Comparative Assessment of In Vitro–In Vivo Extrapolation Methods used for Predicting Hepatic Metabolic Clearance of Drugs
Abstract
The purpose of this study was to perform a comparative analysis of various in vitro--in vivo extrapolation (IVIVE) methods used for predicting hepatic metabolic clearance (CL) of drugs on the basis of intrinsic CL data determined in microsomes. Five IVIVE methods were evaluated: the "conventional and conventional bias-corrected methods" using the unbound fraction in plasma (fu(p) ), the "Berezhkovskiy method" in which the fu(p) is adjusted for drug ionization, the "Poulin et al. method" using the unbound fraction in liver (fu(liver) ), and the "direct scaling method," which does not consider any binding corrections. We investigated the effects of the following scenarios on the prediction of CL: the use of preclinical or human datasets, the extent of plasma protein binding, the magnitude of CL in vivo, and the extent of drug disposition based on biopharmaceutics drug disposition classification system (BDDCS) categorization. A large and diverse dataset of 139 compounds was collected, including those from the literature and in house from Genentech. The results of this study confirm that the Poulin et al. method is robust and showed the greatest accuracy as compared with the other IVIVE methods in the majority of prediction scenarios studied here. The difference across the prediction methods is most pronounced for (a) albumin-bound drugs, (b) highly bound drugs, and (c) low CL drugs. Predictions of CL showed relevant interspecies differences for BDDCS class 2 compounds; the direct scaling method showed the greatest predictivity for these compounds, particularly for a reduced dataset in rat that have unexpectedly high CL in vivo. This result is a reflection of the direct scaling method's natural tendency to overpredict the true metabolic CL. Overall, this study should facilitate the use of IVIVE correlation methods in physiologically based pharmacokinetics (PBPK) model.
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Poulin et al.'s mechanistic IVIVE model overcomes the prediction of human CL for drugs with low CLint and high binding affinity for proteins commonly encountered when predicting human CL from in vitro data.
“This mechanistic IVIVE model overcomes the prediction of human CL for drugs with low CLint and high binding affinity for proteins commonly encountered when predicting human CL from in vitro data.”
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 [84]
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Zhang, Y., Zhu, M., Liu, W., Fu, Z., Li, X., & Chen, J. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-15339-6.00034-5 · Cited by 2 · see citing works
Schulz, J., & Kalvass, J. C. (2024) · Xenobiotica · doi:10.1080/00498254.2024.2404170 · Cited by 2 · see citing works
Poulin, P. (2025) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2025.103827 · Cited by 1 · see citing works
Self-citationIn vitro-in vivo extrapolation of human hepatic and renal clearance
Alluri, R. V., & Varma, M. V. S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-820018-6.00022-3
Mammoliti, O., Bonnaterre, F., Newsome, G., Akkari, R., López‐Ramos, M., Babel, M., Jary, H., Cherel, L., Lemos, E. D., Oršulić, M., et al. (2025) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2025.130386
BindingDB (2016) · UC San Diego · doi:10.7270/q2ft8ns4
- Authors
- Poulin, P., Hop, C. E. C. A., Ho, Q., Halladay, J. S., Haddad, S., & Kenny, J. R.
- Affiliations
- Genentech (US)
- Université de Montréal (CA)
- Corresponding author
- Poulin, Patrick
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 101
- Issue
- 11
- Pages
- 4308-4326
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W2031652509
- Cited by
- 64
- References
- 48
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 5 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 4 · 2013: 11 · 2012: 1
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech
- 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, drug metabolism, plasma protein binding, unbound fraction, drug ionization, albumin binding, interspecies scaling, physiologically based pharmacokinetic modeling
- MeSH terms
- Animals, Humans, Liver, Pharmacokinetics
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