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Recombinant human factor IX: replacement therapy, prophylaxis, and
pharmacokinetics in canine hemophilia B
KM Brinkhous, JL Sigman, MS Read, PF Stewart, KP McCarthy, GA Timony, SD Leppanen, BJ Rup, JC Keith , PD Garzone and RG Schaub
Department of Pathology, University of North Carolina at Chapel Hill
27599-7525, USA.
Recombinant human factor IX (rFIX) has been expressed in transduced
cultured cell systems since 1985. Because there has been limited in vivo
testing of rFIX in hemophilia B subjects, this study was undertaken using
the severe hemophilia B canines of the Chapel Hill strain. Three groups of
hemophilic dogs received either 50, 100, or 200 IU/kg of rFIX. As a
control, a fourth group of hemophilic dogs received 50 IU/kg of a high
purity, plasma-derived human FIX (pdFIX). The coagulant and hemostatic
effects of rFIX and pdFIX were similar with all comparative dosing
regimens. Based on activity data, the elimination half-life of rFIX was
18.9 +/- 2.3 hours and pdFIX was 17.9 +/- 2.1 hours. A prophylactic regimen
administering rFIX daily resulted in a continuous therapeutic level of
plasma FIX and was accompanied by a two-fold increase in recovery levels by
day 5, compared to that observed with administration of a single bolus. The
mechanisms of the high to complete recovery of FIX with the prophylactic
regimen could depend not only on the degree of saturation of the vascular
endothelial binding sites but also on the altered dynamics of the balance
of FIX distribution between the intravascular and extravascular
compartments. The pharmacokinetic (PK) parameters for rFIX and pdFIX were
similar. However, the relative PK values for V1 and V5s of both products on
day 5 differed greatly from day 1 and may reflect the changing equilibrium
of FIX between compartments with elevated levels of plasma FIX.
Neutralizing antihuman FIX antibodies resulting from human FIX antigen
being administered to FIX deficient dogs were observed beginning at 14
days. The antigenicity of rFIX and pdFIX appeared to be comparable. Despite
the very different procedures used for production of rFIX and pdFIX
products, in vivo testing in hemophilia B dogs showed the functional
behavior of these products is similar; they are highly effective for
replacement therapy and for prophylaxis.
Volume 88,
Issue 7,
pp. 2603-2610,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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