PT  - JOURNAL ARTICLE
AU  - Yu, Hongbin
AU  - Balani, Suresh K.
AU  - Chen, Weichao
AU  - Cui, Donghui
AU  - He, Ling
AU  - Humphreys, William Griffith
AU  - Mao, Jialin
AU  - Lai, W. George
AU  - Lee, Anthony J.
AU  - Lim, Heng-Keang
AU  - MacLauchlin, Christopher
AU  - Prakash, Chandra
AU  - Surapaneni, Sekhar
AU  - Tse, Susanna
AU  - Upthagrove, Alana
AU  - Walsky, Robert L.
AU  - Wen, Bo
AU  - Zeng, Zhaopie
TI  - Contribution of Metabolites to P450 Inhibition-Based Drug-Drug Interactions: Scholarship from the IQ DMLG Metabolite Group
AID  - 10.1124/dmd.114.059345
DP  - 2015 Feb 05
TA  - Drug Metabolism and Disposition
PG  - dmd.114.059345
4099  - http://dmd.aspetjournals.org/content/early/2015/02/05/dmd.114.059345.short
4100  - http://dmd.aspetjournals.org/content/early/2015/02/05/dmd.114.059345.full
AB  - Recent EMA (final) and FDA (draft) drug interaction guidances 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% parent and ≥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 of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 inhibition-based DDI. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed 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 low. Only metabolites from 5 out of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDI. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: consider structural alerts that suggest P450 inhibition potential; and use multiple approaches, including approaches by Yu & Tweedie (2013, a metabolite cut-off value of 100% of parent AUC) and Callegari et al. (2013, the Rmet strategy), to predict P450 inhibition-based DDI caused by metabolites in the clinic.