Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven^®) in children vs. adults with haemophilia A

Abstract

To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A. Twelve children (2-12 years) received one single dose of rFVIIa 90 and 180 micrograms kg(-1) in randomized order separated by a washout period of 48 h to 1 month. Six adults (18-55 years) received a single dose of rFVIIa 90 micrograms kg(-1). The pharmacokinetic analyses were based on a non-compartmental method. In children, the plasma level of FVII increased proportionally with the dose. The total body clearance normalized for body weight was significantly faster in children than in adults (FVII:C, 58 vs. 39 mL kg(-1) h(-1) and FVIIa, 78 vs. 53 mL kg(-1) h(-1), P < 0.05). A trend towards a larger volume of distribution at steady-state in children than in adults was observed (P > 0.05). Dose proportionality was established for plasma concentrations of FVII in children with haemophilia A at the dose levels investigated (90 and 180 micrograms kg(-1) rFVIIa). Following administration of rFVIIa 90 micrograms kg(-1), significantly faster clearance was observed in children compared with adults, suggesting that higher doses of rFVIIa may be needed to achieve the same plasma levels as in adults.

A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

“…This linear PK profile enables accurate prediction of plasma ACE910 concentration according to dose. Notably, the mean half-life of ACE910 ranged between 28.3 and 34.4 days, dramatically longer than current drugs (FVIII agents: 8-12 hours 1 ; rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [TG-based half-life] 13 ) and drugs recently approved or under development (#19 hours). 5,[21][22][23][24] Concizumab is a humanized anti-tissue factor pathway inhibitor antibody and is also subcutaneously available in humans.…”

“…1 Patients who develop FVIII inhibitors are treated with bypassing agents, including recombinant activated factor VII (rFVIIa) 7 or activated prothrombin complex concentrate (aPCC). 8 Frequent intravenous administration of these agents is required because of their unstable hemostatic efficacy caused by short half-lives (rFVIIa: 2.3-6.0 hours [9][10][11][12] ; aPCC: 4-7 hours [thrombin generation (TG)-based half-life] 13 ). New treatments with more convenient administration routes, lower administration frequency, and less immunogenicity against coagulation factors are needed.…”

Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality

“…These levels are similar to the peak therapeutic levels seen in patients infused with recombinant FVIIa (10-20 nM; ref. 13). Moreover, these mice exhibited a normal lifespan through the 16-month study duration, similar to AAV-treated mice (Table 2), and at necropsy showed no unusual pathology.…”

Recombinant activated factor seven in acute life-threatening bleeding in neonates: report on three cases and review of literature

“…Elimination half-life in adults is about 3 h. The pharmacokinetics of rFVIIa has been investigated in older children with hemophilia. 15 In children (3 to 12 years), clearance of rFVIIa was significantly faster than in the adult population. Following the administration of 90 mg/kg, the clearance of FVIIa was 78 ml/kg/h in the pediatric population and 53 ml/kg/h in the adult population.…”