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Updated: May 9, 2026
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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
In vitro-in vivo correlation for low-clearance compounds using hepatocyte relay method
Li Di1, Karen Atkinson, Christine C Orozco
1Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut.
Summary
A new hepatocyte relay method enables reliable in vitro-in vivo correlation (IVIVC) for predicting human pharmacokinetics of low-clearance drugs. This assay addresses challenges in preclinical species, improving drug discovery confidence.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Preclinical Drug Development
- In Vitro-In Vivo Correlation (IVIVC)
Background:
- Accurate prediction of human pharmacokinetics is crucial for drug discovery.
- Low-clearance compounds present challenges for traditional in vitro-in vivo correlation (IVIVC) methods in preclinical species.
- Existing methods struggle to reliably predict human pharmacokinetics for compounds with complex clearance mechanisms.
Purpose of the Study:
- To establish an in vitro-in vivo correlation (IVIVC) for intrinsic clearance in preclinical species (rat and dog).
- To support high-confidence prediction of human pharmacokinetics for low-clearance compounds.
- To introduce a novel assay addressing low-clearance challenges in drug discovery.
Main Methods:
- Utilized the hepatocyte relay method to assess intrinsic clearance.
- Established IVIVC for intrinsic clearance in rat and dog models.
- Evaluated compound clearance involving transporter-mediated uptake and extrahepatic metabolism.
Main Results:
- Achieved good IVIVC for intrinsic clearance for most tested compounds.
- Predicted values were within a 2-fold range of observed values.
- Identified exceptions related to transporter activity and extensive extrahepatic metabolism.
Conclusions:
- The hepatocyte relay method provides a reliable IVIVC for low-clearance compounds in preclinical species.
- This assay enhances the prediction of human pharmacokinetics, aiding drug discovery.
- It is the first assay to effectively address low-clearance challenges for IVIVC in drug discovery.
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