Modeling the pharmacokinetic-pharmacodynamic relationship of the monoclonal anti-macaque-IL-15 antibody Hu714MuXHu in cynomolgus monkeys

Abstract

Hu714MuXHu is a recombinant chimeric murine-human monoclonal antibody directed against interleukin-15 (IL-15), a proinflammatory cytokine associated with memory CD8+ and natural killer (NK) T-cell activation and implicated in the pathogenesis of inflammatory diseases. A pharmacokinetic-pharmacodynamic (PK/PD) model was developed to describe the NK cell count reduction in cynomolgus monkeys after treatment with Hu714MuXHu. Cynomolgus monkeys were dosed with Hu714MuXHu in three studies: as a single dose at 0.1 or 1 mg·kg-1 i.v.; weekly for 5 weeks at 0, 30, 60, or 150 mg·kg-1 i.v. or 150 mg·kg-1 s.c.; weekly for 13 weeks at 0, 5, 30, or 150 mg·kg-1 s.c. Serum Hu714MuXHu concentration-time data were analyzed using noncompartmental analysis and the PK/NK cell count relationship was assessed via simultaneous PK/PD modeling. Hu714MuXHu PK was approximately dose-proportional between 0.1-150 mg·kg-1 for i.v. and 5-150 mg·kg-1 for s.c. administration with an elimination half-life of 12.7-18 days. Hu714MuXHu administration resulted in rapid and marked reductions in NK cell counts after the first dose which recovered fully after the serum Hu714MuXHu concentrations approached 0.1 μg·mL-1 (assay limit of quantification). PK/PD modeled Hu714MuXHu effects on NK cells had an EC50 of 0.09 μg·mL-1. In summary, weekly i.v. or s.c. doses with Hu714MuXHu for up to 3 months in cynomolgus monkeys demonstrated linear PK and significant NK cell count reduction, which was described using PK/PD modeling. This approach may be used to guide investigative product dose selections for inflammatory diseases where NK cell count alterations are quantifiable.