title: Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects.
abstract: OBJECTIVE
  Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidase-IV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non-diabetic volunteers.
  
  
  METHODS
  In this single-blind, randomized, placebo-controlled trial, 39 subjects (18-60 years, body mass index 19.9-35.0 kg/m(2)) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC((0-7 days)))] and maximum plasma drug concentration (C(max)) for cohorts 2-5 during week 1.
  
  
  RESULTS
  Albiglutide had a terminal elimination half-life (T(1/2)) of 6-8 days and time to maximum observed plasma drug concentration (T(max)) of 3-4 days. A greater-than-dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose-dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug-related AE, followed by constipation, flatulence and nausea.
  
  
  CONCLUSIONS
  Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Bush
authors.forename: J E
authors.initials: JE
authors.lastname: Matthews
authors.forename: E H
authors.initials: EH
authors.lastname: De Boever
authors.forename: R L
authors.initials: RL
authors.lastname: Dobbins
authors.forename: R J
authors.initials: RJ
authors.lastname: Hodge
authors.forename: S E
authors.initials: SE
authors.lastname: Walker
authors.forename: M C
authors.initials: MC
authors.lastname: Holland
authors.forename: M
authors.initials: M
authors.lastname: Gutierrez
authors.forename: M W
authors.initials: MW
authors.lastname: Stewart
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; C534611:rGLP-1 protein