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Thromb Haemost 2016; 116(03): 461-471
DOI: 10.1160/TH15-04-0275
Coagulation and Fibrinolysis
Schattauer GmbH

Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents

An open-label phase IIa study
Jacqueline M. L. Halton
1   Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
,
Thorsten Lehr
2   Saarland University, Saarbrucken, Germany
,
Lisa Cronin
3   Clinical Development, Boehringer Ingelheim Ltd, Canada
,
Maximilian T. Lobmeyer
4   Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
,
Sebastian Haertter
4   Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
,
Mark Belletrutti
5   Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada
,
Lesley G. Mitchell
5   Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada
6   University of Alberta, Edmonton, Alberta, Canada
› Author Affiliations Financial support: This study was funded by Boehringer Ingelheim.
Further Information

Publication History

Received: 01 April 2015

Accepted after major revision: 17 May 2016

Publication Date:
29 November 2017 (online)

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Summary

Venous thromboembolism (VTE) incidence is increasing among children owing to many factors, including improved diagnosis of VTE. There is a need for alternative treatment options. Our objective was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate in adolescents with VTE. Adolescents aged 12 to <18 years (n = 9) who successfully completed planned treatment for primary VTE were administered dabigatran etexilate twice daily for three days; initially 1.71 (± 10%) mg/kg (80% of a 150 mg/70 kg twice daily adult dose), followed by 2.14 (± 10%) mg/kg (target adult dose adjusted for patient’s weight), if there were no safety concerns. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent AEs, all gastrointestinal-related, occurred in two patients. In these adolescent patients with normal renal function, presumed steady-state trough plasma concentrations of dabigatran were low (geometric mean dosenormalised total dabigatran plasma concentration: 0.493 ng/ml/mg at 72 hours). Total dabigatran concentrations were well predicted by the RE-LY® population PK model (94% of trough concentrations were within the 80% prediction interval). The relationship between total dabigatran plasma concentration, diluted thrombin time and ecarin clotting time (ECT) was linear; the relationship with activated partial thromboplastin time (aPTT) was non-linear. Adult population PK/PD models predicted the adolescent concentration–ECT and –aPTT relationships well. In conclusion, dabigatran etexilate was generally well tolerated, except for occurrence of dyspepsia in two patients, over the three-day treatment period. The dabigatran PK/PD relationship observed in adolescent patients was similar to that in adult patients.

Institution where work was performed: Main clinical study site: Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

This study is registered at ClinicalTrials.gov (NCT00844415).

Keywords

Adolescent - anticoagulants - dabigatran - direct thrombin inhibitors - venous thromboembolism
 

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