Are circulating metabolites important in drug-drug interactions?: Quantitative analysis of risk prediction and inhibitory potency

Abstract

The potential of metabolites to contribute to drug-drug interactions (DDIs) is not well defined. The aim of this study was to determine the quantitative role of circulating metabolites in inhibitory DDIs in vivo. The area under the plasma concentration-time curve (AUC) data related to at least one circulating metabolite was available for 71% of the 102 inhibitor drugs identified. Of the 80 metabolites characterized at steady state, 78% had AUCs >10% of that of the parent drug. A comparison of the inhibitor concentration/inhibition constant ([I]/K(i)) ratios of metabolites and the respective parent drugs showed that 17 of the 21 (80%) reversible inhibitors studied had metabolites that were likely to contribute to in vivo DDIs, with some metabolites predicted to have inhibitory effects greater than those of the parent drug. The in vivo drug interaction risks associated with amiodarone, bupropion, and sertraline could be identified from in vitro data only, when data pertaining to metabolites were included in the predictions. In conclusion, cytochrome P450 (CYP) inhibitors often have circulating metabolites that contribute to clinically observed CYP inhibition.

Figure 1

Distribution of metabolite to parent AUC ratios amongst all analyzed inhibitors. Panel A shows all the inhibitors analyzed in Appendices 1 and 2 with each bar representing a specific metabolite-parent pair. Blue bars refer to steady-state data and red bars to single dose data. The percentages above the bars indicate the fraction of inhibitors in each group (AUC_M/AUC_P≤ 0.1; 0.1<AUC_M/AUC_P >1; AUC_M/AUC_P ≥1). Panel B shows the distribution of AUC_M/AUC_P ratios for the inhibitors that had available in vivo interaction data including clearance or AUC data from marker substrates and were classified according to the FDA-recommended system (www.fda.gov/cder/drug/drugInteractions/) as potent (> 5-fold increase in AUC), moderate (> 2- but < 5-fold increase in AUC), or weak (> 1.25- but < 2-fold increase in AUC) inhibitors of the target enzyme.

Figure 2

Evaluation of DDI risk with [I]/K_i data for inhibitors presented in Table 2. Panels A and B show the correlation between in vitro risk assessment and the magnitude of in vivo DDIs when only parent drug is accounted for (A) and when parent and metabolites are analyzed together (B). Panel C shows the 9 zones for prediction in accordance to panels A and B, including true negative, true positive, false negative, and false positive.