Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Dose Antiinterleukin- 18 Mab GSK1070806 in Healthy and Obese Subjects.

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-time-in-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 A Es 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(infinity) and C-max although a trend for dose-dependent increase in t(1/2) was observed. Serum drug-bound 1L-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-gamma production. Conclusion: GSK1070806 warrants clinical investigation in patients.