Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

Back

Prioritization of Clinical Drug Interaction Studies Using In Vitro Cytochrome P450 Data:“Rank Order” Approach

Author(s): A. David Rodrigues.

Abstract:

For any new chemical entity (NCE), in vitro inhibition constants (Ki) for the different human cytochrome P450 (CYP) forms can be ranked (lowest to highest). The CYP form with the lowest in vitro Ki is evaluated first clinically, employing a suitable probe drug like midazolam (CYP3A4), theophylline (CYP1A2), (S)-warfarin (CYP2C9) and desipramine (CYP2D6), and the NCE is classified as a “none”, “weak”, “moderate”, or “strong” inhibitor. In turn, the classification governs the next steps. A two stage strategy, in vitro ranking followed by classification, has the potential to enable decision making within an industrial and regulatory setting. With additional refinement and validation, the approach could be applied to mechanism-based inhibitors, inducers and substrates of CYPs also.

Keywords: Cytochrome P450, classification, interactions, inhibition, in vitro, strategy

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

VOLUME: 1
ISSUE: 1
Year: 2007
Page: [31 - 35]
Pages: 5
DOI: 10.2174/187231207779814247