Development and Translational Application of a Minimal Physiologically Based Pharmacokinetic Model for a Monoclonal Antibody against Interleukin 23 (IL-23) in IL-23-Induced Psoriasis-Like Mice.

Abstract	The interleukin (IL)-23/Th17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model. A minimal physiologically based pharmacokinetic model with target-mediated drug disposition features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 in both serum and lesional skin site. Furthermore, translational applications of the developed model were evaluated with incorporation of human PK for ustekinumab, an anti-human IL-23/IL-12 mAb developed for treatment of psoriasis, and human disease pathophysiology information in psoriatic patients. The results agreed well with the observed clinical data for ustekinumab. Our work provides an example on how mechanism-based PK/PD modeling can be applied during early drug discovery and how preclinical data can be used for human efficacious dose projection and guide decision making during early clinical development of therapeutic proteins.
Authors	Xi Chen, Xiling Jiang, Rajitha Doddareddy, Brian Geist, Thomas McIntosh, William J Jusko, Honghui Zhou, Weirong Wang
Journal	The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 365 Issue 1 Pg. 140-155 (04 2018) ISSN: 1521-0103 [Electronic] United States
PMID	29420255 (Publication Type: Journal Article)
Copyright	Copyright © 2018 by The Author(s).
Chemical References	Antibodies, Monoclonal Interleukin-23
Topics	Animals Antibodies, Monoclonal (blood, immunology, pharmacokinetics) Female Humans Interleukin-23 (adverse effects, immunology) Mice Models, Biological Psoriasis (chemically induced, immunology, metabolism) Rats Tissue Distribution Translational Research, Biomedical

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