Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability

Abstract

Tartakovsky I, Mitchell LG. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability.J Thromb Haemost 2017; 15: 2147-57. EssentialsDabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic-pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. Summary. Background:The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives: To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods: Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results: Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion: The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

Role of direct oral anticoagulants in patients with kidney disease

“…However, phase 2 pediatric trials of rivaroxaban and dabigatran were recently published and phase 3 trials (clinicaltrial.gov identifiers: NCT02234843 and NCT01895777, respectively) are nearing completion. 140,141 Thus, these agents may soon be available for pediatric use. Anticoagulant dosing in children is complex because of age-related hemostasis system maturation as well as pharmacokinetic differences compared to adults.…”

Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials

“…The three paediatric trials were: study 1160.88 (NCT00844415; patients aged 12 to < 18 years), study 1160.89 (NCT01083732; patients aged 1 to < 12 years) and study 1160.105 (NCT02223260; patients aged < 1 year), details of which have previously been reported. 20 21 22 Study 1160.88 was a phase IIa, open-label, multi-centre, single-arm trial to evaluate the safety and tolerability and assess preliminary pharmacokinetic (PK) and PD parameters of dabigatran in adolescent patients, aged between 12 and < 18 years. After successfully completing treatment with LMWH or oral anticoagulation for primary VTE, patients received weight-adjusted doses of DE administered as capsules twice daily for 3 days.…”

“…However, this was replaced with a single age- and weight-adjusted dose during the course of the study. 21 Study 1160.105 was a phase IIa, open-label, multi-centre, single-arm trial to assess the PK/PD relationship, safety and tolerability of DE in infants aged < 1 year, who had completed standard anticoagulant treatment for VTE. Infants received a single age- and weight-adjusted dose of DE, administered as an oral liquid formulation.…”

Perioperative management of antithrombotic treatment in children

“…There have been no completed randomized controls trials as yet using DOACS to treat VTE or for thromboprophylaxis although several phase III trials are underway for rivaroxaban (EINSTEIN Junior) dabigatran and apixaban . A phase II study of dabigatran in 18 children aged 2‐12 years old has shown that the pharmacokinetics are like that of adults with no significant bleeding or recurrent VTE . Similar trials of rivaroxaban and apixaban have yet to report.…”

“…9 A phase II study of dabigatran in 18 children aged 2-12 years old has shown that the pharmacokinetics are like that of adults with no significant bleeding or recurrent VTE. 16 Similar trials of rivaroxaban and apixaban have yet to report. There are pharmacokinetic studies for rivaroxaban and apixaban that have been described in the neonatal and pediatric populations which have been compared to adults showing similar anti-Xa effects in all age groups.…”