The safety, pharmacokinetics and pharmacodynamics of recombinant human tumour necrosis factor-binding protein-1 (r-hTBP-1, Onercept) were investigated after intravascular and extravascular injection, in three studies in healthy volunteers. Subjects received Onercept as single intravenous doses of 5, 15, 50 and 150 mg, or single IV, IM, SC injection of 50 mg, or six repeated SC injections of 50 mg. Based on vital signs, hematology and blood chemistry, antibodies to study drug and local tolerability, r-hTBP-1 exhibited a remarkably safe profile. There was no evidence of alteration of hepatic oxidative metabolism. Recombinant-hTBP-1 showed linear pharmacokinetics that could be described by a triexponential model, and exhibited an initial half-life of 30 min, an intermediate half-life of 4 hours and a terminal elimination half-life of about 15 hours, although it was prolonged to 21 hours after repeated SC injections. The total clearance was estimated at 4 l/h. The initial (Vc) and steady state (Vss) volumes of distribution were approximately 4 l and 10 l, respectively. Renal clearance was minimal, representing around 2.5% of the total clearance, and remained constant after increasing doses of r-hTBP-1. The absorption was slow and biphasic. The immunoactivity of r-hTBP-1 was closely related to its biological activity, although the assessment was limited to only some of the samples. As anticipated in normal healthy volunteers, the pharmacodynamic response was generally not different from placebo. Total TNF-alpha serum levels increased slightly, 1 hour following IV administration of 50 mg and 150 mg r-hTBP-1. However, no major increase in the active entity levels (free TNF-alpha) was observed. In addition, no TNF-alpha-driven biological response was observed, i.e. C-reactive protein, IL-6 and fibrinogen remained almost constant, as did transferrin and albumin. Its safety profile and pharmacokinetic characteristics make Onercept a candidate drug suitable for antagonising pathologically high levels of TNF-alpha as reported in inflammatory, immune and cardiovascular diseases.