Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII
(2018) In Haemophilia 24(3). p.376-384- 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.
(Less)
- author
- 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
- organization
- publishing date
- 2018-05-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Administration and dosage, Factor VIII, Haemophilia A, Half-life, Pharmacokinetics, Quality of life
- in
- Haemophilia
- volume
- 24
- issue
- 3
- pages
- 376 - 384
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:85046414048
- pmid:29732708
- 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
- 2024-05-27 11:42:11
@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 >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.</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}},
keywords = {{Administration and dosage; Factor VIII; Haemophilia A; Half-life; Pharmacokinetics; Quality of life}},
language = {{eng}},
month = {{05}},
number = {{3}},
pages = {{376--384}},
publisher = {{Wiley-Blackwell}},
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}},
doi = {{10.1111/hae.13483}},
volume = {{24}},
year = {{2018}},
}