Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency

Abstract

Background and objectives: Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleedings occurring in hemophiliacs with inhibitors. Very few reports exist on the use of rFVIIa in patients with inherited FVII deficiency. Pharmacokinetic studies on rFVIIa have been performed exclusively in hemophiliacs, patients with cirrhosis or volunteers pretreated with acenocoumarol. The aim of this study was to evaluate the kinetics of rFVIIa in patients naturally deficient of FVII.

Design and methods: A single dose kinetic study with rFVIIa was performed in 5 patients affected by severe congenital deficiency of factor VII in order to evaluate the true kinetic parameters of rFVIIa without the interference of FVII. Two dosages, 15 and 30 microg/kg, were used in a crossover schedule. FVII:C and FVIIa concentration/time curves were analyzed by a model-independent method. Antithrombin (AT), prothombin fragment 1+2 (F1+2) and tissue factor pathway inhibitor (TFPI) were assayed.

Results: No differences emerged between the dosages with respect to dose-independent parameters [total body clearance (CL), volume of distribution area (VdArea), mean residence time (MRT)]. No significant changes of AT, TFPI, and F1+2 were observed. Comparing the results with those of other studies performed in adult hemophiliacs, in patients affected by cirrhosis or in volunteers on oral anticoagulant therapy (OAT), CL and VdArea of rFVIIa were definitely higher and in vivo recovery was lower.

Interpretation and conclusions: These findings suggest that the kinetics of rFVIIa are not dose-dependent. In the absence of FVII, the changes of VdArea and CL may be in agreement with a mechanism of competition between FVII and rFVIIa for tissue factor binding.