Association between circadian and chemotherapeutic cycle effects on plasma concentration of 5‑fluorouracil and the clinical outcome following definitive 5‑fluorouracil/cisplatin‑based chemoradiotherapy in patients with esophageal squamous cell carcinoma

Abstract

Therapeutic drug monitoring (TDM) of 5-fluorouracil (5-FU) is believed to be a clinical option for improving clinical responses. Evaluating the potential factors contributing to plasma 5-FU concentration is important to develop TDM of 5-FU. Our aim was to evaluate the association of the circadian and treatment cycle effects on plasma 5-FU concentration with the clinical response. A post hoc population analysis was performed using the plasma concentration of 5-FU and clinical response data, including prognosis from 49 patients with esophageal squamous cell carcinoma after treatment with definitive 5-FU/cisplatin-based chemoradiotherapy, consisting of prolonged infusion of 5-FU at 400 mg/(m 2 •day) for 5 days. The circadian rhythm and treatment cycle were applied as covariates to the model equation. The plasma 5-FU concentration in the evening was 1.3-fold higher compared with the morning, and in the second cycle, it was 1.5-fold increased compared with the first cycle, with relatively small inter-individual variations (23.3 and 16.8%). Clinical efficacy depended on the plasma 5-FU concentration, excluding the covariate effects (P=0.025), which correlated with age and height but not body surface area. Circadian variation did not contribute to the clinical response, and the increase in 5-FU plasma concentration in the second cycle significantly correlated with leucocyte counts obtained before chemoradiotherapy. The higher plasma concentration of 5-FU in the early phase of treatment may be the key determinant of clinical efficacy, whereas the variations in the plasma concentration of 5-FU owing to the time of day and treatment cycle are small contributors.

The association of ABCC5 and ABCC11 polymorphisms with the pharmacokinetics of 5-FU in advanced gastric cancer patients

“…Because of the short half-life of 5-FU (10-15 minutes), the C ss of the samples are suggested to be taken at least 18 hr after the start of 5-FU infusion (9,10). 5-FU infusion started at the same time for all patient and plasma samples were collected near the same time of the day after starting infusion to eliminate circadian changes in 5-FU metabolism (19)(20)(21).…”

Overcoming barriers to implementing precision dosing with 5‐fluorouracil and capecitabine

“…In a study using population model analysis in oesophageal squamous cell carcinoma patients receiving an 5FU IV infusion over 5 days, plasma 5FU concentrations were observed to be higher in the evening compared to the morning. The authors reported that circadian variations in 5FU plasma concentration during continuous infusion was relatively small and did not contribute to clinical response or toxicity 17 …”

“…##DPYD variants screening is being used in routine clinical practice for both 5FU and capecitabine variations in 5FU plasma concentration during continuous infusion was relatively small and did not contribute to clinical response or toxicity. 17 Inhibition of DPD activity by coadministered drugs will also affect 5FU pharmacokinetics. Fatalities due to DPD inhibition occurred when the antiviral drug sorivudine was coadministered with 5FU.…”

Current status and future outlooks on therapeutic drug monitoring of fluorouracil

“…However, the proper identification of covariates influencing 5FU PK would be crucial for such models. So far, published 5FU models could only include a very heterogenous set of covariates [89,[92][93][94][173][174][175][176]. Particularly, DPYD genotypes could not be successfully implemented.…”