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Contribution of Metabolites to P450 Inhibition-Based Drug-Drug Interactions: Scholarship from the IQ DMLG Metabolite Group

Yu, Hongbin and Balani, Suresh and Chen, Weichao and Cui, Donghui and He, Ling and Humphreys, H. Griffith and Mao, Jialin and Lai, George and Lee, Anthony and Lim, Heng-Keang and MacLauchlin, Christopher and Prakash, Chandra and Surapeneni, Sekhar and Tse, Susanna and Upthagrove, Alana and Walsky, Robert and Wen, Bo and Zheng, Zhaopie (2015) Contribution of Metabolites to P450 Inhibition-Based Drug-Drug Interactions: Scholarship from the IQ DMLG Metabolite Group. Drug Metabolism and Disposition.

Abstract

The 2012 EMA drug interaction guidance and the FDA draft drug interaction guidance proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of parent AUC (FDA) or >25% & >10% of total drug-related AUC (EMA). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group (DMLG) of the Innovation and Quality Consortium (IQ), conducted a scholarship over a 2.5-year period to assess the contributions of metabolites to P450 inhibition-based DDI. The group assessed the risk of having a metabolite as the sole contributor to a DDI based on literature and analysis of 140 most frequently prescribed drugs (as of 2012), defined structural alerts associated with P450 inhibition and inactivation by metabolites, and analyzed the current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is relatively low. Only 8 drugs out of the 140 most frequently prescribed drugs (6%) showed in vivo DDI which were not predicted based on the in vitro P450 inhibition properties of the parent drug. The group recommended two main considerations when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1. Consider key structural alerts that suggest P450 inhibition potential (e.g. alkylamines for mechanism-based inhibition); and 2. Use multiple approaches, including the two literature approaches by Yu & Tweedie (2013) and Callegari et al. (2013), which involved a metabolite cut-off value of approximately 100% of AUC of parent, and consideration of metabolite Cmax/Ki, to minimize surprises in P450 inhibition-based DDI in the clinic.

Item Type: Article
Keywords: Metabolites, P450 inhibition, DDI
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21713

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