1. 25 UI/kg of BDD-rFVIII injected
Pharmacokinetics of the reformulated B-domain deleted recombinant factor VIII
(BDD-rFVIII) concentrate using chromogenic and one-stage assays
with Pooled Normal Plasma (PNP) and ReFacto Laboratory Standard (RLS).
Santoro C,° Mazzucconi MG°, Pignoloni P,° Rago A,° Biondo F,° Iorio A,* Ferrante F,* Agnelli G,* Foà R.°
° Haematology, Department of Cellular Biotechnology ed Haematology, University “La Sapienza” Roma
* Internal and Vascular Medicine, University of Perugia
Background and aim of the study
The use of RLS in one stage clotting assay was proposed to reduce underestimation of F VIII plasma concentration measurement after infusion of BDD-rFVIII in hemophilia A patients.
Both BBD-rFVIII and RLS were recently reformulated.
Aim of this study was to evaluate the performance of reformulated RLS in the measurement of F VIII plasma concentration after infusion of reformulated BDD-rFVIII.
Patients and methods
13 hemophilia A patients
FVIII < 1%,
inhibitor <0.6 UB/mL,
age > 12 years,
not on antiretroviral therapy for HIV
25 UI/kg of BDD-rFVIII injected
intravenously.
Time points of blood samples collection:
0.25, 0.5, 1, 3, 6, 9, 24, 28 and 32 h
after the end of infusion
One-stage clotting assay was performed using a FVIII immune depleted plasma.
The Electrachrome Factor VIII Chromogenic Assay was performed according to manufacturer.
The reference calibration curves were built using PNP or RLS from Wyeth Pharma gmbh.
Pharmacokinetic analysis was performed using a model-independent method fitted with WinNonlin (Pharsight, Inc).
Comparisons among assays and standards were performed using an ANOVA model for repeated measures
Results
Chromogenic Assay
One stage assay
Refacto ST
Plasma ST
Mean SD p r2
0.98
0.99
0.97
Cmax (U/mL)
0.63
0.14
0.09
0.60
0.13
0.58 ns
Tmax (minutes) 17 5 18 6 15
Half_life (hours)
9.4
3.8
7.7
4.3
10.4
2.8
13.0
4.7
<.05
AUC inf
431.0
148.0
469.0
166.0
468.0
161.0
575.0
147.0
Conclusions
We confirm previous results about a better sensitivity of the one stage method for the lowest concentrations of F VIII, with a more accurate evaluation of terminal half life.
Measured Cmax is slightly superior to expected values and independent from the assay used.
The clinical utility of RLS in the evaluation of FVIII concentration after infusion of BDD-rFVIII seems to be lower after reformulation of the product.
References
Morfini M, Cinotti S et al. A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standards.
J Thromb Haemost Nov;1(11):2283-9
Kessler CM, Gill JC et al. B-domain deleted recombinant factor VIII preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor VIII
concentrate: a randomized, three-way crossover study. Haemophilia Mar;11(2):84-91.
Shapiro AD, Korth Bradley J, Poon MC. Use of pharmacokinetics in the coagulation factor treatment of patients with haemophilia. Haemophilia Nov;11(6): Review.