Pharmacokinetics of recombinant factor IX after intravenous and subcutaneous administration in dogs and cynomolgus monkeys

• Published in: Thrombosis and haemostasis Vol. 87; no. 5; p. 824
• Main Authors: McCarthy, K, Stewart, P, Sigman, J, Read, M, Keith, Jr, J C, Brinkhous, K M, Nichols, T C, Schaub, R G
• Format: Journal Article
• Language: English
• Published: Germany 01-05-2002
• Subjects: Animals; Biological Availability; Disease Models, Animal; Dog Diseases - drug therapy; Dogs; Enzyme-Linked Immunosorbent Assay; Factor IX - administration & dosage; Factor IX - pharmacokinetics; Factor IX - therapeutic use; Hemophilia B - drug therapy; Hemophilia B - veterinary; Injections, Subcutaneous; Macaca fascicularis; Male; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Species Specificity
• ISSN: 0340-6245
• DOI: 10.1055/s-0037-1613091

Hemophilia B therapy requires intravenous (IV) infusions of large volumes of factor IX due to the low concentration of factor IX in concentrates (approximately 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.