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Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII

Hermans, C.; Mahlangu, J.; Booth, J.; Schütz, H.; Santagostino, E.; Young, G.; Lee, H. Y.; Steinitz-Trost, K. N.; Blanchette, V. and Berntorp, E. LU (2018) In Haemophilia
Abstract

Introduction: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. Aim: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. Methods: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels... (More)

Introduction: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. Aim: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. Methods: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. Results: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. Conclusion: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Administration and dosage, Factor VIII, Haemophilia A, Half-life, Pharmacokinetics, Quality of life
in
Haemophilia
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • scopus:85046414048
ISSN
1351-8216
DOI
10.1111/hae.13483
language
English
LU publication?
yes
id
8ca510fc-df01-4837-8446-a452899be009
date added to LUP
2018-05-17 14:09:41
date last changed
2018-10-03 10:20:42
@article{8ca510fc-df01-4837-8446-a452899be009,
  abstract     = {<p>Introduction: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. Aim: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. Methods: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always &gt;1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII &gt;1 IU/dL equalled that of the benchmark regimen. Results: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always &gt;1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels &gt;1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII &gt;1 IU/dL. Conclusion: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.</p>},
  author       = {Hermans, C. and Mahlangu, J. and Booth, J. and Schütz, H. and Santagostino, E. and Young, G. and Lee, H. Y. and Steinitz-Trost, K. N. and Blanchette, V. and Berntorp, E.},
  issn         = {1351-8216},
  keyword      = {Administration and dosage,Factor VIII,Haemophilia A,Half-life,Pharmacokinetics,Quality of life},
  language     = {eng},
  month        = {05},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Haemophilia},
  title        = {Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII},
  url          = {http://dx.doi.org/10.1111/hae.13483},
  year         = {2018},
}