title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects.
abstract: OBJECTIVE
  To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK1070806, a novel IgG1 mAb that neutralizes human interleukin (IL)-18.
  
  
  METHODS
  In this first-timein-human (FTIH) study, cohorts of healthy and obese subjects were randomly allocated to receive single doses of GSK1070806 (0.008 - 10 mg/kg) or placebo. Blood was sampled ≤ 274 days post-dosing, and safety monitored.
  
  
  RESULTS
  GSK1070806 was generally well tolerated. The most common AEs were nasopharyngitis and headache, arising as frequently in the placebo as in the active drug groups; most AEs were mild to moderate and unrelated to dose level. There were no allergic, delayed-type hypersensitivity, or infusion-related reactions and the incidence of immunogenicity was low. GSK1070806 plasma pharmacokinetic profiles were comparable in healthy and obese subjects; there was no major deviation from dose proportionality for AUC(∞) and C(max) although a trend for dose-dependent increase in t(1/2) was observed. Serum drug-bound IL-18 levels increased post-dosing and were sustained for a long time-period following GSK1070806 administration. Ex-vivo whole blood assay demonstrated prolonged pharmacological activity of GSK1070806 as determined by its primary immunological mechanism of action, inhibition of IL-18-induced IFN-γ production.
  
  
  CONCLUSIONS
  GSK1070806 warrants clinical investigation in patients.
authors.forename: Prafull
authors.initials: P
authors.lastname: Mistry
authors.forename: Juliet
authors.initials: J
authors.lastname: Reid
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pouliquen
authors.forename: Simon
authors.initials: S
authors.lastname: McHugh
authors.forename: Lee
authors.initials: L
authors.lastname: Abberley
authors.forename: Stephen
authors.initials: S
authors.lastname: DeWall
authors.forename: Adam
authors.initials: A
authors.lastname: Taylor
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.forename: Marian
authors.initials: M
authors.lastname: Rocha Del Cura
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McKie
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020382:Interleukin-18 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D016037:Single-Blind Method
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C000608195:GSK1070806; D020382:Interleukin-18