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Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico SimulationsFunding 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).
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.
L.H.B., T.P., and M.W.F.S. performed the pharmacokinetic analyses. L.H.B. wrote the manuscript. R.A.A.M. and M.H.C. supervised the study, while F.W.G.L. gave critical guidance. All authors contributed substantially to the critical revision of the manuscript and approved the final draft of the manuscript.
* Both are last authors.
Received: 04 September 2020
Accepted: 27 October 2020
27 January 2021 (online)
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