Hepatobiliary Clearance Prediction: Species Scaling From Monkey, Dog, and Rat, and In Vitro–In Vivo Extrapolation of Sandwich-Cultured Human Hepatocytes Using 17 Drugs
Open accessAbstract
Hepatobiliary elimination can be a major clearance pathway dictating the pharmacokinetics of drugs. Here, we first compared the dose eliminated in bile in preclinical species (monkey, dog, and rat) with that in human and further evaluated single-species scaling (SSS) to predict human hepatobiliary clearance. Six compounds dosed in bile duct-cannulated (BDC) monkeys showed biliary excretion comparable to human; and the SSS of hepatobiliary clearance with plasma fraction unbound correction yielded reasonable predictions (within 3-fold). Although dog SSS also showed reasonable predictions, rat overpredicted hepatobiliary clearance for 13 of 24 compounds. Second, we evaluated the translatability of in vitro sandwich-cultured human hepatocytes (SCHHs) to predict human hepatobiliary clearance for 17 drugs. For drugs with no significant active uptake in SCHH studies (i.e., with or without rifamycin SV), measured intrinsic biliary clearance was directly scalable with good predictability (absolute average fold error [AAFE] = 1.6). Drugs showing significant active uptake in SCHH, however, showed improved predictability when scaled based on extended clearance term (AAFE = 2.0), which incorporated sinusoidal uptake along with a global scaling factor for active uptake and the canalicular efflux clearance. In conclusion, SCHH is a useful tool to predict human hepatobiliary clearance, whereas BDC monkey model may provide further confidence in the prospective predictions.
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Monkeys are a valuable model for verification of hepatic disposition for transported molecules, particularly for substrates of OATP transporter.
“It has also emerged that monkeys are a valuable model for the verification of hepatic disposition for transported molecules [44] particularly for substrates of the organic anion transporting polypeptide transporter [35].”
From Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies (2019) · cites this paper as [44]
The Discussion reports reasonable concordance between monkey and human hepatobiliary handling, and the Conclusions say monkey models show potential for predicting human hepatobiliary clearance. The source cautions that its monkey dataset is limited, so calling monkeys an established valuable model for verification is stronger than its conclusion. The OATP-specific clause is attached to a different citation [35] and is not assessed here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredData from sandwich-cultured hepatocytes and a consistent IVIVE approach could predict hepatobiliary clearance in humans for 17 diverse drugs.
“For hepatobiliary clearance, it was recently demonstrated that data from sandwich-cultured hepatocytes and a consistent IVIVE approach could predict in humans for 17 diverse drugs [44].”
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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
“For hepatobiliary clearance, it was recently demonstrated that data from sandwich-cultured hepatocytes and a consistent IVIVE approach could predict in humans for 17 diverse drugs [44].”
BackgroundDe Bruyn, T., Ufuk, A., Cantrill, C., Kosa, R. E., Bi, Y.-A., Niosi, M., Modi, S., Rodrigues, A. D., Tremaine, L. M., Varma, M. V. S., et al. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.118.081315 · Cited by 53 · see citing works
Self-citation
- Authors
- Kimoto, E., Bi, Y.-A., Kosa, R. E., Tremaine, L. M., & Varma, M. V. S.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Varma, Manthena V.S.
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 106
- Issue
- 9
- Pages
- 2795-2804
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W2609016189
- Cited by
- 66
- References
- 52
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 8 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 1
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- hepatobiliary clearance, biliary excretion, in vitro-in vivo extrapolation, active uptake, unbound fraction, drug clearance prediction
- MeSH terms
- Animals, Haplorhini, Bile, Cells, Cultured, Dogs, Pharmaceutical Preparations, Humans, Male, Models, Biological, Species Specificity, Cell Culture Techniques, Hepatocytes, Rats, Hepatobiliary Elimination
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