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Human clearance prediction: shifting the paradigm.

Thierry Lavé¹, Kathryn Chapman, Paul Goldsmith

¹F. Hoffmann-La Roche Ltd, Basel, Switzerland. thierry.lave@roche.com

Expert Opinion on Drug Metabolism & Toxicology

|July 21, 2009

Summary

This summary is machine-generated.

Predicting human clearance is shifting from in vivo to in vitro methods integrated with physiologically based pharmacokinetic models. While effective for hepatic clearance, challenges remain for transport-mediated elimination, necessitating mechanistic approaches for accuracy and variability assessment.

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Area of Science:

Pharmacokinetics
Drug Metabolism and Disposition
Toxicology

Background:

Traditional in vivo allometric scaling for human clearance prediction is being supplanted by in vitro methods.
In vitro data integrated with in silico physiologically based pharmacokinetic (PBPK) models are emerging as a primary prediction source.
Established methods exist for hepatic clearance of lipophilic compounds, but limitations persist for other elimination routes.

Purpose of the Study:

To review advances in in vitro methods for predicting hepatic and renal clearance.
To emphasize the role of mechanistic approaches in clearance prediction.
To address challenges in assessing variability and uncertainty in clearance predictions.

Main Methods:

Assessment of in vitro methodologies for drug clearance prediction.
Integration of in vitro data with in silico physiologically based pharmacokinetic (PBPK) models.
Focus on mechanistic approaches for scaling and variability assessment.

Main Results:

In vitro methods show high accuracy for hepatic clearance of lipophilic metabolised compounds.
Limitations of in vitro methods are noted for clearance mechanisms involving active transport (hepatobiliary and renal elimination).
Physiologically based scaling offers a promising approach for integrating variability and uncertainty.

Conclusions:

A paradigm shift towards in vitro and in silico methods for human clearance prediction is underway.
Mechanistic and integrative approaches are crucial for addressing limitations in current in vitro methods, especially for transport-mediated elimination.
Further development of in vitro and mechanistic models is needed for comprehensive and accurate clearance predictions, including variability assessment.