Pharmacokinetics (Pk) And Pharmacodynamics (Pd), Safety And Tolerability Of A Single-Dose Oral Solution Of Dabigatran Etexilate Given After Standard Anticoagulant Therapy In Children From Birth To Less Than One Year Old, With Venous Thromboembolism

Background : Venous thromboembolism (VTE) events are more frequent in neonates than in children of other age groups. The standard of care for pediatric anticoagulation includes unfractionated or low-molecular-weight heparin, or vitamin K antagonists. However, these treatments have limitations in terms of practicality of use in infants, such as parenteral administration, frequent monitoring and drug interactions. Alternative oral agents that address these shortcomings may improve compliance, efficacy and safety. The safety and efficacy of dabigatran etexilate (DE), a direct thrombin inhibitor, are established in adults; pharmacokinetic/pharmacodynamic (PK/PD) studies indicate linear PK. There is a relationship between dabigatran plasma concentration (PK) and its PD effects, resulting in reproducible dose-dependent prolongation in clotting times with rapid onset and offset of effect, which is consistent across populations. Although phase IIa studies suggest a similar PK/PD relationship of dabigatran in children and adults, the hemostatic system in infants differs from older children and adults, which may lead to a different PK/PD effect. Objective : To demonstrate comparable PK/PD relationship of DE oral liquid formulation (OLF) between infants and older children and adults, and to assess safety and tolerability. Methods : Open-label, multicenter, single-dose, single-arm, phase IIa pediatric study. Infants aged max model to confirm whether models used in previous studies were consistent with the pediatric data of this study. Results: Ten patients were screened and 8 entered the study (mean age [SD]: 89 [52] days; range: 41-169 days). Patients received a single dose of DE OLF. The geometric mean (gMean) total dabigatran plasma concentrations 2 hrs post dose (around peak concentrations) was 120 ng/mL with geometric coefficient of variation (gCV) of 62.1%, which indicated moderate variability. The gMean at 12 hrs post dosing was 60.4 ng/mL (gCV 30%), which indicated low variability. The projected steady-state dabigatran trough concentrations were largely comparable to those observed in adults with VTE (Table). A linear PK/PD relationship was observed for ECT (ECT ratio) and dTT (dTT ratio) (Figure). The relationship between total dabigatran concentration and aPTT (aPTT ratio) was nonlinear. The observed PK/PD relationships were similar to those in adult and adolescent patients with VTE, except for patients aged Conclusion : In this small population of infants (aged Disclosures Halton: Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim. Picard: Boehringer Ingelheim: Employment. Harper: Boehringer Ingelheim: Employment. Huang: Boehringer Ingelheim: Employment. Brueckmann: Boehringer Ingelheim: Employment. Gropper: Boehringer Ingelheim: Employment. Maas: Boehringer Ingelheim: Employment. Tartakovsky: Boehringer Ingelheim: Employment. Nurmeev: Boehringer Ingelheim: Other: Investigator fees. Mitchell: Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Albisetti: Boehringer Ingelheim: Other: Pediatric Expert Working Group.