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

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 EC (50) 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.