• J Gallagher, C Fisher, B Sherman, M Munger, B Meyers, T Ellison, S Fischkoff, W T Barchuk, L Teoh, and R Velagapudi.
• Department of Anaesthesia, College of Medicine, University of Florida, Gainesville 32610-0254, USA. gallaghe@anest1.anest.ufl.edu
• Intensive Care Med. 2001 Jul 1; 27 (7): 1169-78.

ObjectiveTo investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha in patients with sepsis.DesignMulticenter, randomized, open-label, placebo-controlled phase I/II clinical trial.SettingIntensive care units of six academic medical centers in the United States.PatientsForty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy.InterventionsPatients 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 ResultsAfelimomab 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.ConclusionsMultidose 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.

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