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• W3142333332 abstract "Evaluating the potential of new drugs and their metabolites to cause drug‐drug interactions (DDIs) is critical for understanding drug safety and efficacy. Although multiple analyses of proprietary metabolite testing data have been published, no systematic analyses of metabolite data collected according to current testing criteria have been conducted. To address this knowledge gap, 120 new molecular entities approved between 2013 and 2018 were reviewed. Comprehensive data on metabolite‐to‐parent area under the curve ratios (AUC M /AUC P ), inhibitory potency of parent and metabolites, and clinical DDIs were collected. Sixty‐four percent of the metabolites quantified in vivo had AUC M /AUC P ≥ 0.25 and 75% of these metabolites were tested for cytochrome P450 (CYP) inhibition in vitro , resulting in 15 metabolites with potential DDI risk identification. Although 50% of the metabolites with AUC M /AUC P < 0.25 were also tested in vitro , none of them showed meaningful CYP inhibition potential. The metabolite percentage of plasma total radioactivity cutoff of ≥ 10% did not appear to add value to metabolite testing strategies. No relationship between metabolite versus parent drug polarity and inhibition potency was observed. Comparison of metabolite and parent maximum concentration (C max ) divided by inhibition constant ( K i ) values suggested that metabolites can contribute to in vivo DDIs and, hence, quantitative prediction of clinical DDI magnitude may require both parent and metabolite data. This systematic analysis of metabolite data for newly approved drugs supports an AUC M /AUC P cutoff of ≥ 0.25 to warrant metabolite in vitro CYP screening to adequately characterize metabolite inhibitory DDI potential and support quantitative DDI predictions." @default.
• W3142333332 created "2021-04-13" @default.
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• W3142333332 date "2021-05-08" @default.
• W3142333332 modified "2023-10-18" @default.
• W3142333332 title "Do Inhibitory Metabolites Impact DDI Risk Assessment? Analysis of in vitro and in vivo Data from NDA Reviews Between 2013 and 2018" @default.
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• W3142333332 doi "https://doi.org/10.1002/cpt.2259" @default.
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