Pharmacology Journal

Recombinant activated factor VII (rFVIIa, NovoSeven®; Novo Nordisk A/S, Bagsværd, Denmark) is established for the treatment of bleeding episodes and for the prevention of bleeding during surgery or invasive procedures in patients with congenital haemophilia A and B with inhibitors to coagulation factors VIII (FVIII) or IX (FIX) or in those expected to have a high anamnestic response to FVIII or FIX, acquired haemophilia, congenital FVII deficiency or Glanzmann’s thrombasthenia refractory to platelet transfusions.

In addition to these indications, the therapeutic potential of rFVIIa has been explored for a number of critical bleeding situations. For example, rFVIIa successfully reversed coagulopathy in 75% (61/81) of patients with bleeding and coagulopathy resulting from a number of different causes, including acute traumatic haemorrhage and traumatic brain injury. In a multicentre, random ized, controlled Phase II trial, rFVIIa reduced red blood cell (RBC) transfusion requirements and the need for massive transfusion vs. placebo in patients with severe blunt trauma and a confirmatory Phase III trial evaluating rFVIIa for the treatment of traumatic haemorrhage is ongoing. In addition rFVIIa has been shown to reduce haematoma growth in intracerebral haemorrhage, although this reduction did not translate into improved long-term clinical outcome. A number of clinical guidelines on rFVIIa use in nonhaemophilia indications has been published.

At pharmacological doses, rFVIIa binds to the surface of locally activated platelets following vascular injury, directly activating factor X, and thereby enhancing localized thrombin generation and formation of a stable fibrin clot only at the site of vascular injury. Although not the focus of this paper, pharmacokinetics are relevant for an understanding of drug safety and the incidence of drug related adverse events. In addition, by improving the understanding of drug distribution and elimination processes of rFVIIa, pharmacokinetics may offer insight into the design of optimal therapeutic regimens for this unique agent, particularly in cases of severe or poorly characterized bleeding. This paper aims to address this by reviewing pharmacokinetic data from clinical studies of rFVIIa following single and multiple i.v. bolus administration. The findings and their relevance to the therapeutic use of rFVIIa are discussed.

Several studies have examined the pharmacokinetics of rFVIIa in healthy adult volunteers. The most recent showed that healthy Japanese and Caucasian volunteers had comparable estimates of plasma clearance (33–37 ml kg−1 h−1), terminal half-life (3.90–05.99 h−1) and steady-state volume of distribution (130–165 ml kg−1). No sex-related differences in these parameters were observed. These results are consistent with those in healthy Caucasian volunteers who were anticoagulated with acenocoumarol to international normalized ratio 2–2.5 prior to dosing. Analysis using a two-compartment model provided estimates of half-life, clearance and steady-state volume of distribution for doses above and below 20 μg kg−1. Clearance rates of 31–35 ml kg−1 h−1 were reported, which were comparable with those observed in the study by Fridberg et al.

Correlation between pharmacokinetic parameters and bleeding
Examination of plasma clearance values from studies of rFVIIa across a range of indications, from healthy volunteers to patients with severe trauma, suggests the existence of two distinct populations. In healthy volunteers, plasma clearance values were approximately 30–40 ml kg−1 h−1. Plasma clearance values for adult patients with haemophilia, who typically are classified as having no bleeding or only low-level bleeding, and for nonbleeding patients with cirrhosis are also within this ‘normal’ range. Clearance of rFVIIa appears to be unaffected by dose in the range of 20–320 μg kg−1.
In contrast, patients with liver disease and active, high levels of bleeding (e.g. cirrhotic patients undergoing OLT and noncirrhotic patients undergoing major liver resection) have much higher plasma clearance rates of between 60 and 90 ml kg−1 h−1. This is approximately twice that seen in patients with low-level bleeding or healthy volunteers. Moreover, in the OLT group, plasma clearance increased significantly after transplantation and during liver reperfusion, a finding which supports the hypothesis that the liver is the principal site of rFVIIa metabolism. The finding of an association between increased RBC transfusion requirement and increased clearance in trauma patients provides further evidence to support the link between bleeding levels (as estimated from RBC transfusion requirements) and plasma clearance values.
The relationship between RBC requirements and clearance may well be multifactorial. In patients with massive bleeding, the combination of coagulation factor consumption due to continued clot formation, loss due to ongoing bleeding, and dilution due to fluid and blood component therapy may reduce the rFVIIa concentration to a potentially suboptimal level for effective clot formation.

Furthermore, underlying liver disease seen in some of these patients is likely to reduce the endogenous production of a number of key coagulation factors, including FVII, and may be associated with both thrombocytopenia and platelet dysfunction. It could be hypothesized that reduced production of coagulation factors and functional platelets may lead to ineffective or reduced coagulation. However, the overall impact this may have on rFVIIa clearance in the liver-diseased patient remains speculative.

Three other patient groups also had increased clearance rates relative to normal levels, namely, patients with congenital FVII deficiency, paediatric patients with haemophilia, and patients with UGIB and cirrhosis.
In patients with congenital FVII deficiency, increased clearance rates of rFVIIa may be linked to the absence of endogenous production of functional FVII/FVIIa. In haemophilia A patients, following administration of rFVIIa 90 μg 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 concentrations as in adults. Finally, in patients with cirrhosis and UGIB, clearance was increased, although bleeding and RBC transfusion requirements during the period of pharmacokinetic sampling were relatively small (average RBC requirement during first 24 h: 0.9 ± 1.8 units). At present it is not clear why the rFVIIa metabolism appears to be altered in these patients.

It appears from these studies that plasma clearance may provide more useful information than half-life for assessing the behaviour of rFVIIa following dosing. Half-life estimates are often only based on a few terminal timepoints, and short sampling profiles may bias half-life estimates downwards, as a pure elimination phase towards the end of the pharmacokinetic profile will not have been recorded. In addition, mean plasma half-life estimates may be affected by the modelling approach used to fit the available data. In contrast, plasma clearance is more robust as a parameter for comparing rFVIIa pharmacokinetics between patient groups.

In conclusion, this overview has demonstrated that human subjects may be stratified into two distinct groups in terms of rFVIIa pharmacokinetics. In one, comprising healthy volunteers, adult patients with haemophilia and nonbleeding patients with cirrhosis, plasma clearance is relatively low (30–40 ml kg−1 h−1). In the other, comprising children with haemophilia, patients with congenital FVII deficiency and patients with active, high levels of bleeding, plasma clearance appears to be higher (60–90 ml kg−1 h−1). Differences in rFVIIa pharmacokinetics among patient groups may have clinical implications in terms of how to adapt the dosing regimen, depending on the expected bleeding rate/blood loss and the underlying disease.

Filed under: Pharmacology Review Articles