A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome

Intensive Care Med. 2001 Jul;27(7):1169-78. doi: 10.1007/s001340100973.

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.

Design: Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial.

Setting: Intensive care units of six academic medical centers in the United States.

Patients: Forty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy.

Interventions: 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.

Measurements and main 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacokinetics*
  • Consumer Product Safety
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Interleukin-6 / blood
  • Logistic Models
  • Male
  • Middle Aged
  • Survival Rate
  • Systemic Inflammatory Response Syndrome / drug therapy*
  • Systemic Inflammatory Response Syndrome / mortality
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • United States / epidemiology

Substances

  • Antibodies, Monoclonal
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • afelimomab