Objective:
The recombinant fusion protein linking the human coagulation factor VIIa to human albumin, rVIIa-FP (CSL Behring GmbH), is currently undergoing clinical investigation in the clinical trial program PROLONG-7P. The present study has been conducted to evaluate and better understand the biodistribution of rVIIa-FP.
Methods:
[3H]-rVIIa-FP, [3H]-rFVIIa, or [3H]-albumin were administered intravenously to male rats at a single radioactive dose of 300-400 μCi/kg. Using whole-body autoradiography, tissue radioactivity was determined up to 24 ([3H]-rFVIIa) or 240 ([3H]-rVIIa-FP, [3H]-albumin) hours. In addition to full body sections, the hind limbs were separately subjected to autoradiography to obtain more detailed information on the product distribution within the bone marrow, articular capsule, and synovial region of the knee joints. In parallel, plasma, urine, and feces were collected at pre-dose and at several sampling points throughout the 240-h study period to calculate excretion balance and assess physiological elimination pathways.
Summary:
Overall, both [3H]-rVIIa-FP and [3H]-rFVIIa were distributed predominantly into well-perfused tissues and organs and were rapidly present in synovial and mineralized regions of knee joint sections and seem to mostly localize to the zone of calcified cartilage within the growth plate regions of long bones. The longest retention time was observed in the bone marrow and endosteum of long bones. While [3H]-rVIIa-FP–associated radioactivity was well detectable at 72 h, comparable [3H]-rFVIIa–derived signals could only be observed up to 24 h after administration. The major route of elimination was urinary excretion. At 240 h, 74% and 18% of radioactivity was recovered in urine and feces, respectively. Plasma profiling showed that up to 8 h, 100% of the radioactivity could be assigned to unchanged [3H]-rVIIa- FP.
Conclusions:
Consequently, this study shows that rVIIa-FP exhibits biodistribution characteristics comparable to competitor products,1 but clearly distinguishes itself by its extended tissue half-life, potentially allowing a reduction in dosing frequency leading to increased convenience and compliance in hemophilia patients with inhibitors.
1. Nakatomi Y, et al. Thromb Res. 2012;129:62-67.