title: Pharmacokinetics and safety of FFR-rFVIIa after single doses in healthy subjects.
abstract: FFR-rFVIIa is an antithrombotic agent, which has also proven to have antirestenotic properties in animal models. FFR-rFVIIa is a modified recombinant FVIIa in which the catalytic site is irreversibly inactivated by a synthetic tripeptide covalently bound with the FVIIa molecule. The modified rFVIIa retains its tissue factor (TF) binding capacity but is otherwise enzymatically inactive. A double-blind, placebo-controlled, randomized dose escalation trial was conducted to investigate eight single i.v. doses of FFR-rFVIIa (0.01, 0.02, 0.05, 0.08, 0.12, 0.18, 0.27, or 0.40 mg/kg body weight) in healthy male volunteers (n = 62). Safety, pharmacokinetics, and pharmacodynamics of FFR-rFVIIa were assessed. Mean (SD)AUC0-infinity ranged from 0.35 (0.11) to 28.8 (3.5)microg.h/ml, and mean Cmax ranged from 0.078 (0.019) to 4.8 (0.7) microg/ml. The mean elimination half-life ranged from 3.8 to 5.8 hours. Mean AUC0-infinity increased with increasing dose levels. Cmax appeared to be proportional to the dose level, with the exception of the lowest dose level. A dose-dependent prolongation of the prothrombin time was found, demonstrating that FFR-rFVIIa inhibited coagulation via the TF-dependent pathway FFR-rFVIIa was generally well tolerated at all dose levels studied.
authors.affiliation: Novo Nordisk A/S, Clinical Development, Bagsvaerd, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Erhardtsen
authors.forename: P
authors.initials: P
authors.lastname: Nilsson
authors.forename: M
authors.initials: M
authors.lastname: Johannessen
authors.forename: M S
authors.initials: MS
authors.lastname: Thomsen
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D004311:Double-Blind Method; D015942:Factor VIIa / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic
chemical_list: D005343:Fibrinolytic Agents; C427263:phenylalanyl-phenylalanyl-arginyl-recombinant FVIIa; D015942:Factor VIIa