Modeling the pharmacokinetic‐pharmacodynamic relationship of the monoclonal anti‐macaque‐ IL ‐15 antibody Hu714Mu XH u in cynomolgus monkeys

Hu714Mu XH u is a recombinant chimeric murine‐human monoclonal antibody directed against interleukin‐15 ( IL ‐15), a proinflammatory cytokine associated with memory CD 8+ 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 Hu714Mu XH u. Cynomolgus monkeys were dosed with Hu714Mu XH u 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 Hu714Mu XH u concentration‐time data were analyzed using noncompartmental analysis and the PK / NK cell count relationship was assessed via simultaneous PK/PD modeling. Hu714Mu XH u 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. Hu714Mu XH u administration resulted in rapid and marked reductions in NK cell counts after the first dose which recovered fully after the serum Hu714Mu XH u concentrations approached 0.1 μ g·mL −1 (assay limit of quantification). PK/PD modeled Hu714Mu XH u effects on NK cells had an EC 50 of 0.09 μ g·mL −1 . In summary, weekly i.v. or s.c. doses with Hu714Mu XH u 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.