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CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs

Zimmerlin, Alfred Gilbert, Trunzer, Markus and Faller, Bernard (2011) CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs. Drug Metabolism and Disposition, 39 (6). pp. 1039-1046. ISSN 0090-9556


Although reversible CYP3A inhibition testing is well established to predict the drug to drug interaction potential of clinical candidates it is only recently that time dependent inhibition (TDI) became the focus of drug designers. This particular inhibition mechanism was indeed the source of a few documented late stage failures and is strongly suspected to participate in the frequently disqualifying liver toxicities in pre-clinical species. Because of the specific challenges of measuring enzyme inactivation rates and its characteristic parameters kinact and KI, a great deal of variability can be found in the literature. In this paper we measured these parameters for 63 known CYP3A inactivators using a single robust method. Taking advantage of its specific design and miniaturisation, a screening assay based on inactivation rate (kobs) at 10 µM test article concentration was validated versus the current gold standard assay, the IC50 shift. More than 375 World Drug Index compounds have been profiled and used to exemplify the specific advantages of this alternative method. Using an empirically defined positive/negative kobs bin of 0.02 min-1, 4% of WDI drugs only were found positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of filtering this property out to make good drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure activity relationships and in silico modelling.

Item Type: Article
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Keywords: cytochrome P450, CYP3A4, Time dependent inhibition, Drug interaction, Inactivation, mechanism-based
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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