Amplifying the Impact of Kidney Micro-physiological Systems: Predicting Renal Clearance Using Mechanistic Modelling Based on Reconstructed Drug Secretion.
| Title: | Amplifying the Impact of Kidney Micro-physiological Systems: Predicting Renal Clearance Using Mechanistic Modelling Based on Reconstructed Drug Secretion. |
|---|---|
| Authors: | Caetano-Pinto, Pedro, Nordell, Pär, Nieskens, Tom, Haughan, Katie, Fenner, Katherine S., Stahl, Simone H. |
| Source: | Altex; 2023, Vol. 40 Issue 3, p408-424, 29p |
| Abstract: | Accurate prediction of pharmacokinetic parameters, such as renal clearance, is fundamental to the development of effective and safe new treatments for patients. However, conventional renal models have a limited ability to predict renal drug secretion, a process that is dependent on transporters in the proximal tubule. Improvements in microphysiological systems (MPS) have extended our in vitro capabilities to predict pharmacokinetic parameters. In this study a kidney-MPS model was developed that successfully recreated renal drug secretion. Human proximal tubule cells grown in the kidney-MPS, resembling an in vivo phenotype, actively secreted the organic cation drug metformin and organic anion drug cidofovir, in contrast to cells cultured in conventional culture formats. Metformin and cidofovir renal secretory clearance were predicted from kidney- MPS data within 3.3- and 1.3-fold, respectively, of clinically reported values by employing a semi-mechanistic drug distribution model using kidney-MPS drug transport parameters together with in vitro to in vivo extrapolation. This approach introduces an effective application of a kidney-MPS model coupled with pharmacokinetic modelling tools to evaluate and predict renal drug clearance in humans. Kidney-MPS renal clearance predictions can potentially complement pharmacokinetic animal studies and contribute to the reduction of pre-clinical species use during drug development. [ABSTRACT FROM AUTHOR] |
| Copyright of Altex is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Complementary Index |
Be the first to leave a comment!