Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9)
Application of PK/PD Modeling in Lead Optimization and Human Dose Projection in a Covalent Inhibitor-Based Drug Discovery Project
Aberra Fura, Mary Obermeier, Joe Tino, Jim Burke, Punit Marathe and Zheng Yang
Bristol-Myers Squibb, Princeton, NJ; Research and Development, USA
Objectives: This work demonstrates how PK/PD modeling that integrates drug and system properties was used in a covalent inhibitor-based drug discovery project to guide lead optimization, selection and projection of human dose.
Methods:The model was developed using data generated in a preclinical mouse model of PK/PD/efficacy with BMS-X and further substantiated with clinical data. Basal level and rate of degradation of the target protein, and apparent rate of inactivation were determined. A PK/PD model was built using the system parameters and the drug pharmacokinetics parameters to predict the extent and time course of inactivation of the target protein. The PK/PD model was then used to guide optimization...