Summary
Recombinant human factor VII a (rFVIIa) is an activated coagulation factor for intravenous
use as a haemostatic agent in haemophiliacs who generate antibodies against factor
VIII or IX. Plasma kinetic studies are important for the understanding of the action
of rFVIIa which is exerted in the vascular compartment of the body, more specifically
on the vessel walls at the site of injury. In the present study, rats were dosed 100
or 500 μg/kg 125I-rFVIIa i. V., without any side effects being observed, and the plasma profile of
rFVIIa was studied by 3 different assays that were shown to correlate well at early
times post-dose: trichloroacetic acid (TCA)-precipitable drug-related radioactivity,
rFVIIa antigen determination by ELISA technique, and the assay of clot activity which
is the only clinically applicable assay. The plasma concentration curve could be resolved
into 1-3 exponentials, depending on the FVIIa detection principle that was employed.
Initially, there was a short (ca. 10 min) phase of increasing concentrations before
the attainment of C
max. This was followed by a plasma recovery (C
max × plasma volume/dose) in the vicinity of one half of the administered dose. The initial
volume of distribution (V
1) corresponded to the vascular compartment whereas the volume of distribution at steady
state (V
ss) was somewhat larger. Whole body clearance (CL-B) of rFVIIa was approx. 1 ml/min
per kg, and mean residence time (MRT) and the half-life assumed to be associated with
the loss of biological activity was approx. 1 h and 20-45 min, respectively. From
these plasma data, rFVIIa appears to be a low clearance compound with limited tissue
distribution and a short half-life. Tissue distribution studies showed that high 125I levels, assumed to be rFVIIa-related, included mineralised bone and well-perfused
organs such as the liver which suggested that this organ was responsible for a major
proportion of CL-B. Finally, mass balance studies showed that almost 90% of the administered
radioactivity could be accounted for following an i. v. dose, predominantly as non
drug-related radioactivity, even though a small amount of TCA-precipitable radioactivity
was excreted via the biliary route. In conclusion, dose- or sex-dependent plasma kinetics
and tissue distribution within a dose range of 100 to 500 μg/kg of rFVIIa was not
observed. In the early and pharmacologically relevant phase after rFVIIa administration
there appears to be good agreement between the various plasma assays employed in the
study, indicating that the clot assay yields useful information in studies of rFVIIa
plasma pharmacokinetics.
