Pharmacokinetics and pharmacodynamics of a new recombinant FVIII (N8) in haemophilia A mice

Summary.  N8 is a new recombinant factor VIII (rFVIII) compound produced and formulated without human- or animal-derived protein. The aims of the present studies were to evaluate the pharmacokinetics and pharmacodynamics properties of N8 and to compare with a commercially available rFVIII product (Advate®) in haemophilia A mice. The pharmacokinetics were evaluated after single i.v. administration of 80, 120 and 280 IU kg−1 of N8 and Advate® and measurements of FVIII blood concentrations as a function of time. The efficacy and dose response curves of N8 and Advate® (1–200 IU kg−1) were evaluated in a tail bleeding model. Furthermore, the effects in a newly developed haemophilia knee joint haemarthrosis model were investigated. No significant differences were found in the pharmacokinetic parameters between N8 and Advate®. The clearances were 11 ± 1 vs. 10 ± 2 mL h−1 kg−1 (P = 0.14) and the half-lives 7.2 ± 0.9 vs. 7.7 ± 1.4 h (P = 0.31) after administration of N8 and Advate® respectively. Dose-independent pharmacokinetics was shown, and comparable efficacy and potency were shown between N8 and Advate® in the tail bleeding model. Both compounds normalized the bleeding at the dose of 200 IU kg−1, and for blood loss ED50 values of 27 IU kg−1 (N8) and 28 IU/kg (Advate®) were found (P = 0.97). In the haemarthrosis model, treatment with N8 and Advate® at 200 IU kg−1 reduced the mean increase in the joint diameter significantly from 1.23 ± 0.19 to 0.32 ± 0.08 mm (P < 0.01) and 0.25 ± 0.08 mm (P < 0.001) respectively. Pharmacokinetics and pharmacodynamics of N8 and Advate® were comparable after i.v. administration to haemophilia A mice.