Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa).

Research output: Contribution to journalArticle

Abstract

Background: Recombinant 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. Objectives: A study was conducted to determine the safety of subcutaneously administered rFVIIa in patients with hemophilia and the pharmacokinetic profile (including bioavailability). Patients/Methods: This was a multi-center, open-label, cross-over comparison of single doses of intravenous rFVIIa 90 μg/kg and a new formulation of rFVIIa for subcutaneous injection at dose levels of 45, 90, 180, 270 and 360 μg/kg. 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) :0.44-5.16 IU/mL [across doses], t(1/2) :12.4 hours, t(max) :5.6 hours) compared with intravenously administered rFVIIa (C(max) :51.7 IU/mL, t(1/2) :2.7 hours, t(max) :<10 minutes). The absolute bioavailability of subcutaneous rFVIIa ranged from 21.1%-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. Conclusion: This phase I clinical trial did not identify safety concerns of prolonged exposure to rFVIIa administered subcutaneously in single doses to hemophilia patients.

Details

Authors
  • A Tiede
  • Ute Friedrich
  • C Stenmo
  • G Allen
  • P Giangrande
  • J Goudemand
  • C Hay
  • Eva M Holmström
  • R Klamroth
  • Stefan Lethagen
  • S McKenzie
  • W Miesbach
  • C Negrier
  • V J Yuste
  • Erik Berntorp
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems
Original languageEnglish
Pages (from-to)1191-1199
JournalJournal of Thrombosis and Haemostasis
Volume9
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Clinical Coagulation Research Unit (013242510), Emergency medicine/Medicine/Surgery (013240200), Division of Microbiology, Immunology and Glycobiology - MIG (013025200)