The quest for balance between capturing data and model complexity: A quantitative clinical pharmacology approach applied to monoclonal antibodies

Abstract

The main objective of this tutorial is to provide the readers with a roadmap of how to establish increasingly complex target‐mediated drug disposition (TMDD) models for monoclonal antibodies. To this end, we built mathematical models, each with a detailed visualization, starting from the basic TMDD model by Mager and Jusko to the well‐established, physiologically based model by Li et al. in a step‐wise fashion to highlight the relative importance of key physiological processes that impact mAb kinetics and system dynamics. As the models become more complex, the question of structural and parameter identifiability arises. To address this question, we work through a trastuzumab case example to guide the modeler's choice for model and parameter optimization in light of the context of use. We leave the readers of this tutorial with a brief summary of the advantages and limitations of each model expansion, as well as the model source codes for further self‐guided exploration and hands‐on analysis.

Application of population physiologically based pharmacokinetic modelling to optimize target expression and clearance mechanisms of therapeutic monoclonal antibodies

“…Therefore, the shedding process was not included in the PBPK modelling of HER2‐directed mAbs to increase model parsimony and structural and model parameters identifiability. Notwithstanding, the impact of the cHER2‐ECD on receptor occupancy (membrane‐attached) and thus, on pharmacological effect, should be carefully evaluated to establish an optimal dosing regimen in a case‐by‐case basis 45 …”

“…Notwithstanding, the impact of the cHER2-ECD on receptor occupancy (membrane-attached) and thus, on pharmacological effect, should be carefully evaluated to establish an optimal dosing regimen in a case-by-case basis. 45 HER2 overexpression has been demonstrated to inhibit downregulation of EGFR and of itself probably because the endocytic and endosomal sorting machinery can be impaired via saturation at high receptor levels, as the regulatory molecules involved in these processes have limited levels. 6,7 The optimized HER2 k deg value in normal tissues of 0.398 h À1 is in good agreement with that reported by Hendriks et al (0.252 h À1 ).…”

TDM of belatacept and other biologicals in transplantation.

“…A lot of work has been invested to better understand the contributions of physiological processes and drug characteristics that govern the PK and PD and hence can guide the model development. The more complex descriptions may be more relevant in the process of mAbs development [19,25], however there may also be lessons to learn for models. How the application of a PK/PD model can improve the personalization of a biologic like eculizumab, has been elegantly demonstrated by the work of a group at Cincinnati Children's Hospital.…”