title: Prolonged effect of GlycoPEGylated rFVIIa (40k-PEG-rFVIIa) in rabbits correlates to activity in plasma.
abstract: The pharmacokinetics and pharmacodynamics of 40k-PEG-rFVIIa, a GlycoPEGylated derivative of recombinant wild-type FVIIa, were compared with rFVIIa in rabbits. The procoagulant effect was determined as the weight of the clot formed in a defined segment of a facial vein. A time course study was conducted where ligation was made 10 minutes, 12 or 24 hours after i.v. injection of equimolar doses of 40k-PEG-FVIIa or rFVIIa (2 mg/kg). This dose was selected based on a dose response study and a duration of effect study with rFVIIa. The clot weight increased with increasing doses of rFVIIa, and the duration of effect correlated with the plasma FVIIa clot activity. The plasma half-life of 40k-PEG-rFVIIa measured as FVIIa clot activity was found to be 25 hours, which was 5-6 times longer than rFVIIa. The aPTT and PT were reduced, and the measured increase in thrombin-antithrombin correlated to the effect on clot formation. Thus, the effect was similar at ligation 10 minutes after administration of 40k-PEG-rFVIIa or rFVIIa. At 12 hours, the effect of rFVIIa was absent while significant effect was seen 12 and 24 hours post dosing with 40k-PEG-rFVIIa. No consumption of platelets or fibrinogen was found and no thrombi formation was seen in histological examination of various organs. In conclusion, 40k-PEG-rFVIIa has shown prolonged duration of effect that correlated to various plasma markers and FVIIa clot activity. In perspective, the data support further clinical development of 40k-PEG-rFVIIa to potentially become a long-acting recombinant treatment option for prophylaxis in haemophilia patients with inhibitors.
authors.affiliation: Haemostasis Pharmacology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark. pjoh@novonordisk.com
authors.forename: Peter B
authors.initials: PB
authors.lastname: Johansen
authors.forename: Søren E
authors.initials: SE
authors.lastname: Bjørn
authors.forename: Henrik
authors.initials: H
authors.lastname: Agersø
authors.forename: Inger
authors.initials: I
authors.lastname: Thorup
authors.forename: Mette B
authors.initials: MB
authors.lastname: Hermit
authors.forename: Brit
authors.initials: B
authors.lastname: Sørensen
authors.forename: Henning R
authors.initials: HR
authors.lastname: Stennicke
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
authors.forename: Mikael
authors.initials: M
authors.lastname: Tranholm
mesh_terms: D000818:Animals; D001778:Blood Coagulation Disorders; D001798:Blood Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D003029:Coagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006031:Glycosylation; D006801:Humans; D023421:Models, Animal; D011092:Polyethylene Glycols / Q000737:chemistry*; D054070:Postthrombotic Syndrome / Q000188:drug therapy*; D055550:Protein Stability / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001798:Blood Proteins; D003029:Coagulants; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C103587:recombinant FVIIa; D015942:Factor VIIa