New IVIVE method for the prediction of total human clearance and relative elimination pathway contributions from in vitro hepatocyte and microsome data
Abstract
Total human clearance is a key determinant for the pharmacokinetic behavior of drug candidates. Our group recently introduced the Extended Clearance Model (ECM) as an accurate in vitro-in vivo extrapolation (IVIVE) method for the prediction of hepatic clearance. Yet, knowledge about relative elimination pathway contributions is needed in order to predict the total human clearance of drug candidates. In the present work, a training set of 18 drug compounds was used to describe the affiliations between in vitro sinusoidal uptake clearance and the fractional contributions of hepatic (metabolic and biliary) or renal clearance to overall in vivo elimination. By means of these quantitative relationships and using a validation set of 10 diverse drug molecules covering different (sub)classes of the Extended Clearance Concept Classification System (ECCCS), the relative contributions of elimination pathways were calculated and demonstrated to well correlate with human reference data. Likewise, ECM- and pathway-based predictions of total clearances from both data sets demonstrated a strong correlation with the observed clinical values with 26 out of 28 compounds within a three-fold deviation. Hence, total human clearance and relative contributions of elimination pathways were successfully predicted by the presented method using solely hepatocyte and microsome in vitro data.
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IVIVE is more physiologically relevant than AS because it incorporates physiological factors and includes the possibility to expand with mechanistic models.
“it is more physiologically relevant than AS, considering that IVIVE incorporates physiological factors and includes the possibility to expand with the mechanistic model [8,9].”
From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [8]
Cites
Pang, K. S., & Rowland, M. (1977) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01059688 · Cited by 797 · see citing works
Ring, B. J., Chien, J. Y., Adkison, K. K., Jones, H. M., Rowland, M., Jones, R. D., Yates, J. W. T., Ku, M. S., Gibson, C. R., He, H., et al. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22552 · Cited by 206 · see citing works
Camenisch, G., & Umehara, K. (2012) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1784 · Cited by 76 · see citing works
Self-citationNovel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat
Umehara, K.-I., & Camenisch, G. (2012) · Pharmaceutical Research · doi:10.1007/s11095-011-0607-2 · Cited by 65 · see citing works
Self-citationThe extended clearance model and its use for the interpretation of hepatobiliary elimination data
Camenisch, G., Riede, J., Kunze, A., Huwyler, J., Poller, B., & Umehara, K. (2015) · ADMET & DMPK · doi:10.5599/admet.3.1.144 · Cited by 32 · see citing works
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Choi, G.-W., Lee, Y.-B., & Cho, H.-Y. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11040168 · Cited by 76 · see citing works
“Although to project in vitro to in vivo data is difficult due to the complexity of the interdependent biological processes and their dynamic nature [7], it is more physiologically relevant than AS, considering that IVIVE incorporates physiological factors and includes the possibility to expand with the mechanistic mod…”
BackgroundMethod
- Authors
- Riede, J., Poller, B., Umehara, K.-I., Huwyler, J., & Camenisch, G.
- Affiliations
- University of Basel (CH)
- Novartis Institutes for BioMedical Research (CH)
- Novartis (Switzerland) (CH)
- Corresponding author
- Camenisch, Gian
- Venue
- European Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 86
- Pages
- 96-102
- ISSN
- 0928-0987 (ISSN-L)
- OpenAlex
- W2289426885
- Cited by
- 21
- References
- 5
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 1
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- in vitro-in vivo extrapolation, biliary excretion, renal clearance, hepatic drug metabolism, drug clearance prediction
- MeSH terms
- Pharmaceutical Preparations, Humans, Kidney, Metabolic Clearance Rate, Microsomes, Liver, Models, Biological, Hepatocytes
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