title: Pharmacokinetics of recombinant factor IX after intravenous and subcutaneous administration in dogs and cynomolgus monkeys.
abstract: 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.
authors.affiliation: Wyeth Research, Cambridge, MA 02140, USA.
authors.forename: K
authors.initials: K
authors.lastname: McCarthy
authors.forename: P
authors.initials: P
authors.lastname: Stewart
authors.forename: J
authors.initials: J
authors.lastname: Sigman
authors.forename: M
authors.initials: M
authors.lastname: Read
authors.forename: J C
authors.initials: JC
authors.lastname: Keith
authors.forename: K M
authors.initials: KM
authors.lastname: Brinkhous
authors.forename: T C
authors.initials: TC
authors.lastname: Nichols
authors.forename: R G
authors.initials: RG
authors.lastname: Schaub
mesh_terms: D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000188:drug therapy; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005164:Factor IX / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002836:Hemophilia B / Q000188:drug therapy / Q000662:veterinary; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013045:Species Specificity
chemical_list: D011994:Recombinant Proteins; D005164:Factor IX