In Vitro–In Vivo Extrapolation Method to Predict Human Renal Clearance of Drugs
Abstract
Renal clearance is a key determinant of the elimination of drugs. To date, only few in vitro-in vivo 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.
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Renal and biliary elimination involving active transport are challenging to model mechanistically from in-vitro data, and prediction of human pharmacokinetics for transported molecules is difficult.
“Renal [39, 40] and biliary [41] elimination involving active transport are also challenging to model mechanistically from in-vitro data, and, in general, prediction of human pharmacokinetics for transported molecules is difficult because absorption, distribution and elimination can all be affected [18].”
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Miller, N. A., Reddy, M. B., Heikkinen, A. T., Lukacova, V., & Parrott, N. (2019) · Clinical Pharmacokinetics · doi:10.1007/s40262-019-00741-9 · Cited by 142 · see citing works
“Renal [39, 40] and biliary [41] elimination involving active transport are also challenging to model mechanistically from in-vitro data, and, in general, prediction of human pharmacokinetics for transported molecules is difficult because absorption, distribution and elimination can all be affected [18].”
BackgroundMathialagan, S., Piotrowski, M. A., Tess, D. A., Feng, B., Litchfield, J., & Varma, M. V. (2017) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.074294 · Cited by 128 · see citing works
Development of a Dynamic Physiologically Based Mechanistic Kidney Model to Predict Renal Clearance
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- Authors
- Kunze, A., Huwyler, J., Poller, B., Gutmann, H., & Camenisch, G.
- Affiliations
- Novartis (Switzerland) (CH)
- University of Basel (CH)
- Corresponding author
- Camenisch, Gian
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 103
- Issue
- 3
- Pages
- 994-1001
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W2105151902
- Cited by
- 48
- References
- 29
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 1 · 2022: 9 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 1
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- in vitro-in vivo extrapolation, renal clearance, glomerular filtration, renal tubular secretion, tubular reabsorption, LLC-PK1 cells, kidney model, anionic drugs
- MeSH terms
- Absorption, Algorithms, Animals, Biological Transport, Cell Membrane Permeability, Pharmaceutical Preparations, Glomerular Filtration Rate, Humans, Kidney, Kidney Tubules, Metabolic Clearance Rate, Models, Biological, Permeability, Pharmacokinetics, Swine, Reproducibility of Results, LLC-PK1 Cells
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