Collecting Metabolite Pharmacokinetics in Drug-Drug Interaction Studies: A Review of Industry Practices and Data Utilization.

INTRODUCTION: Systemic exposure of a sensitive probe is considered a 'gold standard' for assessment of clinical relevance of a potential cytochrome P450 (CYP)-driven drug-drug interaction (DDI). Typically, the change in systemic exposure is judged by the area under the concentration-time curve [AUC]) of the parent, but sometimes metabolite exposure is used to further elucidate the mechanism of the DDI.

METHODS: For this review, we retrieved records of clinical DDI studies conducted between September 2014 and September 2024 for commonly used CYP probes (midazolam [CYP3A4], flurbiprofen [CYP2C9], omeprazole [CYP2C19], bupropion [CYP2B6], repaglinide [CYP2C8], and dextromethorphan [CYP2D6]). We reviewed these records for reported systemic or urinary metabolite endpoints, concordance of parent and metabolite results, and utilization of metabolite data in clinical recommendations reflected in the label of the investigational medicinal product (IMP).

RESULTS: Although DDI studies with probes primarily metabolized by a single pathway (i.e. midazolam, flurbiprofen, omeprazole) often included metabolite endpoints, metabolite data did not add additional sensitivity in detecting the DDI and often were not used in the label recommendations. In contrast, DDI studies with probes that are metabolized by several pathways (i.e. bupropion, repaglinide) demonstrated a higher sensitivity of metabolite-to-parent ratio to detect a DDI compared with use of the parent AUC alone. Urinary phenotyping indexes (as exemplified by dextromethorphan) are rarely collected.

CONCLUSIONS: Based on these findings, we formulated criteria for deciding on the relevance of metabolite endpoints in clinical DDI studies.