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

摘要: Summary. Background: Extensive research is currently ongoing to prolong the half-life of coagulation factors. One these techniques glycoPEGylation, which has also been applied recombinant activated factor VII (rFVIIa), resulting in a rFVIIa derivative (N7-GP) with prolonged terminal (t1/2). The main clinical purpose N7-GP provide safe and effective prophylaxis patients hemophilia inhibitors. t1/2 can potentially reduce dosing frequency thereby facilitate convenience compliance, are two significant barriers prophylaxis. Objectives: To determine safety pharmacokinetics single doses healthy men. Methods: A randomized, placebo-controlled, dose-escalation trial five cohorts (N7-GP dose 12.5–100 μg kg−1) was performed. In each cohort, eight subjects were randomized receive (n = 6) or placebo (n = 2). Results: The mean FVIIa activity measurable for up at least 72 h after dosing, overall 15 h. appeared be dose-proportional range investigated. No serious adverse events (including thromboembolic events) reported. similar both groups. neutralizing antibodies against detected. A pharmacologic effect apparent from dose-dependent statistically decrease prothrombin time all groups as compared placebo. Conclusions: N7-GP had plasma 15 h profile that makes it potential candidate