Fondaparinux for the Treatment of Thrombosis in Children: A Prospective, Dose-Finding, Pharmacodynamic and Safety Study.

Fondaparinux is a synthetic, antithrombin-dependent selective inhibitor of factor Xa currently licensed for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism in adults prior to conversion to warfarin. Fondaparinux is not approved for use in children in whom description of its use are limited to a few case reports. In comparison to low molecular weight heparin, fondaparinux has several properties which make it attractive for use in children for the treatment of DVT including a longer half-life potentially allowing once-daily dosing, lack of effects on bone metabolism, reduced risk of heparin-induced thrombocytopenia (HIT), and no risk of contamination from animal sources. With this in mind, we conducted a prospective study to determine the dosing, pharmacodynamics and safety of fondaparinux in children.

Children between 1 and 18 years of age with either an objectively confirmed DVT or pulmonary embolism or confirmed HIT were eligible to participate. Patients were excluded if they had evidence of a coagulation disorder, renal dysfunction or were pregnant. After obtaining consent, patients were enrolled and received fondaparinux 0.1 mg/kg up to a maximum of 7.5 mg once daily. Plasma fondaparinux levels determined via a fondaparinux-standard anti-factor Xa assay with results expressed in mg/L were measured immediately before and 2, 4, 12, and 24 hours after the first dose. Subsequently, peak levels were drawn at 4 hours twice weekly and following dose changes until either study drug discontinuation or hospital discharge. Blood counts, renal and liver function tests, and coagulation parameters (PT, PTT, fibrinogen) were monitored. The target peak (4 hour post dose) fondaparinux level was 0.5-1 mg/L. Patients whose levels were outside this range had doses adjusted by 10% or 25% depending on the level. If the level at 12 hours was below 0.2 mg/L, the dosing interval was changed to every 12 hours. Major and minor bleeding and adverse events were recorded per pre-defined criteria. A population pharmacokinetic model was developed from the data and simulations were performed to compare observed and predicted fondaparinux concentrations achieved in children to those typically observed in adults receiving treatment of DVT and PE.

A total of 24 patients from 3 age cohorts (1-5, 6-12, and 13-18 years) were enrolled with 10, 7, and 7 in each cohort, respectively. The average time on study drug was 5.8 days (range 2-19 days). Overall, 87.5% of patients achieved a therapeutic level following the first dose and no patients required twice daily dosing. Three patients (12.5%) required a dose adjustment (increased in 2 and decreased in 1). Pharmacokinetic modeling demonstrated that Cmax and Cmin concentrations at 0.1 mg/kg once-daily dosing were similar to those of previously studied adults. Two bleeding events occurred: 1) an intracranial hemorrhage which in retrospect likely occurred prior to study drug initiation (the patient had a history of hypertensive encephalopathy and a subacute parenchymal hemorrhage was noted on a follow up MRI performed 2 days after initiation of study drug), and 2) an episode of occult blood in the stool which led to temporary discontinuation of study drug (study drug was resumed after 2 days despite ongoing occult blood in the stool which subsequently resolved while still on study drug). No other adverse events were attributed to fondaparinux.

Fondaparinux at once daily dosing of 0.1 mg/kg administered to children with DVT or HIT reliably led to the targeted pharmacodynamic effect with minimal adverse events. These results support such initial dosing in carefully selected pediatric patients for whom fondaparinux may provide a net benefit over other anticoagulants. Future studies should further assess the efficacy of this agent in the management of pediatric venous thromboembolism.

Young:GlaxoSmithKline: Royalty Fee. Off Label Use: Fondaparinux is not approved for use in children and this is the subject of the abstract. Khanna:GlaxoSmithKline: Royalty fee.