Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients.
OBJECTIVE
The objective of the present study was to evaluate the pharmacokinetics and the clearance pathways of rFVIIa after intravenous administration to hemophilia patients.


METHODS
Ten severe hemophilia patients were included in the study; all patients were intravenously administered a clinically relevant dose of 90 μg kg(-1) (1.8 nmol kg(-1)) rFVIIa. Blood samples were collected consecutively to describe the pharmacokinetics of rFVIIa. All samples were analyzed using three different assays: a clot assay to measure the activity (FVIIa:C), an enzyme immunoassay (EIA) to measure the antigen levels (FVII:Ag), and an EIA (FVIIa-AT) to measure the FVIIa antithrombin III (AT) complex. Pharmacokinetic parameters were evaluated both by use of standard non-compartmental methods and by use of mixed effects methods. A population pharmacokinetic model was used to simultaneously model all three datasets. The total body clearance of rFVIIa:C was estimated to be 38 mL h(-1) kg(-1). The rFVII-AT complex formation was responsible for 65% of the total rFVIIa:C clearance. The initial and the terminal half-life of rFVIIa:C was estimated to be 0.6 and 2.6 h, respectively. The formation of rFVII-AT complex was able to explain the difference observed between the rFVIIa:C and the rFVII:Ag concentration. The non-compartmental analysis resulted in almost identical parameters.
Pharmacology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark. hkag@novonordisk.com
H
H
Agersø
D F
DF
Brophy
H
H
Pelzer
E J
EJ
Martin
M
M
Carr
U
U
Hedner
M
M
Ezban
D000941:Antigens / Q000097:blood; D000991:Antithrombins / Q000008:administration & dosage* / Q000627:therapeutic use; D015942:Factor VIIa / Q000276:immunology / Q000493:pharmacokinetics*; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D007124:Immunoenzyme Techniques; D007262:Infusions, Intravenous; D011994:Recombinant Proteins / Q000493:pharmacokinetics
D000941:Antigens; D000991:Antithrombins; D011994:Recombinant Proteins; D015942:Factor VIIa