Abstract
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.
- The American Society for Pharmacology and Experimental Therapeutics