Safety pharmacology, toxicology and pharmacokinetic assessment of VDBP.
VDBP is an important protein of the plasma actin-scavenger system. As such, it has been shown to bind free actin and prevent hypercoagulation and shock in patients with massive actin release resulting from severe tissue injuries.
Treatment of such patients with VDBP could therefore potentially be life-saving.
The VDBP formulation was shown to be stable for at least 4 years with full retention of actin-binding capacity. In vitro studies did not reveal activation of the kallikrein system or the complement system and cellular studies showed no toxic effects on a variety of human cell lines. In vivo studies showed no acute toxic effects in mice, rats or guinea pigs upon intravenous infusion.
A 14-day local tolerance study in rabbits showed no adverse effects, and 14-day toxicity studies in rats and horses did not show any unwanted reactions.
A 14-day toxicology study in beagle dogs, formation of antibodies was seen and in the end of the study period, three out of four dogs showed clinical immunological reactions, which could be ascribed to the formation of antibodies.
The half-life, T, for human VDBP was 12 hr in rats, 16 hr in horses and 30 hr in dogs. The safety profile of plasma-derived VDBP is concluded to be consistent to that required for use in man.