title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects.
abstract: OBJECTIVE
  The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective was to investigate the pharmacodynamics of NN2211.
  
  
  METHODS
  In a double-blind, randomized dose, escalation, placebo-controlled study, healthy male subjects were enrolled at eight consecutive dose levels (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5, and 20.0 microg/kg) with eight subjects per dose level at a 3:1 active:placebo randomization. After subcutaneous dosing with NN2211, 48-h pharmacokinetic, and 24-h glucose, insulin and glucagon profiles were assessed. In addition, three subjects at each dose level were randomly assigned (one placebo/two active) to an intravenous glucose tolerance test (IVGTT) 9 h after the dose (corresponding to the time to maximal plasma concentration of NN2211).
  
  
  RESULTS
  After subcutaneous administration, the half-life of NN2211 was found to be 11-15 h. Overall, although there were no statistically significant differences compared with placebo in the area under the curve (0-9 h for insulin or glucagon), there was a borderline- significant lowering of glucose levels (P = 0.066). During the IVGTT, there was a statistically significant increase in insulin secretion (P = 0.0002), but there was no significant effect on glucagon levels. Although no significant effect was observed on glucose levels during the IVGTT, there was a dose-dependent increase in the glucose disappearance constant. Whereas no serious adverse events were observed, there was a higher incidence of adverse events after active treatment compared with placebo treatment (notably headache, dizziness, nausea, and vomiting).
  
  
  CONCLUSIONS
  This study provides evidence that NN2211 has a pharmacokinetic profile consistent with once-daily dosing in humans.
authors.affiliation: Novo Nordisk A/S, Health Care Development, Bagsvaerd, Denmark.
authors.forename: Bodil
authors.initials: B
authors.lastname: Elbrønd
authors.forename: Grethe
authors.initials: G
authors.lastname: Jakobsen
authors.forename: Søren
authors.initials: S
authors.lastname: Larsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Agersø
authors.forename: Lisbeth Bjerring
authors.initials: LB
authors.lastname: Jensen
authors.forename: Paul
authors.initials: P
authors.lastname: Rolan
authors.forename: Jeppe
authors.initials: J
authors.lastname: Sturis
authors.forename: Vibeke
authors.initials: V
authors.lastname: Hatorp
authors.forename: Milan
authors.initials: M
authors.lastname: Zdravkovic
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose; D004311:Double-Blind Method; D005934:Glucagon / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007328:Insulin / Q000097:blood; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon