Quantitative Pharmacology and Individualized Therapy Strategies in Development of Therapeutic Proteins for Immune-Mediated Inflammatory Diseases
by Honghui Zhou, Diane R. Mould
3 Mechanism and Physiologically Based PK/PD Model in Assisting Translation from Preclinical to Clinical: Understanding PK/PD of Therapeutic Proteins at Site‐of‐Action
Xi Chen1 and Weirong Wang2
1Bristol‐Myers Squibb, Clinical Pharmacology and Pharmacometrics, Route 206 and Province Line Road, Princeton, NJ, 08543 USA
2Janssen BioTherapeutics (JBIO), Janssen R&D, Biologics Development Sciences, 1400 McKean Road, Spring House, PA, 19447, USA
3.1 Introduction
Understanding the Exposure–Response (ER) relationship is critical for translation of biologics from preclinical to clinical stage and for projection of safe and efficacious doses in humans. The mechanism of action (MOA) of biologics commonly involves binding to specific target, and the extent and duration of target engagement (TE) drives down stream pharmacological effects. For biologics against therapeutic target in central circulation, ER relationship can usually be established correlating plasma or serum exposure with target engagement and drug efficacy measurements. However, for biologics whose targets reside in tissues, their concentration and target engagement at the tissue site of action is what associates directly with the pharmacological effects. Moreover, the preclinical animal models used to assess drug effect can be of considerable difference from the clinical scenarios. Thus, simple extrapolation based on ER relationship in plasma/serum may be misleading, and the specific differences in target expression ...