Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents

Abstract

SummaryVenous 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).