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

• Published in: Pharmacology research & perspectives 2015-12, Vol.3 (6)
• Main Authors: Pan, Wei. J., Li, Hong, Xiao, Jim J., Horner, Michelle J., Lebrec, Herve N., Butz, Eric A., Kaliyaperumal, Arunan, Cheah, Tsui C., Ortiz, Robert C., Prokop, Samantha P., Buntich, Sabina A., Boren, Babette M., Wolford, Suzanne T., Tsuji, Wayne H., Wienkers, Larry C., Köck, Kathleen
• Format: Article
• Language: English
• Subjects: Arthritis; Celiac disease; Cytokines; Dendritic cells; Disease; Inflammatory diseases; Laboratory animals; Pharmacodynamics; Pharmacokinetics; Pharmacology; Psoriasis; Tumor necrosis factor-TNF
• ISSN: 2052-1707; 2052-1707
• DOI: 10.1002/prp2.199

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.