Contribution of Metabolites to P450 Inhibition–Based Drug–Drug Interactions: Scholarship from the Drug Metabolism Leadership Group of the Innovation and Quality Consortium Metabolite Group

Abstract

Recent European Medicines Agency (final) and US Food and Drug Administration (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 the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ‡25% of the parent and ‡10% of the total drug-related AUC (European Medicines Agency). 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 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 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 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R met strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the “Metabolites in Safety Testing” Regulatory Guidance

“…Such cases are relatively infrequent (Yeung et al, 2011;Callegari et al, 2013;Yu and Tweedie, 2013;Yu et al, 2015). However in one instance the inhibition of cerivastatin clearance (mediated by CYP2C8 and OATP1B1) by the glucuronide metabolite of gemfibrozil led to tragic consequences (Staffa et al, 2002;Shitara et al, 2004).…”

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

“…Recently, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted an evaluation of having a metabolite as the sole contributor to P450 inhibition-based DDIs. After a thorough review of the literature and analysis of frequently prescribed drugs, the group concluded that the risk of P450 inhibition caused by a metabolite alone is low (Yu et al, 2015). In the current study, we highlight the role of AO in the formation of the hydroxyl metabolite of decernotinib [(R)-2-((2-(1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509)], which may be the major contributor involved in a TDI-based DDI.…”

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

“…AMIO, itself, appears to be a fairly weak in vitro inhibitor of these enzymes (Kobayashi et al, 1998;Ohyama et al, 2000), which raises the possibility that inhibitory metabolites play a more direct role than the parent drug. In fact, a recent literature review identified AMIO as one of only five out of 137 total pharmaceuticals to cause a metabolism-dependent clinical DDI judged to be due entirely to an inhibitory metabolite(s), with little to no contribution of the parent drug (Yu et al, 2015). Therefore, a more complete analysis of AMIO-P450 inhibition should provide a useful case study in helping to determine which future drugs are more at risk of a metabolism-dependent DDI caused by inhibitory metabolites.…”