Recombinant fusion protein linking factor VIIa with albumin (rVIIa-FP): Tissue distribution in rats.

Introduction: A novel fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) is currently undergoing clinical investigations. Objective: This study was conducted to examine the biodistribution of rVIIa-FP in comparison to recombinant factor VIIa (rFVIIa). Materials and Methods: [H-3]-rVIIa-FP (10 mg kg(-1)) or [H-3]-rFVIIa (1.6 mg kg(-1)) were administered intravenously to rats, followed by quantitative whole-body and knee joint autoradiography for 24 ([H-3]-rFVIIa) or 240 ([H-3]-rVIIa- FP) hours post-dose. Pharmacokinetic and excretion balance analyses were performed. Results: In contrast to [H-3]-albumin, the tissue distributions of [H-3]-rVIIa-FP and [H-3]-rFVIIa were similar. Within the knee, both were rapidly present within synovial and mineralized regions. Importantly, rVIIa-FP-and albumin-derived radioactivity were detectable up to 72-120 hours, whereas [H-3]-rFVIIa signals were already close to detection limits at 24 hours. The longest rVIIa-FP retention times were observed in bone marrow and endosteum, in which the retention times were up to 5 times longer for rVIIa-FP compared with rFVIIa. Up to 8 hours post-dose, 100% of radioactivity was assigned to unchanged [H-3]-rVIIa-FP. Elimination of both proteins occurred primarily via the urine. Conclusions: The data suggest that the FVIIa moiety is directing rVIIa-FP's tissue distribution while the albumin moiety is responsible for the prolonged tissue retention. Importantly, rVIIa-FP is highly concentrated and retained over a long period in the growth plate of the knee joint - a vulnerable site in haemophilia patients. Overall, these improved tissue distribution characteristics of rVIIa-FP may enhance compliance and allow a more convenient dosing frequency. (C) 2014 Elsevier Ltd. All rights reserved.