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In Vitro- in Vivo Extrapolation (IVIVE) Method to Predict Human Renal Clearance of Drugs

Kunze, Annett and Huwyler, Jörg and Poller, Birk and Gutmann, Heike and Camenisch, Gian P. (2014) In Vitro- in Vivo Extrapolation (IVIVE) Method to Predict Human Renal Clearance of Drugs. Journal of Pharmaceutical Sciences.

Abstract

Renal clearance is a key determinant of the elimination of drugs. To date, only few
in vitro – in vi v o extrapolation (IVIVE)
approaches have been described to predict the renal organ clearance as the net result of glomerular filtration, tubular secretion, and tubular reabsorption. In this study, we measured in LLC-PK1 cells the transport of 20 compounds that cover all four classes of the Biopharmaceutical Drug Disposition System. These data were incorporated into a novel kidney model to predict all renal clearance processes in human. We showed that filtration and secretion were main contributors to the renal organ clearance for all compounds, whereas reabsorption was predominant for compounds assigned to classes 1 and 2. Our results suggest that anionic drugs were not significantly secreted in LLC-PK1 cells, resulting in under-predicted clearances.When all study compounds were included a high overall correlation between the reported and predicted renal organ clearances was obtained (R2 = 0.83). The prediction accuracy in terms of percentage within twofold and threefold error was 70% and 95%, respectively. In conclusion, our novel IVIVE method allowed to predict the human renal organ clearance and the contribution of each underlying process.

Item Type: Article
Keywords: in vitro–in vivo correlations (IVIVC);renal clearance;renal reabsorption;permeability;drug transport;in vitro models;membrane transport;pharmacokinetics;LLC-PK1 cell line;clearance prediction
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/11280

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