title: A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome.
abstract: OBJECTIVE
  To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha in patients with sepsis.
  
  
  METHODS
  Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial.
  
  
  METHODS
  Intensive care units of six academic medical centers in the United States.
  
  
  METHODS
  Forty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy.
  
  
  METHODS
  Patients received 0.3, 1.0, or 3.0 mg/kg afelimomab or placebo intravenously over 20 min. Three patients in each dose group received single doses; the remaining nine patients in each group received multiple (nine) doses at 8-h intervals over 72 h.
  
  
  RESULTS
  Afelimomab appeared safe and well tolerated. Single- and multiple-dose kinetics were predictable and dose related. The elimination half-life was 44.7 h. Afelimomab treatment resulted in increased serum concentrations of TNF (includes TNF-antibody complexes) and decreased serum interleukin-6 concentrations, whereas no discernible trends were observed in placebo-treated patients. There was no significant treatment effect on 28-day mortality as was expected given the small number of patients. However, overall mortality was significantly (p = 0.001) associated with baseline interleukin-6 concentration. All patients experienced adverse events, but the vast majority were considered unrelated to the study drug and demonstrated no apparent relationship to afelimomab dose. Although 41% of patients developed human anti-murine antibodies, there were no clinical sequelae.
  
  
  CONCLUSIONS
  Multidose therapy with afelimomab was safe, well tolerated, and had predictable linear kinetics. A large randomized trial comparing afelimomab to placebo in patients with well defined sepsis has recently been completed.
authors.affiliation: Department of Anaesthesia, College of Medicine, University of Florida, Gainesville 32610-0254, USA. gallaghe@anest1.anest.ufl.edu
authors.forename: J
authors.initials: J
authors.lastname: Gallagher
authors.forename: C
authors.initials: C
authors.lastname: Fisher
authors.forename: B
authors.initials: B
authors.lastname: Sherman
authors.forename: M
authors.initials: M
authors.lastname: Munger
authors.forename: B
authors.initials: B
authors.lastname: Meyers
authors.forename: T
authors.initials: T
authors.lastname: Ellison
authors.forename: S
authors.initials: S
authors.lastname: Fischkoff
authors.forename: W T
authors.initials: WT
authors.lastname: Barchuk
authors.forename: L
authors.initials: L
authors.lastname: Teoh
authors.forename: R
authors.initials: R
authors.lastname: Velagapudi
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003257:Consumer Product Safety; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014481:United States / Q000453:epidemiology
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C427683:afelimomab