Objective:
The present study has been conducted to explore the biodistribution of rIX-FP, a recombinant fusion protein linking the human coagulation factor IX to human albumin (CSL Behring GmbH), which is currently being investigated in clinical phase II/III trials (PROLONG- 9FP) for prophylaxis and on-demand treatment of bleeding in hemophilia B patients.
Methods:
Therefore, [3H]-rIX-FP, [3H]-rFIX, or [3H]-albumin were administered intravenously to male rats at a single radioactive dose of 320-420 μCi/kg. Using whole-body autoradiography, tissue radioactivity was determined up to 240 and 24 h following [3H]-rIX-FP and [3H]-albumin, and [3H]-rFIX administration, respectively. In addition to full body sections, the hind limbs were analyzed separately and plasma, urine, and feces were collected to calculate excretion balance and assess physiological elimination pathways.
Summary:
Overall, the tissue distribution of [3H]-rIX-FP and [3H]-rFIX was comparable; both penetrated predominantly into well-perfused tissues, were rapidly present in synovial and mineralized regions of knee joint sections, and seemed to mostly localize to the zone of calcified cartilage within the growth plate regions of long bones, with the longest retention time observed in the bone marrow and endosteum of long bones. Intriguingly, [3H]-rIX-FP signal was detectable over 72 h, whereas comparable [3H]-rFIX signal could only be detected until 24 h post-dosing. Elimination occurred primarily via the urinary route. For [3H]-rIX-FP, after 240 h, 73% of radioactivity was recovered in urine, ≤5% of radioactivity was eliminated in feces, and approximately 20% of radioactivity was present in tissues.
Conclusions:
The study shows that rIX-FP exhibits equal biodistribution compared to other marketed recombinant FIX products, but clearly distinguishes itself from rFIX (BeneFIX®) by its extended plasma half-life, allowing a reduction in dosing frequency leading to increased therapeutic convenience and compliance.