title: Pharmacokinetics and pharmacodynamics of a new recombinant FVIII (N8) in haemophilia A mice.
abstract: 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 ED(50) 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.
authors.affiliation: Biopharmaceutical Research Unit, Maaloev, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Elm
authors.forename: D M
authors.initials: DM
authors.lastname: Karpf
authors.forename: K
authors.initials: K
authors.lastname: Øvlisen
authors.forename: H
authors.initials: H
authors.lastname: Pelzer
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: M
authors.initials: M
authors.lastname: Kjalke
authors.forename: M
authors.initials: M
authors.lastname: Tranholm
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006395:Hemarthrosis / Q000188:drug therapy / Q000378:metabolism; D006467:Hemophilia A / Q000188:drug therapy* / Q000378:metabolism; D006470:Hemorrhage / Q000188:drug therapy; D007719:Knee Joint; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D005169:Factor VIII