plasma concentration profiles were generated for each tissue, and profiles for a given tissue were compared across the four species being analyzed. time profiles for non-binding mAbs (i.e., mAbs that do not bind to any target) in mouse, rat, monkey and human were simulated.
To understand the relationship between the plasma and tissue concentrations for mAbs in a time-independent manner, we used the platform PBPK model 1 where plasma and tissue concentrations vs. plasma drug concentration profile to get a time-independent analysis of the relationship between the plasma and tissue concentrations of a drug in a given tissue. time profile of a drug is used as a forcing function to understand the time and dose-dependent changes in tissue drug concentrations. To understand the distribution characteristics of a drug in a given tissue, ‘local’ PBPK models can be used 2 where the plasma concentrations vs. 1 The analysis presented here attempts to verify tissue distribution predictions made by the aforementioned platform PBPK model for mAb, and define the quantitative relationship between the plasma and tissue concentrations of mAb. One such PBPK model for mAbs can simultaneously characterize the disposition data obtained from various published mAb PBPK models, and it is also capable of characterizing mAb disposition in various preclinical species and human simultaneously. The intricacy of PBPK models enables detailed quantitative assessment of the plasma and tissue disposition of drugs, and facilitates scale-up of the model to different species because the structural model is relatively common to most mammalian species. Use of a physiologically-based pharmacokinetic (PBPK) model is an alternative to performing cumbersome in vivo biodistribution studies. For mAbs, the tissue distribution is usually investigated by performing biodistribution studies with radiolabeled molecules, but such studies are labor intensive, costly, and require large numbers of animals. It thus becomes important to characterize and accurately predict the tissue distribution of the molecule to better understand the dose-response relationship. It can also help eliminate or optimize biodistribution studies, and interpret efficacy or toxicity of the drug in a particular tissue.įor many monoclonal antibodies (mAbs) and other targeted drug modalities, the molecular target may be located within tissues, making their pharmacodynamic (PD) and exaggerated-PD/toxic effects a function of tissue concentrations. The use of ABC to infer tissue concentrations of mAbs and related molecules provides a valuable tool for investigating preclinical or clinical disposition of these molecules. The validity of using the ABC to predict mAb concentrations in different tissues of mouse, rat, monkey, and human species was evaluated by generating validation data sets, which demonstrated that predicted concentrations were within 2-fold of the observed concentrations.
#LITTLE LS MODELS NUDE SKIN#
Estimated ABC values suggest that typically the concentration of mAb in lung is 14.9%, heart 10.2%, kidney 13.7%, muscle 3.97%, skin 15.7%, small intestine 5.22%, large intestine 5.03%, spleen 12.8%, liver 12.1%, bone 7.27%, stomach 4.98%, lymph node 8.46%, adipose 4.78%, brain 0.351%, pancreas 6.4%, testes 5.88%, thyroid 67.5% and thymus is 6.62% of the plasma concentration. The relationship between the plasma and various tissue concentrations was mathematically characterized using the antibody biodistribution coefficient (ABC). The hypothesis was verified for various tissues in mice, rat, monkey, and human using mAb or antibody-drug conjugate tissue distribution data collected from diverse literature. Based on the profiles, we hypothesized that a linear relationship between the plasma and tissue concentrations of non-binding mAbs could exist and that the relationship may be generally constant irrespective of the absolute mAb concentration, time, and animal species being analyzed. plasma concentration profiles have been generated from a physiologically-based pharmacokinetic model of monoclonal antibody (mAb).
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