A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Abstract

The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at >25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and >10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s).When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety.

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

“…Since DDI potential is an important part of drug safety, it is highly important to proactively manage the DDI risk of metabolites. The combination of the two literature approaches (Callegari et al, 2013;Yu and Tweedie, 2013), which involved a metabolite cut-off value of approximately 100% of the AUC of the parent and consideration of metabolite C max /K i , was able to flag the metabolites of 8 of 10 drugs in category 3 for investigating metabolite P450 inhibition potential in vitro. Structural alerts of metabolites can also be used proactively in planning and prioritizing in vitro DDI studies for metabolites, as in the case of escitalopram and amiodarone.…”

“…Subsequently, Yu and Tweedie (2013) and Callegari et al (2013) published strategies that can be adopted by drug researchers in assessing risks of circulating metabolites as P450 enzyme inhibitors. It has been well known that metabolites can be the perpetrators of DDIs via P450 inhibition.…”

“…There are currently two approaches in the literature to trigger the in vitro assessment of P450 inhibition potential of metabolites (Callegari et al, 2013;Yu and Tweedie, 2013). These two approaches emphasize the importance of considering both the abundance (AUC or C max ) and inhibition potency of metabolites (K i ) in assessing their P450 inhibition potential.…”

“…These two approaches emphasize the importance of considering both the abundance (AUC or C max ) and inhibition potency of metabolites (K i ) in assessing their P450 inhibition potential. Yu and Tweedie (2013) proposed to conduct clinical DDI studies to assess the in vivo inhibition potential for both the parent and metabolites when the parent drug is an inhibitor of one or more P450 enzymes in vitro (i.e., [I]/K i . 0.1, where [I] is the total concentration).…”

“…If both approaches are combined, it would have covered 8 of 10 drugs in category 3 (only ciprofloxacin was not covered by either of these two approaches and these two approaches were not applied to amlodipine due to the lack of data). It is interesting to note that gemfibrozil glucuronide is not covered by the Yu and Tweedie (2013) approach if the 100% of AUC of parent cut-off value is strictly applied; however, it is covered by the Callegari et al (2013) approach using the R met strategy. The opposite is true for the venlafaxine O-desmethyl metabolite, which is not covered by the Callegari et al (2013) approach but is covered by the Yu and Tweedie (2013) approach.…”