Prioritization of clinical drug interaction studies using in vitro cytochrome P450 data: proposed refinement and expansion of the "rank order" approach.
For any new chemical entity (NCE), in vitro inhibition constants (K(i)) for the different human cytochrome P450 (CYP) forms can be ranked (lowest to highest). The CYP form with the lowest in vitro K(i) 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.
Bristol-Myers Squibb, Pharmaceutical Research Institute, Mailstop F14-04, P.O. Box 4000, Princeton, NJ 08543, USA. david.rodrigues@bms.com
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D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004345:Drug Industry / Q000379:methods; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000145:classification / Q000494:pharmacology*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System