EXTRAVASCULAR ADMINISTRATION OF FACTOR-IX - POTENTIAL FOR REPLACEMENTTHERAPY OF CANINE AND HUMAN HEMOPHILIA-B

Current therapy for hemophilia B requires large intravenous doses of f actor IX (F.IX) given in the clinic or at home. Although home therapy is possible for many patients, it is often complicated by factors such as the lack of good venous access. Very little is known about extrava scular routes for administering proteins like F.IX (57 kD) or other vi tamin K-dependent procoagulant factors into the circulation. Questions about the absorption rate from extravascular administration as well a s plasma recovery and bioavailability have arisen recently with the gr owing availibility of highly purified procoagulant proteins and increa sed interest in gene therapy of hemophilia B. Therefore, a group of st udies were undertaken to determine the absorption rate, plasma recover y, and bioavailability of high purity, human plasma-derived F.IX conce ntrates administered via extravascular routes in hemophilia B dogs and in one human hemophilia B subject. Five hemophilia B dogs were given human F.IX via either a subcutaneous (SC), intramuscular (IM), intrape ritoneal (IF) or intravenous (IV) route. In a subsequent study, a sing le SC administration of human F.IX was compared to an identical IV dos e of F.IX in the human hemophilia B subject. All extravascular routes of F.IX administration in both the canine and human gave lower levels of circulating plasma F.IX than the IV route, however all routes resul ted in measurable F.IX activity. Of the extravascular routes, the IM i njection in the canine resulted in a bioavailibility of 82.8%, while t he SC injection resulted in a bioavailability of 63.5%. F.IX reached t he plasma compartment by all extravascular routes used, confirming tha t F.IX can be absorbed extravascularly. The duration of measurable F.I X activity following extravascular administration is prolonged beyond that typically seen with IV administration. These data show that signi ficant levels of F.IX may be obtained via SC injection in canine and h uman hemophilia B subjects and further highlight the potential of extr avascular routes of administration for future experimental and clinica l uses of F.IX and other procoagulant proteins.