Do Inhibitory Metabolites Impact DDI Risk Assessment? Analysis of in vitro and in vivo Data from NDA Reviews Between 2013 and 2018

Abstract

Evaluating the potential of new drugs and their metabolites to cause drug-drug interactions (DDIs) is critical for understanding drug safety and efficacy. Although multiple analyses of proprietary metabolite testing data have been published, no systematic analyses of metabolite data collected according to current testing criteria have been conducted. To address this knowledge gap, 120 new molecular entities approved between 2013 and 2018 were reviewed. Comprehensive data on metabolite-to-parent area under the curve ratios (AUC_M /AUC_P ), inhibitory potency of parent and metabolites, and clinical DDIs were collected. Sixty-four percent of the metabolites quantified in vivo had AUC_M /AUC_P ≥ 0.25 and 75% of these metabolites were tested for cytochrome P450 (CYP) inhibition in vitro, resulting in 15 metabolites with potential DDI risk identification. Although 50% of the metabolites with AUC_M /AUC_P < 0.25 were also tested in vitro, none of them showed meaningful CYP inhibition potential. The metabolite percentage of plasma total radioactivity cutoff of ≥ 10% did not appear to add value to metabolite testing strategies. No relationship between metabolite versus parent drug polarity and inhibition potency was observed. Comparison of metabolite and parent maximum concentration (C_max ) divided by inhibition constant (K_i ) values suggested that metabolites can contribute to in vivo DDIs and, hence, quantitative prediction of clinical DDI magnitude may require both parent and metabolite data. This systematic analysis of metabolite data for newly approved drugs supports an AUC_M /AUC_P cutoff of ≥ 0.25 to warrant metabolite in vitro CYP screening to adequately characterize metabolite inhibitory DDI potential and support quantitative DDI predictions.

Figure 1:

Workflow for the conducted analysis from the New Drug Applications (NDAs) approved between 2013 and 2018. A prodrug was defined as an inactive compound with no pharmacological activity that must be activated by a metabolic process to the active moiety. Bolded text indicates the analyses directly addressing project aims. PK, pharmacokinetics; PBPK, physiologically based pharmacokinetics; DDI, drug-drug interactions; CYP, cytochrome P450

Figure 2:

A) Distribution of the ratio of metabolite area under the curve (AUC_M) to parent area under the curve (AUC_P) (AUC_M/AUC_P) of the 104 quantified metabolites from 55 parent drugs collected from the analyzed new drug applications. Purple bars indicate metabolites for which in vitro cytochrome P450 (CYP) inhibition data were available for and yellow bars show metabolites that lacked in vitro CYP inhibition data. B) Analysis of the correlation between AUC_M/AUC_P and % total radioactivity in plasma (%TRA) for all quantified metabolites with mass balance data (n=79). Purple symbols indicate metabolites for which in vitro CYP inhibition data were available for and yellow symbols show metabolites that lacked in vitro CYP inhibition data. The quadrants show the following: Quadrant I - AUC_M/AUC_P <25%, %TRA ≥10% (n=5); Quadrant II - AUC_M/AUC_P ≥25%, %TRA ≥10% (n=40); Quadrant III - AUC_M/AUC_P <25%, %TRA <10% (n=19); Quadrant IV - AUC_M/AUC_P ≥25%, %TRA <10% (n=15). C) Venn diagram showing the overlap between metabolites that had AUC_M/AUC_P ≥25%, or %TRA ≥10% for the metabolites that were quantified in vivo and tested for CYP inhibition in vitro (n=58).

Figure 3:

Distribution of the ratio of metabolite area under the curve (AUC_M) to parent area under the curve (AUC_P) (AUC_M/AUC_P) (n=68) data and % total radioactivity in plasma (%TRA) of the metabolite in plasma (n=57) data for metabolites that were tested for cytochrome P450 (CYP) inhibition. For each metabolite with AUC or %TRA data the panels below show the highest metabolite R Value for a given CYP and the bottom panels show the corresponding parent R values for the same CYP as tested with the metabolite. The gray dashed horizontal lines in metabolite and parent R value plots indicate the 1.1 cutoff value while vertical dashed line separates metabolite R-values for metabolites that had AUC_M/AUC_P <25% or AUC_M/AUC_P ≥25% (left panel) or %TRA<10% or ≥10%.