Algorithmic multiscale analysis for the FcRn mediated regulation of antibody PK in human

Abstract

AbstractA demonstration is provided on how algorithmic asymptotic analysis of multi-scale pharmacokinetics (PK) systems can provide (1) system level understanding and (2) predictions on the response of the model when parameters vary. Being algorithmic, this type of analysis is not hindered by the size or complexity of the model and requires no input from the investigator. The algorithm identifies the constraints that are generated by the fast part of the model and the components of the slow part of the model that drive the system within these constraints. The demonstration is based on a typical monoclonal antibody PK model. It is shown that the findings produced by the traditional methodologies, which require significant input by the investigator, can be produced algorithmically and more accurately. Moreover, additional insights are provided by the algorithm, which cannot be obtained by the traditional methodologies; notably, the dual influence of certain reactions depending on whether their fast or slow component dominates. The analysis reveals that the importance of physiological processes in determining the systemic exposure of monoclonal antibodies (mAb) varies with time. The analysis also confirms that the rate of mAb uptake by the cells, the binding affinity of mAb to neonatal Fc receptor (FcRn), and the intracellular degradation rate of mAb are the most sensitive parameters in determining systemic exposure of mAbs. The algorithmic framework for analysis introduced and the resulting novel insights can be used to engineer antibodies with desired PK properties.