Prediction of in vivo drug clearance from in vitro data. I: Impact of inter-individual variability
Abstract
The Simcyp Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data. Fifteen drugs satisfied the entry criteria for the study and the relevant information (in vitro metabolism data and in vivo human clearance values) were collated from the literature. Predicted values of median clearances fell within 2-fold of observed values for 73% of the drugs (oral route) and 78% of the drugs (intravenous route) when microsomal binding was disregarded, and for 93% (oral) and 100% (intravenous) when it was considered. Irrespective of whether microsomal binding was considered, the predicted fold variability fell within 2-fold of the observed variability for 80% (oral) and 67% (intravenous) of the drugs.
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Howgate et al. revealed that most fu,mic values are high enough to be ignored in the prediction of clearance, but few compounds with high microsomal binding should be considered to accurately predict in vivo clearance.
“Howgate et al. [65] revealed that most of the fu,mic values are high enough to be ignored in the prediction of clearance. However, the few compounds with high microsomal binding should be considered to accurately predict the in vivo clearance.”
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 [65]
Inclusion of the microsomal protein content and CYP abundances that affect the IIV did not show the trend of underestimation.
“Inclusion of the microsomal protein content and CYP abundances that affect the IIV did not show the trend of underestimation.”
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 [65]
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“[65] revealed that most of the fu,mic values are high enough to be ignored in the prediction of clearance.”
Background
- Authors
- Howgate, E. M., Rowland Yeo, K., Proctor, N. J., Tucker, G. T., & Rostami-Hodjegan, A.
- Affiliations
- Simcyp (United Kingdom) (GB)
- Royal Hallamshire Hospital (GB)
- Venue
- Xenobiotica
- Publisher
- Informa UK Limited
- Published
- 2006-06
- Volume
- 36
- Issue
- 6
- Pages
- 473-497
- ISSN
- 0049-8254 (ISSN-L)
- 1366-5928
- OpenAlex
- W2114464891
- Cited by
- 223
- References
- 2
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 18 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 12 · 2018: 9 · 2017: 12 · 2016: 15 · 2015: 14 · 2014: 6 · 2013: 16 · 2012: 17
- FWCI
- 9.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Xenobiotica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- in vitro-in vivo extrapolation, interindividual variability, SimCYP, drug metabolism, microsomal binding, clearance prediction
- MeSH terms
- Administration, Oral, Animals, Drug Evaluation, Preclinical, Pharmaceutical Preparations, Humans, Injections, Intravenous, Models, Biological, Pharmacokinetics, Predictive Value of Tests, Software, Observer Variation
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