title: Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs.
abstract: N8, a new recombinant factor VIII (rFVIII) compound developed for the treatment of haemophilia A, is produced in Chinese hamster ovary (CHO) cells and formulated without human- or animal-derived materials. The aim of the present study was to compare the pharmacokinetics (PK) and the procoagulant effect, measured by ex vivo whole blood clot formation, of N8 and a commercial rFVIII in a cross-over study in haemophilia A dogs. N8 and Advate® (100 IU kg⁻¹) were administered intravenously to three haemophilia A dogs. Blood was sampled between 0 and 120 h postdose and FVIII:C analysed. PK parameters maximum plasma concentration, area under the curve, half-life (t(½)), clearance, mean residence time (MRT) and volume of distribution and incremental recovery were calculated. Whole blood clotting time (WBCT) and thromboelastography (TEG®) were used to determine the haemostatic potential. No adverse reactions were observed with N8 or Advate ®. N8 and Advate® exhibited similar PK parameters, with t(½) 7.7-11 h and MRT 11-14 h. Both rFVIII compounds corrected the prolonged WBCT (> 48 min) to the range of normal dogs (8-12 min), i.e. N8 to 7.5-10.5 min and Advate® to 7.5-11.5 min. N8 and Advate® also normalized the whole blood clot formation according to TEG®. The native whole blood clotting assays (WBCT, TEG®) appeared to be more sensitive to low concentrations of FVIII than assays in citrated plasma samples. In conclusion, comparison of N8 and Advate ® in haemophilia A dogs revealed similar safety, similar PK and similar effects in whole blood clot formation assays.
authors.affiliation: Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: D M
authors.initials: DM
authors.lastname: Karpf
authors.forename: M
authors.initials: M
authors.lastname: Kjalke
authors.forename: L
authors.initials: L
authors.lastname: Thim
authors.forename: H
authors.initials: H
authors.lastname: Agersø
authors.forename: E P
authors.initials: EP
authors.lastname: Merricks
authors.forename: N
authors.initials: N
authors.lastname: Defriess
authors.forename: T C
authors.initials: TC
authors.lastname: Nichols
authors.forename: M
authors.initials: M
authors.lastname: Ezban
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D018592:Cross-Over Studies; D004283:Dog Diseases / Q000097:blood / Q000188:drug therapy; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005169:Factor VIII / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000662:veterinary; D006487:Hemostasis / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D011994:Recombinant Proteins / Q000493:pharmacokinetics*
chemical_list: D011994:Recombinant Proteins; D005169:Factor VIII