Pharmacokinetics of recombinant factor IX after intravenous and subcutaneous administration in dogs and cynomolgus monkeys.
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.
McCarthy
K
K
Wyeth Research, Cambridge, MA 02140, USA.
Stewart
P
P
Sigman
J
J
Read
M
M
Keith
J C
JC
Brinkhous
K M
KM
Nichols
T C
TC
Schaub
R G
RG
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
D011994:Recombinant Proteins; D005164:Factor IX