title: Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa).
abstract: BACKGROUND
  Recombinant activated factor VIIa (rFVIIa) is used to treat bleeds in hemophilia patients with inhibitors. A subcutaneous formulation could potentially improve its half-life and make it suitable for prophylactic treatment.
  
  
  OBJECTIVE
  A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability).
  
  
  METHODS
  This was a multicenter, open-label, cross-over comparison of single doses of intravenous rFVIIa 90μgkg(-1) and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360μgkg(-1) . Sixty subjects (12 per dose cohort) with hemophilia A or B were enrolled.
  
  
  RESULTS
  Subcutaneously administered rFVIIa showed lower mean peak plasma concentrations and prolonged FVII activity (C(max) , 0.44-5.16IU mL(-1) [across doses]; t(1/2) , 12.4h; t(max) , 5.6h) compared with intravenously administered rFVIIa (C(max) , 51.7IUmL(-1) ; t(1/2) , 2.7h; t(max) , <10min). The absolute bioavailability of subcutaneous rFVIIa ranged from 21.1 to 30.1% across dose levels. Dose proportionality was observed within a 2-fold dose increase but not across the full dose range. No thromboembolic events, drug-related serious adverse events, severe injection-site reactions or neutralizing antibodies were reported (primary endpoint). Mild and moderate injection-site reactions were more frequent with subcutaneous than with intravenous injections.
  
  
  CONCLUSIONS
  This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.
authors.affiliation: Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Tiede
authors.forename: U
authors.initials: U
authors.lastname: Friedrich
authors.forename: C
authors.initials: C
authors.lastname: Stenmo
authors.forename: G
authors.initials: G
authors.lastname: Allen
authors.forename: P
authors.initials: P
authors.lastname: Giangrande
authors.forename: J
authors.initials: J
authors.lastname: Goudemand
authors.forename: C
authors.initials: C
authors.lastname: Hay
authors.forename: M
authors.initials: M
authors.lastname: Holmström
authors.forename: R
authors.initials: R
authors.lastname: Klamroth
authors.forename: S
authors.initials: S
authors.lastname: Lethagen
authors.forename: S
authors.initials: S
authors.lastname: McKenzie
authors.forename: W
authors.initials: W
authors.lastname: Miesbach
authors.forename: C
authors.initials: C
authors.lastname: Negrier
authors.forename: V J
authors.initials: VJ
authors.lastname: Yuste
authors.forename: E
authors.initials: E
authors.lastname: Berntorp
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D002648:Child; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D015942:Factor VIIa / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006467:Hemophilia A / Q000188:drug therapy*; D002836:Hemophilia B / Q000188:drug therapy*; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D010599:Pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa