A one day workshop on Modeling Biologics with Target-Mediated Disposition
The 1-day workshop is intended for PK scientists with or without prior experience in population PK modeling of therapeutic proteins. It will provide an overview of the PK of biologics, introduce target-mediated drug disposition (TMDD) modeling concepts, and discuss some applications of TMDD modeling to drug development of biologics. We will start with the detailed introduction of the TMDD system. Equations that describe the TMDD process will be introduced and implicit and explicit assumptions of these equations will be reviewed. Characteristic features of the TMDD system will be demonstrated on the simulated examples. Data that are typically available for the analysis and assay properties will be reviewed. It will be demonstrated why TMDD models are often overparameterized and poorly identifiable. The hierarchy of TMDD approximations (rapid binding, quasi-steady-state, irreversible binding, and Michaelis-Menten) will be derived and discussed. Extensions of the TMDD equations to more general systems, including antibody-drug conjugates will be demonstrated. Experience-based recommendations for modeling of TMDD systems will be discussed and demonstrated on case studies. Nonmem control streams that implement TMDD equations and its approximations will be provided. Biological considerations for choice of TMDD approximations will be introduced. We will review allometric scaling for FIH exposure predictions, covariates that may influence PK properties of biologics, and possible drug-drug interactions. Methods for detection, evaluation and modeling of immunogenicity will be discussed. Use of different Nonmem estimation methods and parallelization for TMDD models will be reviewed.
Part I: TMDD Model and Equations
Part II: TMDD Model Approximations: Derivations, Selection and Applications
Part III: Applications to Drug Development of Biologics
Part IV: Nonmem Implementation of the TMDD Equations