Physiologically Based Modeling to Predict Monoclonal Antibody Pharmacokinetics in Humans from in vitro Physiochemical Properties
| Autor: | Shihao Hu, Amita Datta-Mannan, David Z. D’Argenio |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | mAbs, Vol 14, Iss 1 (2022) |
| Druh dokumentu: | article |
| ISSN: | 19420862 1942-0870 1942-0862 |
| DOI: | 10.1080/19420862.2022.2056944 |
| Popis: | A model-based framework is presented to predict monoclonal antibody (mAb) pharmacokinetics (PK) in humans based on in vitro measures of antibody physiochemical properties. A physiologically based pharmacokinetic (PBPK) model is used to explore the predictive potential of 14 in vitro assays designed to measure various antibody physiochemical properties, including nonspecific cell-surface interactions, FcRn binding, thermal stability, hydrophobicity, and self-association. Based on the mean plasma PK time course data of 22 mAbs from humans reported in the literature, we found a significant positive correlation (R = 0.64, p = .0013) between the model parameter representing antibody-specific vascular to endothelial clearance and heparin relative retention time, an in vitro measure of nonspecific binding. We also found that antibody-specific differences in paracellular transport due to convection and diffusion could be partially explained by antibody heparin relative retention time (R = 0.52, p = .012). Other physiochemical properties, including antibody thermal stability, hydrophobicity, cross-interaction and self-association, in and of themselves were not predictive of model-based transport parameters. In contrast to other studies that have reported empirically derived expressions relating in vitro measures of antibody physiochemical properties directly to antibody clearance, the proposed PBPK model-based approach for predicting mAb PK incorporates fundamental mechanisms governing antibody transport and processing, informed by in vitro measures of antibody physiochemical properties, and can be expanded to include more descriptive representations of each of the antibody processing subsystems, as well as other antibody-specific information. |
| Databáze: | Directory of Open Access Journals |
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