Premium
Pharmacokinetics and pharmacodynamics of a new recombinant FVIII (N8) in haemophilia A mice
Author(s) -
ELM T.,
KARPF D. M.,
ØVLISEN K.,
PELZER H.,
EZBAN M.,
KJALKE M.,
TRANHOLM M.
Publication year - 2012
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/j.1365-2516.2011.02608.x
Subject(s) - pharmacodynamics , pharmacokinetics , medicine , haemophilia , potency , haemophilia a , pharmacology , surgery , biology , biochemistry , in vitro
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 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.