Pharmacokinetics and Safety of FFR‐rFVIIa after Single Doses in Healthy Subjects

FFR‐rFVIIa is an antithrombotic agent, which has also proven to have antirestenotic properties in animal models. FFR‐rFVIIa is a modified recombinant FVIIa in which the catalytic site is irreversibly inactivated by a synthetic tripeptide covalently bound with the FVIIa molecule. The modified rFVIIa retains its tissue factor (TF) binding capacity but is otherwise enzymatically inactive. A double‐blind, placebo‐controlled, randomized dose escalation trial was conducted to investigate eight single i.v. doses of FFR‐rFVIIa (0.01, 0.02, 0.05, 0.08, 0.12, 0.18, 0.27, or 0.40 mg/kg body weight) in healthy male volunteers (n = 62). Safety, pharmacokinetics, and pharmacodynamics of FFR‐rFVIIa were assessed. Mean (SD) AUC 0‐∞ ranged from 0.35 (0.11)to 28.8 (3.5) g•h/ml, and mean C max ranged from 0.078 (0.019) to 4.8 (0.7) g/ml. The mean elimination half‐life ranged from 3.8 to 5.8 hours. Mean AUC 0‐∞ increased with increasing dose levels . C max appeared to be proportional to the dose level, with the exception of the lowest dose level. A dose‐dependent prolongation of the prothrombin time was found, demonstrating that FFR‐rFVIIa inhibited coagulation via the TF‐dependent pathway. FFR‐rFVIIa was generally well tolerated at all dose levels studied .