Raloxifene as a candidate intestinal UGT1A probe during irinotecan-based chemotherapy: an open-label, two-cohort pilot pharmacokinetic and short-term safety study

Objective Preclinical studies suggested that raloxifene (Ral) metabolite-to-parent ratios may reflect intestinal UGT1A activity during irinotecan-induced intestinal injury, but clinical feasibility and short-term safety remain unclear. This open-label, two-cohort pilot study aimed to evaluate the feasibility of Ral pharmacokinetic and metabolite-to-parent ratio profiling in patients receiving irinotecan-based chemotherapy and to describe short-term safety findings during protocol-defined co-administration with Xiao Chai Hu Tang (XCHT) and/or FOLFIRI. Methods Group A enrolled six irinotecan-naïve postmenopausal women. Conventional pharmacokinetic summaries included five patients after exclusion of one aberrant pharmacokinetic profile, whereas six patients were retained for metabolic-ratio and safety summaries. Group B enrolled eighteen patients with prior grade ≥2 irinotecan-associated diarrhoea; four did not complete all treatment rounds, leaving fourteen patients for repeated-measures pharmacokinetic and cycle-level safety analyses. Adverse events were summarized using participant-level or chemotherapy-cycle-level denominators, as appropriate. Results Ral pharmacokinetic profiles were obtained under protocol-defined treatment conditions, including Ral alone, Ral with XCHT, and Ral around FOLFIRI chemotherapy. Conventional Ral pharmacokinetic parameters showed variability across treatment conditions, and no marked short-term pharmacokinetic change was detected descriptively in this small pilot study. Metabolite-to-parent ratios varied across rounds and remained exploratory. No grade 4 or life-threatening toxicity was observed during the study period. Conclusion Ral pharmacokinetic and metabolite-to-parent ratio profiling was feasible during irinotecan-based chemotherapy. No grade 4 or life-threatening toxicity was observed in this open-label pilot study. However, the small nonrandomized design precludes conclusions about overall safety, pharmacokinetic equivalence, drug–drug interactions, or raloxifene probe validity. Larger controlled studies are needed.