Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 39, 2009 - Issue 9
347
Views
19
CrossRef citations to date
0
Altmetric
Research Article

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

, , , , &
Pages 637-648 | Received 02 Mar 2009, Accepted 07 Apr 2009, Published online: 29 May 2009
 

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 Tmax were acceptable with greater than or equal to 70% of the predicted data being within three-fold of the observed values. However, prediction of Cmax 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.

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.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 65.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 897.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.