TY - JOUR
T1 - Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by in Silico Simulations
AU - Bukkems, Laura H.
AU - Preijers, Tim
AU - van Spengler, Max W. F.
AU - Leebeek, Frank W. G.
AU - Cnossen, Marjon H.
AU - Mathôt, Ron A. A.
N1 - Funding Information: This study was investigator-initiated and was supported with a unrestricted research grant from Bayer (Mijdrecht, The Netherlands) and Swedish Orphan Biovitrum AB (SOBI, Stockholm, Sweden). Funding Information: F.W.G.L. reports grants from CSL Behring, Shire, uniQure; consultancy for uniQure, Shire, and Biomarin, for which fees go to the university; travel support from Sobi; and has served as a DSMB member for a study by Roche, outside the submitted work. M.H.C. has received grants from governmental research institutes such as Dutch Research Institute (NWO), ZonMW, and Innovation Fund, and unrestricted investigator initiated research grants as well as educational and travel funding from the following companies over the years: Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi, Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a member on steering boards of Roche and Bayer; all grants, awards, and fees go to the institution. R.A.A.M. reports grants from Bayer, grants from Shire, grants from Merck Sharpe Dome, grants from CSL Behring, other from Bayer, other from Publisher Copyright: © 2021 Georg Thieme Verlag. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Background The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. Methods FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). Results Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. Conclusion BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.
AB - Background The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. Methods FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). Results Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. Conclusion BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.
KW - factor VIII
KW - half-life
KW - hemophilia A
UR - http://www.scopus.com/inward/record.url?scp=85100491087&partnerID=8YFLogxK
U2 - https://doi.org/10.1055/s-0040-1721484
DO - https://doi.org/10.1055/s-0040-1721484
M3 - Article
C2 - 33506481
SN - 0340-6245
VL - 121
SP - 731
EP - 740
JO - Thrombosis and haemostasis
JF - Thrombosis and haemostasis
IS - 6
ER -