Plasma endogenous metabolome as superior biomarkers for adverse effects compared to drug and its metabolites.

[AIMS] This study aims to assess whether pre-chemotherapy endogenous plasma metabolome can offer improved predictive values for Capecitabine chemotherapy-related adverse events (CRAEs).

[RESEARCH DESIGN AND METHODS] Plasma samples were collected from 25 colorectal cancer patients at different time points: 0 hours (before), and 1, 2.5, 4 hours after oral Capecitabine administration, to assess individual variations in exposure levels. Additionally, the endogenous metabolome profile was analyzed using UHPLC/Q-TOF-MS.

[RESULTS] Capecitabine and its metabolites can predict two CRAEs, with 5-FU, 5'-DFCR, and FUH2 exposures being associated with diarrhea and thrombocytopenia, respectively. In contrast, identified plasma endogenous biomarker metabolites can predict all seven observed CRAEs. These CRAE-related endogenous plasma metabolites are involved in various physiological functions, including cell proliferation, maintenance, and inflammation. Pre-chemotherapy endogenous plasma metabolites established superior predictive performance for CRAEs (AUROC values ranging from 0.718 to 0.998) compared to conventional drug exposure (AUROC values ranging from 0.737 to 0.773). Additionally, the endogenous plasma metabolome demonstrated a strong correlation with drug exposures.

[CONCLUSIONS] Our study demonstrates that pre-chemotherapy endogenous plasma metabolome serve as superior biomarkers for predicting CRAEs, outperforming drug exposure levels. However, the limited sample size may impact the generalizability of these findings, and validation in larger patient cohorts is warranted. NCT03030508 (registered at www.clinicaltrials.gov).