title: Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study.
abstract: 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 dose-normalised 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.
authors.affiliation: Jacqueline Halton, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada, Tel.: +1 613 737 7600, Fax: +1 613 738 4828, E-mail: halton@cheo.on.ca.
authors.forename: Jacqueline M L
authors.initials: JM
authors.lastname: Halton
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.forename: Lisa
authors.initials: L
authors.lastname: Cronin
authors.forename: Maximilian T
authors.initials: MT
authors.lastname: Lobmeyer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haertter
authors.forename: Mark
authors.initials: M
authors.lastname: Belletrutti
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Mitchell
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000991:Antithrombins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069604:Dabigatran / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004415:Dyspepsia / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D054556:Venous Thromboembolism / Q000097:blood / Q000188:drug therapy*
chemical_list: D000991:Antithrombins; D011355:Prodrugs; D000069604:Dabigatran
keywords: Adolescent; anticoagulants; dabigatran; direct thrombin inhibitors; venous thromboembolism