TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 140 LP - 155 DO - 10.1124/jpet.117.244855 VL - 365 IS - 1 AU - Xi Chen AU - Xiling Jiang AU - Rajitha Doddareddy AU - Brian Geist AU - Thomas McIntosh AU - William J. Jusko AU - Honghui Zhou AU - Weirong Wang Y1 - 2018/04/01 UR - http://jpet.aspetjournals.org/content/365/1/140.abstract N2 - 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. ER -