Prediction of Phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling

Abstract

1. Ten compounds from the Merck Research Laboratories pipeline were selected to evaluate the utility of using intrinsic clearance derived from recombinantly expressed cytochromes P450 (CYP) and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics using simCYP. The compounds selected were anticipated to be eliminated predominantly by P450 metabolism.

2. There was a reasonable agreement between the predicted and actual clinical exposure with 80% of the predicted exposures being within three-fold of the observed values. Furthermore, prediction of C(t) (plasma concentration at a specified time point) and T_max were acceptable with greater than or equal to 70% of the predicted data being within three-fold of the observed values. However, prediction of C_max was unreliable and may have been due to error in predicting the time-dependent change in volume of distribution and/or error in estimating absorption rate.

3. Although it is acknowledged that research is needed to improve predictive performance, the data presented are supportive of using recombinant P450 intrinsic clearance and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics for compounds eliminated by P450 metabolism.

Keywords::

• Recombinant cytochrome P450 (rCYP)
• physiologically based pharmacokinetic modelling (PBPK)
• prediction

Acknowledgement

The authors would like to thank all of their colleagues at Merck Research Laboratories who worked on the compounds included in this analysis. They also would like to thank BD Gentest for graciously providing the immunoquantitation data for the pooled human liver microsomes used in this study. Finally, the authors would like to thank Professor Malcolm Rowland for his helpful suggestions.

Declaration of interest: The authors report no conflicts of interest.