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

Tiede, A; Friedrich, Ute; Stenmo, C; Allen, G; Giangrande, P; Goudemand, J; Hay, C; Holmström, Eva M LU ; Klamroth, R and Lethagen, Stefan LU , et al. (2011) In Journal of Thrombosis and Haemostasis 9. p.1191-1199
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... (More)
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. (Less)
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published
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Journal of Thrombosis and Haemostasis
volume
9
pages
1191 - 1199
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000291315600014
  • pmid:21489128
  • scopus:79958065035
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2011.04293.x
language
English
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yes
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f357245d-851c-48de-889d-4aaaac51efa8 (old id 1937152)
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http://www.ncbi.nlm.nih.gov/pubmed/21489128?dopt=Abstract
date added to LUP
2011-05-02 14:13:27
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2017-01-01 07:33:44
@article{f357245d-851c-48de-889d-4aaaac51efa8,
  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) :&lt;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.},
  author       = {Tiede, A and Friedrich, Ute and Stenmo, C and Allen, G and Giangrande, P and Goudemand, J and Hay, C and Holmström, Eva M and Klamroth, R and Lethagen, Stefan and McKenzie, S and Miesbach, W and Negrier, C and Yuste, V J and Berntorp, Erik},
  issn         = {1538-7933},
  language     = {eng},
  pages        = {1191--1199},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa).},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2011.04293.x},
  volume       = {9},
  year         = {2011},
}