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

• Published in: Pharmacology research & perspectives Vol. 3; no. 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: Journal Article
• Language: English
• Published: Bognor Regis John Wiley & Sons, Inc 01-12-2015
• 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

Abstract
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.