, United States, ¹³Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany

Abstract Number: PB1272

Meeting: ISTH 2020 Congress

Theme: Pediatrics » Thrombosis in Neonates and Children

Background: Dabigatran etexilate, a direct oral thrombin inhibitor effective for treating venous thromboembolism (VTE) in adults, is being evaluated for the treatment of VTE in paediatric patients.

Aims: This study characterized the population pharmacokinetic/pharmacodynamic (PK/PD) relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (measured by central lab: activated partial thromboplastin time [aPTT], diluted thrombin time [dTT] and ecarin clotting time [ECT]) in the paediatric VTE patient population, including a comparison with adults.

Methods: Paediatric PK/PD data from three phase IIa and two phase IIb/III paediatric studies (N=382 for aPTT, N=343 for dTT, N=381 for ECT) were compared to data from adult patients with VTE (N=1881 for aPTT, N=702 for dTT, N=1179 for ECT), and healthy adult subjects (N=97); consent obtained, ethics committee approved. Separate PK/PD models were developed for each of the coagulation laboratory parameters, using non-linear mixed-effects modelling. Co-variates, such as sex and age, were assessed on baseline and drug-effect parameters, using a stepwise co-variate model-building procedure.

Results: Graphical explorations of observed data showed similar PK/PD relationships in children and adults for all three laboratory coagulation parameters. aPTT increased non-linearly with increasing plasma total dabigatran concentration (E_max [maximum effect] relationship). dTT and ECT increased linearly with increasing plasma total dabigatran concentration (Figure). On average, baseline ECT and aPTT was estimated slightly higher for children below approximately 5 months than for other children. Overall, model predictions showed similar PK/PD relationships in children and healthy adults for all three laboratory coagulation parameters across all paediatric age groups.

Conclusions: Population PK/PD models have been developed for aPTT, dTT and ECT in paediatric patients with VTE. PK/PD response of dTT and ECT was linear with less variability than aPTT. PK/PD relationships were similar in paediatric and adult patients with VTE, as well as in healthy adults.

[Figure: PK/PD relationships between dabigatran total plasma concentrations and aPTT, dTT and ECT.]

To cite this abstract in AMA style:

Mitchell L, Roeshammar D, Huang F, Albisetti M, Brandão L, Bomgaars L, Chalmers E, Halton J, Luciani M, Joseph D, Tartakovsky I, Gropper S, Reilly P, Brueckmann M, Stangier J, on Behalf of the Study Investigators . Pharmacokinetic-Pharmacodynamic Relationship between Dabigatran Plasma Concentrations and Coagulation Laboratory Parameters in Paediatric Patients with Venous Thromboembolism [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/pharmacokinetic-pharmacodynamic-relationship-between-dabigatran-plasma-concentrations-and-coagulation-laboratory-parameters-in-paediatric-patients-with-venous-thromboembolism/. Accessed October 1, 2023.

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