title: Evaluation of the safety and pharmacokinetics of a fast-acting recombinant FVIIa analogue, NN1731, in healthy male subjects.
abstract: BACKGROUND
  NN1731 is a recombinant activated factor VII (rFVIIa) analog with enhanced activity.
  
  
  OBJECTIVE
  This clinical trial aimed to assess the safety and pharmacokinetics of single doses of NN1731 in healthy male subjects.
  
  
  METHODS
  This was a randomized, placebo-controlled dose-escalation trial with four dose tiers (NN1731 5-30 microg kg(-1)). Eight subjects were randomized to either NN1731 (n = 6) or placebo (n = 2) in each tier.
  
  
  RESULTS
  No thromboembolic or serious adverse events were reported and no antibody formation towards NN1731 was detected. NN1731 was demonstrated to be pharmacologically active based on coagulation-related parameters (prothrombin fragment 1+2, activated partial thromboplastin time and prothrombin time). There were five mild/moderate adverse events in three subjects. The FVIIa activity of NN1731 after ascending single-dose administration of NN1731 fits well with a two-compartment model, indicating a bi-exponential decline with a rapid initial distribution of approximately 73% FVIIa activity (half-life = 20 min), followed by a less rapid terminal elimination phase eliminating the remaining 27% (half-life = 3 h). Dose proportionality in healthy male subjects at the dose levels investigated (5-30 microg kg(-1)) was supported by the FVIIa activity data.
  
  
  CONCLUSIONS
  Based on the results of this trial, NN1731 appears safe and well tolerated in healthy subjects at doses up to 30 microg kg(-1). No immunogenic or thromboembolic events were reported. The pharmacokinetic profile of NN1731 as measured by FVIIa activity appears to follow two-compartment pharmacokinetics characterized by an initial rapid distribution phase followed by a less rapid elimination phase.
authors.affiliation: Medical and Science, Novo Nordisk A/S, Bagsvaerd, Denmark. judm@novonordisk.com
authors.forename: J
authors.initials: J
authors.lastname: Møss
authors.forename: B
authors.initials: B
authors.lastname: Scharling
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: T
authors.initials: T
authors.lastname: Møller Sørensen
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005167:Factor VII / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010599:Pharmacokinetics; D013923:Thromboembolism; D019851:Thrombophilia; D055815:Young Adult
chemical_list: D015415:Biomarkers; C519901:NN1731; D005167:Factor VII