Influence of age on pharmacokinetics of capecitabine and its metabolites in older adults with cancer: a pilot study.

Abstract

Capecitabine is an oral chemotherapy prodrug of 5-fluorouracil (5-FU) with unpredictable toxicity, especially in older adults. The aim of this study was to evaluate the pharmacokinetics (PK) of capecitabine and its metabolites in younger adults (< 70years) and older adults (≥ 70years) receiving capecitabine for solid cancer. Eligible participants receiving capecitabine had 2 venous samples collected on day 14 of cycle 1 and cycle 2 of their treatment. Capecitabine and metabolite concentrations were determined using liquid chromatography with tandem mass spectrometry. A Bayesian estimation approach was used to generate individual estimates of PK parameters for 5-FU. A linear mixed-effect analysis of variance (ANOVA) model was used to compare dose-normalised log-transformed PK parameters between age groups. Correlations were determined by linear regression and logistic regression analyses. Of the total 26 participants, 58% were male with a median age of 67years (range, 37-85) with 54% aged < 70years and 46% aged ≥ 70years. Participants aged ≥ 70years, compared to those aged < 70years, had a greater 5-FU exposure based on area under the concentration-time curve (AUC) of 17% (90% CI 103-134%; 0.893 vs. 0.762mg h/L) and 14% increase in maximal concentration, Cmax (90% CI 82.1-159%; 0.343 vs. 0.300mg/L). The 5-FU Cmax was positively associated with time up and go (TUG) (Pearson's correlation 0.77, p = 0.01), but not other geriatric assessment domains or severe toxicity. 5-FU exposure was significantly increased in older adults compared to younger adults receiving equivalent doses of capecitabine, and is a possible cause for increased toxicity in older adults.