title: Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog.
abstract: Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg(-1) to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half-life (FVIIa activity: 1.2-1.8 h; FVIIa antigen 2.8-3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin-activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans.
authors.affiliation: Department of Small Animal Clinical Sciences, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Knudsen
authors.forename: A T
authors.initials: AT
authors.lastname: Kristensen
authors.forename: T C
authors.initials: TC
authors.lastname: Nichols
authors.forename: H
authors.initials: H
authors.lastname: Agersø
authors.forename: A L
authors.initials: AL
authors.lastname: Jensen
authors.forename: M
authors.initials: M
authors.lastname: Kjalke
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: M
authors.initials: M
authors.lastname: Tranholm
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D015942:Factor VIIa / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006467:Hemophilia A / Q000188:drug therapy* / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D010865:Pilot Projects; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics; D013916:Thrombelastography
chemical_list: D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa