Development of a PBPK Model for Monoclonal Antibodies and Simulation of Human and Mice PBPK of a Radiolabelled Monoclonal Antibody

Abstract

Physiology based pharmacokinetic (PBPK) modeling and simulation is a useful method for prediction of biodistribution of both macromolecules and small molecules. It can enhance our understanding of the underlying mechanisms of biodistribution and hence may help in rational design of macromolecules used as diagnostic and therapeutic agents. In this review we discuss PBPK modeling and simulation of a radiolabelled Monoclonal Antibody ((111)In-DOTA-hAFP31 IgG) ("MAB") in mice without tumor and in a human with tumor. This study is part of Xemet Co.'s effort to develop a more accurate and reliable PBPK model and simulation platform, which is applicable both for small molecules and macromolecules. The simulated results were fitted to experimental time series data by varying parameters which were not fixed a priori. It was demonstrated that the PBPK model describes the main features of the pharmacokinetics of the studied systems. It was also shown that simulation can be used for evaluating the parameters of the system and scaling up the pharmacokinetics of MAB from mice to man. We identified several areas of improvement and further development needed to improve the accuracy of PBPK simulation for MAB and other macromolecules. It was concluded that the transvascular permeabilities are the most important parameters and more research is needed to enable prediction of permeabilities from molecular characteristics of macromolecules. It would also be necessary to understand better and describe with a more detailed model the microstructure of the tumor and to measure or predict the antigen concentration in tumor. Non-specific, non-saturable binding in other organs/tissues should be understood better and the kinetic constants of the binding should be measured experimentally. Although the metabolism and clearance were neglected in this study they need to be included in more detailed studies. Also the intracellular trafficking of macromolecules, which was not included in this study, shall be included in the more accurate models.

Translational considerations for cancer nanomedicine

“…This means tissue partitioning coefficients used for small molecule models are not likely to be relevant. As in many of the previous discussions, again it would appear that nanoparticles should be treated similar to biologics [54,55,57]: 1) tissue uptake should be diffusion limited; 2) tissue binding should have both a selective and saturable component, and a non-selective and non-saturable component; 3) multiple pore models of extravasation may be more representative. The PBPK model problems/questions may also be similar to those for macromolecules [57]: 1) how to model selective uptake and saturability (i.e., opsonization and RES saturation), as well as non-specific uptake?…”

“…The PBPK method has been used for both small molecules and macromolecules, such as antibodies [54–57], and could have potential for nanotechnology platforms as well. In the past, small molecule PBPK modeling has been shown to be more predictive of human pharmacokinetics than allometry [58].…”

Mathematical modeling of receptor occupancy data: A valuable technology for biotherapeutic drug development

“…Thus, the RO at the site of action may be only a fraction of the RO calculated from circulating mAb concentrations. In the absence of direct PK measurements, model-based methods can be used to estimate the mAb concentrations in tissues, with several physiologically based pharmacokinetic (PBPK) models available for this purpose (17,18). Alternatively, one could use the previously defined tissue interstitium percentages to calculate tissue mAb concentration from serum values.…”

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

“…This would explain the apparent disconnect with previous determinations of the lung partitioning of monoclonal antibodies by physiology-based pharmacokinetics using labeled antibodies in both mice and humans, as these measured interstitial lung tissue measurements. [29][30][31][32][33] This comparison indicates the lung epithelium further limits therapeutic antibody exposure. Conversely, pharmacokinetic studies that uses BAL measurements to quantify partitioning into the lung lumen under-estimate the partitioning due to dilution with the lavage fluid.…”