scholarly journals Pharmacokinetic Study of Recombinant Human Factor IX in Previously Treated Patients with Hemophilia B in Taiwan

2007 ◽  
Vol 106 (4) ◽  
pp. 281-287 ◽  
Author(s):  
Hsiu-Hao Chang ◽  
Yung-Li Yang ◽  
Mei-Hua Hung ◽  
Woei Tsay ◽  
Ming-Ching Shen
Keyword(s):  
Pharmacokinetic Study ◽  
Human Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Human Factor Ix ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Recombinant Human Factor Ix

Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4393-4398 ◽  
Author(s):  
Karen E. Russell ◽  
Eva H. N. Olsen ◽  
Robin A. Raymer ◽  
Elizabeth P. Merricks ◽  
Dwight A. Bellinger ◽  
...  
Keyword(s):  
Human Factor ◽  
Subcutaneous Administration ◽  
Chronic Administration ◽  
Factor Ix ◽  
Hemophilia B ◽  
Enzyme Linked Immunosorbent Assay ◽  
Bleeding Events ◽  
Human Factor Ix ◽  
Immune Tolerant ◽  
Recombinant Human Factor Ix

AbstractIntravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P < .001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P = .0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B. (Blood. 2003;102:4393-4398)

Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3600-3606 ◽  
Author(s):  
David A. Roth ◽  
Craig M. Kessler ◽  
K. John Pasi ◽  
Bonita Rup ◽  
Suzanne G. Courter ◽  
...  
Keyword(s):  
Virus Transmission ◽  
Factor Ix ◽  
Hemophilia B ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Serious Adverse Events ◽  
Safety And Efficacy ◽  
Human Factor Ix ◽  
Previously Treated ◽  
Recombinant Human Factor Ix

Abstract Human plasma–derived factor IX (pdFIX) concentrates are routinely used to treat patients with hemophilia B, an X-linked bleeding disorder that affects 1 in 30 000 males, but concerns remain regarding transmission of blood-borne pathogens. Therefore, the safety and efficacy of recombinant human factor IX (rFIX) were evaluated. A 20-center international trial was conducted in previously treated patients with severe or moderate (< 5 IU/dL factor IX activity) hemophilia B. Participants received rFIX for pharmacokinetic studies, treatment of or prophylaxis against hemorrhage, or surgical hemostasis, and were assessed at 3-month intervals for 2 years. Fifty-six subjects were treated. Mean incremental rFIX recovery was 0.75 IU/dL per IU/kg, 30% lower than expected for pdFIX, although the mean half-life was similar. Pharmacokinetic parameters were stable over time. Somewhat lower recoveries were seen in subjects younger than 15 years of age and in those with no detectable factor IX antigen. A total of 7362 infusions of rFIX were administered. All 1796 hemorrhages were controlled, 80.9% of which required only one rFIX infusion. Effective hemostasis was also achieved in prophylactic and surgical settings. One individual developed a low titer (1.2 Bethesda unit) transient inhibitor that spontaneously resolved. rFIX was not associated with serious adverse events, thrombogenicity, or virus transmission. rFIX is safe and effective for the treatment of hemophilia B. Despite a lower recovery compared with pdFIX, rFIX controlled hemorrhage in a wide variety of settings and may provide a safety advantage in terms of risk from blood-borne pathogens.

scholarly journals Recombinant human factor IX: replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2603-2610 ◽  
Author(s):  
KM Brinkhous ◽  
JL Sigman ◽  
MS Read ◽  
PF Stewart ◽  
KP McCarthy ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Human Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Degree Of Saturation ◽  
Prophylactic Regimen ◽  
Human Factor Ix ◽  
In Vivo Testing ◽  
Recombinant Human Factor Ix

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.

scholarly journals Production of human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B

Blood ◽  
1989 ◽  
Vol 73 (2) ◽  
pp. 438-445
Author(s):  
TD Palmer ◽  
AR Thompson ◽  
AD Miller
Keyword(s):  
Human Factor ◽  
Normal Skin ◽  
Human Fibroblasts ◽  
Retroviral Vectors ◽  
Factor Ix ◽  
Skin Fibroblasts ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Human Factor Ix

Inherited diseases might be treated by introducing normal genes into a patient's somatic tissues to correct the genetic defects. In the case of hemophilia resulting from a missing clotting factor, the required gene could be introduced into any cell as long as active factor reached the circulation. We previously showed that retroviral vectors can efficiently transfer genes into normal skin fibroblasts and that the infected cells can produce high levels of a therapeutic product in vitro. In the current study, we examined the ability of skin fibroblasts to secrete active clotting factor after infection with different retroviral vectors encoding human clotting factor IX. Normal human fibroblasts infected with one vector secreted greater than 3 micrograms factor IX/10(6) cells/24 h. Of this protein, greater than 70% was structurally and functionally indistinguishable from human factor IX derived from normal plasma. This suggests that infected autologous fibroblasts might provide therapeutic levels of factor IX if transplanted into patients suffering from hemophilia B. By transplanting normal diploid fibroblasts infected with the factor IX vectors, we showed that human factor IX can be produced and is circulated at readily detectable levels in rats and mice.

scholarly journals Development of Monospecific Antibodies to Human Factor IX

1977 ◽  
Author(s):  
Cheryl Y. Tiarks ◽  
Chin-Hai Chang ◽  
Liberto Pechet
Keyword(s):  
Neutralizing Antibodies ◽  
Human Factor ◽  
Human Albumin ◽  
Factor Ix ◽  
Hemophilia B ◽  
Red Cross ◽  
Factor X ◽  
Normal Plasma ◽  
Human Factor Ix ◽  
Monospecific Antibodies

The purpose of this research was to develop neutralizing and precipitating antibodies to factor IX. Human factor IX, purified by the method of Rosenberg et.al. (J. Biol. Chem. 250:8883, 1975), was electrophoresed on acrylamide gel. Two major bands migrating adjacently were eluted. They contained factor IX activity only. The eluates and their homogenized gel segments 7 and 8 were injected separately into two rabbits, Rl and R2, respectively. On immunodiffusion the antiserum Rl showed one precipitating line with normal plasma. It neutralized human factor IX (20 Bethesda units) and also slightly neutralized factor X. It had no effect on factors II and VII. Following absorption of this antiserum with purified factor X it neutralized factor IX only. With continuous immunization, however, this antiserum revealed two new precipitating contaminants. The antiserum R2 neutralized only factor IX; it reached 220 Bethesda inhibitory units. On immunodiffusion it showed two precipitating lines, one of which disappeared after absorption with human albumin. On immunodiffusion and Laurell immunoelectrophoresis, the albumin-absorbed R2 antiserum showed one precipitin line of identity, or one rocket, with normal plasma, a Red Cross factor IX preparation (rich in factors IX, II and X), the original eluates 7 and 8, and a Hemophilia-B antigen-positive plasma. No line or rocket developed with normal plasma absorbed with aluminum hydroxide or with antigen-negative Hemophilia-B plasma. We conclude that the antisera Rl and R2 contain factor IX neutralizing antibodies and that albumin-absorbed R2 has monospecific precipitating antibodies to human non-activated factor IX.

scholarly journals Permanent partial phenotypic correction and tolerance in a mouse model of hemophilia B by stem cell gene delivery of human factor IX

Gene Therapy ◽  
2005 ◽  
Vol 13 (2) ◽  
pp. 117-126 ◽  
Author(s):  
B W Bigger ◽  
E K Siapati ◽  
A Mistry ◽  
S N Waddington ◽  
M S Nivsarkar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Delivery ◽  
Mouse Model ◽  
Human Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Human Factor Ix ◽  
Cell Gene ◽  
Stem Cell Gene

scholarly journals Use of a BamHI polymorphism in the factor IX gene for the determination of hemophilia B carrier status

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1508-1511 ◽  
Author(s):  
CW Hay ◽  
KA Robertson ◽  
SL Yong ◽  
AR Thompson ◽  
GH Growe ◽  
...  
Keyword(s):  
Human Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Carrier Status ◽  
X Chromosomes ◽  
Human Factor Ix ◽  
History Of

Abstract A BamHI polymorphism has been identified in the human factor IX gene. This polymorphism, which occurs in approximately 6% of X chromosomes, has been used to determine the carrier status of a female in a family with a history of hemophilia B. This family was uninformative for the previously reported TaqI and Xmnl polymorphisms in the factor IX gene.

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