Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of a Single-Dose Oral Solution of Dabigatran Given after Standard Anticoagulant Therapy in Children (Two Age Groups: 1-<2 and 2-<12 Years Old), with Venous Thromboembolism
Authors: Halton Jacqueline ML , Albisetti Manuela , Luciani Matteo , Huang Fenglei , Biss Branislav , Brueckmann Martina , Gropper Savion , Maas Hugo , Tartakovsky Igor , Mitchell Lesley G 
Published: October 2019

Abstract
Background:
The incidence of venous thromboembolism (VTE) in children is increasing. The current standard of care is unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and Vitamin K antagonists (VKAs), all of which have limitations. Dabigatran, which is orally administered as the prodrug, dabigatran etexilate (DE), is effective for the treatment of VTE in adults and may overcome some of the limitations associated with standard care.
Objective:
The objectives of this phase IIa study were to obtain pharmacokinetic (PK) and pharmacodynamic (PD) data and to evaluate the tolerability and safety of an oral liquid formulation (OLF) of DE in patients aged 1 to < 12 years.
Methods:
The open-label, multinational, multicenter, non-randomized, single-arm study was conducted in patients aged 1 to < 2 years and 2 to < 12 years with a diagnosis of VTE, who had completed planned treatment with LMWH or oral anticoagulants (VKAs) for VTE.
DE was administered as an OLF at a weight and age-adjusted dose (calculated using a nomogram) equivalent to 150 mg twice daily (bid) in adults. Originally, all patients were to receive multiple dosing (bid for 3 days). However, this was replaced with single dosing (SD) in the course of the study. A 30-day follow-up was included. Here we report data from SD patients only.
The primary PK endpoints were plasma concentration of total dabigatran, free dabigatran, unchanged DE and intermediate metabolites. To compare the exposure to DE in pediatrics with that in adults with VTE, gMean concentrations at 10 hours after SD of DE were extrapolated to steady-state trough concentration. An accumulation ratio was calculated based on the terminal half-life (t1/2) and the dosing interval (for a bid dosing regimen) to project the steady-state dabigatran plasma concentration. Primary PD endpoints were activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). Primary safety endpoints were incidence of all bleeding events and incidence of all adverse events (AEs).
Results:
Six patients aged 1 to < 2 years and 9 patients aged 2 to < 12 years received SD DE; 3 patients aged 2 to < 12 received multiple doses (bid for 3 days).
In the SD groups, plasma concentration of total dabigatran increased at 2 hours (peak) after dosing then decreased until 10 hours after dosing. The projected steady-state dabigatran trough concentrations of both age groups of children studied were largely comparable to those observed in adults with VTE, i.e. the projected results for children fell between the first and the third quartile of adult trough concentrations (Table).
Data from the SD groups indicated that there was a linear PK/PD relationship for ECT and dTT (see Figure) and a non-linear PK/PD relationship for aPTT. The PK/PD relationships were similar to those seen in adults (for all coagulation parameters analyzed) and adolescents (dTT and ECT) with VTE.
During the on-treatment period there were no study drug related AEs; one patient had AEs (leukopenia and dizziness), which were mild in intensity and unrelated to the study drug. No AEs were reported during the post-treatment or post-study periods. No bleeding events were reported.
Conclusion:
The OLF of DE was well tolerated in pediatrics, with no drug-related AEs or bleeding events. Projected steady-state dabigatran trough concentrations were largely comparable to those seen in adults with VTE. The observed PK/PD relationship was similar to that seen in adults and adolescents with VTE.

Disclosures
Halton: Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Luciani:Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Huang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Maas:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy.