Metabolite Measurement in Index Substrate Drug Interaction Studies: A Review of the Literature and Recent New Drug Application Reviews

Abstract

Background/objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug-drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam).

Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites.

Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes.

Discussion and conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions.

Keywords: drug interaction; metabolism; metabolite; pharmacokinetics.

Figure 1

Main pathways and enzymes involved in caffeine degradation. The green pathway highlights paraxanthine formation, the primary metabolic pathway of caffeine [5].

Figure 2

Correlation between caffeine AUC fold-change and paraxanthine/caffeine AUC ratio fold-change in (A) CYP1A2 inhibition studies and (B) CYP1A2 induction studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 3

Biotransformation pathways of bupropion in vitro. AKR, aldo-keto reductase; HSD, 11-β-hydroxysteroid dehydrogenase 1.

Figure 4

Correlation between bupropion AUC fold-change and hydroxybrupopion/bupropioon AUC ratio fold-change in (A) CYP2B6 inhibition studies and (B) CYP2B6 induction studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 5

Biotransformation pathways of repaglinide in vitro. The principal enzyme responsible is highlighted in bold [19].

Figure 6

Correlation between repaglinide AUC fold-change and M4/repaglinide AUC ratio fold-change in CYP2C8 inhibition studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 7

Correlation between flurbiprofen AUC fold-change and 4′-hydroxyflurbiprofen/flurbiprofen AUC ratio fold-change in CYP2C9 inhibition studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 8

Correlation between omeprazole AUC fold-change and 5-hydroxyomeprazole/omeprazole AUC ratio fold-change in (A) CYP2C19 inhibition studies (B) CYP2C19 induction studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 9

Correlation between desipramine AUC fold-change and 2-hydroxydesipramine/desipramine AUC ratio fold-change CYP2D6 inhibition studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 10

Dextromethorphan demethylation pathways catalyzed by recombinant human CYP2D6 and CYP3A4 [44].

Figure 11

Correlation between dextromethorphan AUC fold-change and dextrorphan/dextromethorphan AUC ratio fold-change in CYP2D6 inhibition studies. The black line represents unity. Light grey shading denotes (+/−) ≥ 2- to 5-fold change.

Figure 12

Correlation between midazolam AUC fold-change and 1′-hydroxymidazolam/midazolam AUC ratio fold-change in (A) CYP3A inhibition studies and (B) CYP3A induction studies. The black line represents unity. Dark grey shading denotes (+/−) ≥ 1.25- to 2-fold change; light grey shading denotes (+/−) ≥ 2- to 5-fold change.