Summary
Current therapy for hemophilia B requires large intravenous doses of factor 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 extravascular routes for administering proteins like F.IX (57 kD) or
other vitamin K-dependent procoagulant factors into the circulation. Questions about
the absorption rate from extravascular administration as well as plasma recovery and
bioavailability have arisen recently with the growing availibility of highly purified
procoagulant proteins and increased interest in gene therapy of hemophilia B. Therefore,
a group of studies were undertaken to determine the absorption rate, plasma recovery,
and bioavailability of high purity, human plasma-derived F.IX concentrates 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), intra- peritoneal (IP) or intravenous (IV) route. In a subsequent study, a single
SC administration of human F.IX was compared to an identical IV dose 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 resulted in measurable F.IX activity. Of the extravascular routes,
the IM injection in the canine resulted in a bioavailibility of 82.8%, while the SC
injection resulted in a bioavailability of 63.5%. F.IX reached the plasma compartment
by all extravascular routes used, confirming that F.IX can be absorbed extravascularly.
The duration of measurable F.IX activity following extravascular administration is
prolonged beyond that typically seen with IV administration. These data show that
significant levels of F.IX may be obtained via SC injection in canine and ‘ human
hemophilia B subjects and further highlight the potential of extravascular routes
of administration for future experimental and clinical uses of F.IX and other procoagulant
proteins.
