Abstract 18482: Pharmacokinetics and Pharmacodynamics of Dabigatran Etexilate in Adolescents: An Open-label Phase IIa Study
Introduction: Dabigatran etexilate (DE) is an oral direct thrombin inhibitor. It is approved for multiple indications in adults.
HYPOTHESIS: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in adolescents with venous thromboembolism (VTE).
METHODS: Patients aged 12-< 18 years, who had completed anticoagulation treatment with low molecular weight heparin or an oral anticoagulant for VTE as required for clinical management, received DE twice daily for 3 days at exploratory doses targeting 1.71 mg/kg for the first dose, followed by 5 doses of 2.14 mg/kg, if there were no safety concerns. Blood samples for PK/PD purposes were taken at peak (2 h after morning dose) and trough (12 h after the evening dose). Observed plasma concentrations of total dabigatran were compared to simulated concentrations based on a population-pharmacokinetic (PopPK) model. The PK/PD relationships between total dabigatran plasma concentrations and activated partial thromboplastin (aPTT), diluted thrombin time (dTT), or ecarin clotting time (ECT) were assessed.
RESULTS: Nine patients entered the study. 94% of total dabigatran trough concentrations were within the 80% prediction interval. The relationship between total dabigatran plasma concentration and dTT or ECT was linear; the relationship with aPTT was non-linear. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent non-serious AEs, all gastrointestinal-related, occurred in two patients (gastro-esophageal reflux and abdominal pain in one patient and abdominal discomfort in the other patient).
CONCLUSIONS: We report on the first study in a pediatric patient population receiving DE. DE was well tolerated. PK/PD relationships were similar to the PK/PD relationships seen in adults. PopPK modelling techniques described the observed data well and may help in refining doses for the pediatric VTE patient population by adjusting for maturation of renal function.
Author Disclosures: M.T. Lobmeyer: Employment; Significant; Boehringer Ingelheim Pharma GmbH & Co. KG. T. Lehr: None. J.M. Halton: None. L. Cronin: Employment; Significant; Boehringer Ingelheim (Canada) Ltd/Lte. S. Haertter: Employment; Significant; Boehringer Ingelheim Pharma GmbH & Co. KG. L. Mitchell: Consultant/Advisory Board; Modest; Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer.
- © 2014 by American Heart Association, Inc.