Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Paediatric Patients: Combined Data from Five Paediatric Clinical Trials

Background:

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

Aims:

This study characterized the relationships between dabigatran plasma concentration and coagulation laboratory parameters measured by central lab: activated partial thromboplastin time [aPTT], diluted thrombin time [dTT], and ecarin clotting time [ECT]) in the pediatric VTE patient population, including a comparison with adults.

Methods:

Pediatric data from three phase IIa and two phase IIb/III pediatric studies (N = 382 for aPTT, N = 343 for dTT, N = 381 for ECT) were compared with 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 models were developed for each of the coagulation laboratory parameters, using nonlinear mixed-effects modelling. Covariates, such as sex and age, were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure.

Results:

Graphical explorations of observed data showed similar relationships in children and adults between dabigatran concentration and all three laboratory coagulation parameters. The aPTT increased nonlinearly with increasing plasma total dabigatran concentration (E_max [maximum effect] relationship). The dTT and ECT increased linearly with increasing plasma total dabigatran concentration (Figure). On average, the baseline for ECT and aPTT was estimated to be slightly higher for children below approximately 6 months than for other children. Overall, model predictions showed similar relationships in children and healthy adults between dabigatran concentration and all three laboratory coagulation parameters across all pediatric age groups. ECT or dTT performed better than aPTT.

Conclusions:

Population models have been developed for aPTT, dTT, and ECT in pediatric patients with VTE. Relationships between dabigatran concentration and the three laboratory coagulation parameters evaluated were similar in pediatric and adult patients with VTE, as well as in healthy adults. Despite developmental hemostasis differences, relationships between dabigatran concentrations and the three laboratory coagulation parameters evaluated were similar in pediatric and adult patients with VTE, as well as in healthy adults.