Association Between Changes in Plasma Capecitabine Concentrations and Adverse Events in the Treatment of Colorectal Cancer.

Background Therapeutic drug monitoring (TDM) is an effective approach to improving the efficacy of drugs with a narrow therapeutic index and high toxicity. TDM-guided dosing of 5-fluorouracil (5-FU) has been shown to result in superior efficacy and fewer adverse events compared to body surface area (BSA)-based dosing. Therefore, accurate measurement of plasma 5-FU concentrations after capecitabine administration is necessary. Capecitabine is a prodrug of 5-FU and is metabolized to 5-FU in multiple steps in the gastrointestinal tract, liver, and within tumors. To solve the problem of frequent blood draws for TDM, we reduced the number of blood draws to two and examined whether changes in 5-FU concentration correlated with adverse events. Methods This study investigated the relationship between the changes in plasma 5-FU concentrations after one and two hours of capecitabine administration in 36 patients and adverse events based on drug concentrations determined after adding 5-NU to the plasma samples. Concentration gradients and adverse events were estimated using the Mann-Whitney test. Results The median one- and two-hour plasma 5-FU concentrations were 67.5 (range 5-307) and 85.5 (range 19-246) ng/mL, respectively. The plasma 5-FU concentration gradient, defined as the difference between the one- and two-hour concentrations, was significantly higher in patients with diarrhea and nausea (p = 0.0234 and p = 0.0409, respectively). Conclusion The high plasma 5-FU concentration gradient suggests rapid degradation of 5-FU into its metabolites, which may lead to predict intestinal mucosal damage, diarrhea, and nausea.