Comparison of methods for the prediction of human clearance from hepatocyte intrinsic clearance for a set of reference compounds and an external evaluation set

Abstract

1. We compared direct scaling, regression model equation and the so-called “Poulin et al.” methods to scale clearance (CL) from in vitro intrinsic clearance (CL_int) measured in human hepatocytes using two sets of compounds. One reference set comprised of 20 compounds with known elimination pathways and one external evaluation set based on 17 compounds development in Merck (MS).

2. A 90% prospective confidence interval was calculated using the reference set. This interval was found relevant for the regression equation method. The three outliers identified were justified on the basis of their elimination mechanism.

3. The direct scaling method showed a systematic underestimation of clearance in both the reference and evaluation sets. The “Poulin et al.” and the regression equation methods showed no obvious bias in either the reference or evaluation sets.

4. The regression model equation was slightly superior to the “Poulin et al.” method in the reference set and showed a better absolute average fold error (AAFE) of value 1.3 compared to 1.6. A larger difference was observed in the evaluation set were the regression method and “Poulin et al.” resulted in an AAFE of 1.7 and 2.6, respectively (removing the three compounds with known issues mentioned above). A similar pattern was observed for the correlation coefficient. Based on these data we suggest the regression equation method combined with a prospective confidence interval as the first choice for the extrapolation of human in vivo hepatic metabolic clearance from in vitro systems.

Keywords:

• Liver
• metabolism
• scaling
• well-stirred model
• in vitro–in vivo extrapolation
• Poulin et al. method
• regression equation

Acknowledgements

Tobias Feige is gratefully acknowledged for help with the clinical data analysis. Christian Stelz and Christiane Müller are gratefully acknowledged for technical assistance.

Declaration of interest

This work was supported by Merck. All authors were employed by Merck at the time this study was performed.