Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects

Background: Extensive research is currently ongoing to prolong the half-life of coagulation factors. One of these techniques is glycoPEGylation, which has also been applied to recombinant activated factor VII (rFVIIa), resulting in a rFVIIa derivative (N7-GP) with a prolonged terminal half-life (t(1/2)). The main clinical purpose of N7-GP is to provide safe and effective prophylaxis to patients with hemophilia and inhibitors. The prolonged t(1/2) of N7-GP can potentially reduce the dosing frequency and thereby facilitate convenience and compliance, which are two significant barriers to effective prophylaxis. Objectives: To determine the safety and pharmacokinetics of single doses of N7-GP in healthy men. Methods: A randomized, placebo-controlled, dose-escalation trial with five cohorts (N7-GP dose of 12.5-100 mu g kg(-1)) was performed. In each cohort, eight subjects were randomized to receive N7-GP (n = 6) or placebo (n = 2). Results: The mean FVIIa activity was measurable for up to at least 72 h after dosing, and the overall mean t(1/2) for FVIIa activity was 15 h. The pharmacokinetics of N7-GP appeared to be dose-proportional in the dose range investigated. No serious adverse events (including thromboembolic events) were reported. The frequency of adverse events was similar in both the placebo and N7-GP groups. No neutralizing antibodies against N7-GP were detected. A pharmacologic effect was apparent from a dose-dependent statistically significant decrease in the mean prothrombin time in all N7-GP groups as compared with placebo. Conclusions: N7-GP had a plasma half-life of 15 h and a profile that makes it a potential candidate for prophylaxis in patients with hemophilia and inhibitors.