title: 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 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.
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Seattle Washington.
authors.forename: Wei J
authors.initials: WJ
authors.lastname: Pan
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Seattle Washington.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Thousand Oaks Washington.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Xiao
authors.affiliation: Comparative Biology and Safety Sciences Amgen Inc. Thousand Oaks California.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Horner
authors.affiliation: Comparative Biology and Safety Sciences Amgen Inc. Seattle Washington.
authors.forename: Herve N
authors.initials: HN
authors.lastname: Lebrec
authors.affiliation: Inflammation Discovery Research Amgen Inc. Seattle Washington.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Butz
authors.affiliation: Medical Sciences Amgen Inc. Thousand Oaks California.
authors.forename: Arunan
authors.initials: A
authors.lastname: Kaliyaperumal
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Thousand Oaks Washington.
authors.forename: Tsui C
authors.initials: TC
authors.lastname: Cheah
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Thousand Oaks Washington.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Ortiz
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Seattle Washington.
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Prokop
authors.affiliation: Comparative Biology and Safety Sciences Amgen Inc. Thousand Oaks California.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Buntich
authors.affiliation: Comparative Biology and Safety Sciences Amgen Inc. Seattle Washington.
authors.forename: Babette M
authors.initials: BM
authors.lastname: Boren
authors.affiliation: Covance Laboratories Inc. Madison Wisconsin.
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Wolford
authors.affiliation: Medical Sciences Amgen Inc. Seattle Washington.
authors.forename: Wayne H
authors.initials: WH
authors.lastname: Tsuji
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Seattle Washington.
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.affiliation: Pharmacokinetics and Drug Metabolism Amgen Inc. Seattle Washington.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
keywords: Anti‐IL‐15 antibody; Hu714MuXHu; PK/PD modeling; anti‐inflammatory; cynomolgus monkeys; natural killer cells