Pharmacokinetic and pharmacodynamic modeling of a humanized anti-IL-13 antibody in naive and Ascaris-challenged cynomolgus monkeys

Abstract

Purpose: 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.