Overview of the human pharmacokinetics of recombinant activated factor VII

Abstract

Aims: To review the pharmacokinetics of rFVIIa in various patient populations, and to discuss the differences observed between groups.

Methods: Based on a registry of Novo Nordisk studies, 14 studies evaluating rFVIIa pharmacokinetics following single and multiple bolus administration in healthy volunteers, adult and paediatric patients with congenital haemophilia and inhibitors, patients undergoing liver surgery and in patients with cirrhosis, inherited FVII deficiency, upper gastrointestinal bleeding or severe trauma were identified. Data on rFVIIa PK, analyzed with noncompartmental and population pharmacokinetic methods, were extracted.

Results: Plasma clearance was a more robust parameter than half-life for comparing rFVIIa pharmacokinetics between groups. In healthy volunteers and patients with no or low-level bleeding (e.g. adults with haemophilia, nonbleeding patients with cirrhosis), plasma clearance was relatively low (30-40 ml kg(-1) h(-1)). In children with haemophilia and adults with high-level bleeding (e.g. cirrhotic patients undergoing orthotopic liver transplantation or resection) and patients with congenital FVII deficiency, plasma clearance was relatively higher (60-90 ml kg(-1) h(-1)).

Conclusions: Comparison of plasma clearance rates in different patient populations suggested that subjects fall into two distinct groups. These differences may have clinical implications in terms of how to adapt the rFVIIa dosing regimen, depending on the expected bleeding rate/blood loss and underlying disease.

Figures

Figure 1

Population pharmacokinetic profiles of rFVIIa for patients with haemophilia A vs. time, following 90 μg kg−1 (adults and children) and 180 μg kg−1 (children only) rFVIIa. Based on PopPK analysis of (A) FVIIa clot activity and (B) FVII:C activity in Villar et al.[15]. Adults 90 μg kg−1, (—); Children 90 μg kg−1, (––); Children 180 μg kg−1, (- - - -)

Figure 2

Individual estimates of clearance (CL) vs. weight for adult and paediatric patients with haemophilia, based on PopPK analysis of data from Villar et al.[15]. Estimated linear relationship between CL and weight based on FVIIa clot activity assay (full line, open circles) and FVII:C activity assay (dashed line, filled circles). Based on FVIIa, (○—); Based on FVII:C, (• - - - -)

Figure 3

Population pharmacokinetic profiles of rFVIIa during phases with and without liver circulation, for patients undergoing orthotopic liver transplantation, following a single dose of 80 μg kg−1 rFVIIa. Analysis of data from Planinsic et al.[17]. (Erichsen, Klitgaard, data on file 2004) No liver circulation, (—); Liver circulation, (––)

Figure 4

Population pharmacokinetic profiles of rFVIIa after administration of three doses (200, 100 and 100 μg/kg) at 0, 1 and 3 h, simulated for various postdose RBC transfusion requirements. Based on PopPK analysis of data in trauma patients [23]. Figure adapted from [23] by kind permission of BioMed Central. RBC = 8.7 units (mean), (); RBC = 20 units, (······); RBC = 30 units, (––); RBC = 40 units, (- - - -)