Recombinant fusion protein linking factor VIIa with albumin (rVIIa­FP): Tissue distribution in rats

IntroductionA novel fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) is currently undergoing clinical investigations.ObjectiveThis study was conducted to examine the biodistribution of rVIIa-FP in comparison to recombinant factor VIIa (rFVIIa).Materials and Methods[3H]-rVIIa-FP (10 mg kg− 1) or [3H]-rFVIIa (1.6 mg kg− 1) were administered intravenously to rats, followed by quantitative whole-body and knee joint autoradiography for 24 ([3H]-rFVIIa) or 240 ([3H]-rVIIa-FP) hours post-dose. Pharmacokinetic and excretion balance analyses were performed.ResultsIn contrast to [3H]-albumin, the tissue distributions of [3H]-rVIIa-FP and [3H]-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 [3H]-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 [3H]-rVIIa-FP. Elimination of both proteins occurred primarily via the urine.ConclusionsThe 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.