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Thromb Haemost 2002; 87(05): 824-830
DOI: 10.1055/s-0037-1613091
Review Article
Schattauer GmbH

Pharmacokinetics of Recombinant Factor IX after Intravenous and Subcutaneous Administration in Dogs and Cynomolgus Monkeys

K. McCarthy
1   Wyeth Research, Cambridge MA
,
P. Stewart
2   University of North Carolina at Chapel Hill, School of Medicine Department of Pathology and Laboratory Medicine, NC, USA
,
J. Sigman
2   University of North Carolina at Chapel Hill, School of Medicine Department of Pathology and Laboratory Medicine, NC, USA
,
M. Read
2   University of North Carolina at Chapel Hill, School of Medicine Department of Pathology and Laboratory Medicine, NC, USA
,
J. C. Keith Jr.
1   Wyeth Research, Cambridge MA
,
K. M. Brinkhous
2   University of North Carolina at Chapel Hill, School of Medicine Department of Pathology and Laboratory Medicine, NC, USA
,
T. C. Nichols
2   University of North Carolina at Chapel Hill, School of Medicine Department of Pathology and Laboratory Medicine, NC, USA
,
R. G. Schaub
1   Wyeth Research, Cambridge MA
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Publikationsverlauf

Received 08. September 2001

Accepted after revision 28. Januar 2002

Publikationsdatum:
11. Dezember 2017 (online)

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Summary

Hemophilia B therapy requires intravenous (IV) infusions of large volumes of factor IX due to the low concentration of factor IX in concentrates (∼100 IU/mL). High concentration recombinant factor IX (rFIX) could be a significant advance since it would reduce the large volumes necessary for IV dosing and allow for low-volume subcutaneous (SC) administration. To evaluate high concentration factor IX, we produced formulations with either 2,000 or 4,000 IU/mL and studied the SC bioavailability in beagle dogs, cynomolgus monkeys and hemophilia B dogs along with efficacy in hemophilia B dogs. Beagle dog SC bioavailability was 86.4% using a 2000 IU/mL formulation and 77.0% using a 4000 IU/mL formulation. Monkey bioavailability of a 4000 IU/mL formulation of rFIX was 34.8%. A single SC administration of 200 IU/kg (4000 IU/mL) of rFIX to hemophilia B dogs, produced factor IX clotting activity above 5% for 5 days with a bioavailability of 48.6%. High concentration SC rFIX has an acceptable pharmacokinetic profile in monkeys and dogs, and produces a sustained FIX activity in hemophilic dogs.

Keywords

Factor IX - hemophilia B - subcutaneous - dogs - cynomolgus monkeys
 

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