Pharmacokinetic and pharmacodynamic modeling of a humanized anti-IL-13 antibody in naive and Ascaris-challenged cynomolgus monkeys.
OBJECTIVE
Neutralization of IL-13 is an attractive approach for treatment of asthma. In this report, we developed a novel PK-PD model that described the relationship between the circulating concentrations of total IL-13 and a neutralizing anti-IL-13 antibody (Ab-02) in the model of acute airway inflammation induced by Ascaris challenge to cynomolgus monkeys, as well as in naive monkeys.


METHODS
Cynomolgus monkeys were administered a single intravenous or subcutaneous dose of Ab-02. Total IL-13 and Ab-02 concentrations were measured by immunoassays.


RESULTS
Modeling and simulations indicated that: (1) Ascaris challenge induced approximately three-fold increase in circulating IL-13 concentrations, when compared to naive animals, consistent with the notion that Ascaris-induced airway inflammation was IL-13-mediated; (2) the transient increase in total IL-13 concentrations observed in both naive and Ascaris-challenged monkeys following Ab-02 administration was due to the increase in Ab-02-bound IL-13, while free IL-13 was decreased; and (3) the extent and duration of neutralization of circulating IL-13 were different in naive and Ascaris-challenged monkeys for the same Ab-02 dose regimen.


CONCLUSIONS
The PK-PD model presented in this report may be applied to study drug-ligand interactions when a free ligand cannot be directly assayed but total ligand concentrations are modulated by the drug administration.
Vugmeyster
Yulia
Y
Department of Drug Safety and Metabolism, Wyeth Research, One Burtt Road, Andover, MA 01810, USA. yvugmeyster@wyeth.com
Tian
Xianbin
X
Szklut
Pamela
P
Kasaian
Marion
M
Xu
Xin
X
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001200:Ascaris; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D003198:Computer Simulation; D004195:Disease Models, Animal; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D018793:Interleukin-13 / Q000097:blood / Q000276:immunology*; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological
D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D018793:Interleukin-13; D008024:Ligands