Circadian variation in plasma 5-fluorouracil concentrations during a 24 hour constant-rate infusion

Abstract

BackgroundVarying the rate of continuous intravenous infusions of 5-fluorouracil (5FU) chemotherapy over a 24-hour period has been reported to improve patient outcomes. It has been hypothesized that circadian variation in drug disposition is a contributing factor. We analyzed 5-FU concentrations during a 24-hour continuous 5-FU infusion.MethodsSixty-four subjects with advanced malignancies including pancreatic, hepatocellular, colorectal as well as other epithelial malignancies and either abnormal hepatic or renal function were treated on a phase I and pharmacokinetic study of weekly 24-hour intravenous infusions of 5-FU and leucovorin. No other concomitant anticancer therapy was administered. Blood samples were collected every three hours from 61 subjects for measurement of plasma 5-FU during the first two weekly infusions.ResultsAfter adjusting for differences in dose, elapsed time from start of infusion and infusion number (2 versus 1), mean 5-FU concentration was highest at 6 am and lowest at 3 pm, with an overall change in the mean from 3 pm to 6 am of +20 percent (95% CI = 12–28%). However, this variation in mean concentration associated with time of day was comparable in magnitude to the between-patient differences, within-patient differences between infusions, and the residual variation within infusion (coefficient of variation = 21%).ConclusionsOur data show systematic variation by time of day in plasma concentrations of 5-FU administered at a constant rate over 24 hours, but it is small compared to the total variation in plasma concentration contributed by other sources. Circadian variation in men was more pronounced than in women.

Comparison of the Eight-Hour With the 22-Hour Infusion of 5-Fluorouracil, in the FOLFOX Chemotherapy of Colon Cancer: A Retrospective Study

“…Evidence exists on circadian changes in 5-FU plasma levels, by prolonged drug infusions (21,24). A higher plasma concentration is observed in the evening, compared with lower levels, in the early morning (15), though studies have had controversial results, in this regard (25). This variability in 5-FU plasma concentration may affect variability in tolerance to the drug and lower therapeutic efficacy (15).…”

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

“…Of note, Cyc significantly correlated with pretherapeutic leucocyte counts: Lower leucocyte counts had greater effects on the magnitude of plasma 5-FU level elevation in the second cycle. Higher 5-FU concentrations in the plasma after repeated treatment with 5-FU in animals and patients have been reported (4,5,13,14). This 5-FU elevation is related to a decrease in clearance and hepatic dihydropyrimidine dehydrogenase (DPD) activity levels (13,14).…”

“…However, circadian variations in the plasma 5-FU concentration were observed during continuous infusion of 5-FU, and the repeated treatment cycle also affected the plasma 5-FU concentration, thereby complicating the analysis of the degree to which these factors affect plasma 5-FU concentrations. These effects make it difficult to analyze the data (5) 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 and to determine appropriate blood sampling time points and plasma 5-FU levels. In our previous study, to normalize the circadian rhythm and the treatment cycle effects on plasma 5-FU concentration, an eight-point average value was used to investigate the association with the clinical response (3).…”

Personalizing fluoropyrimidine administration in colorectal cancer patients

“…A phase I study investigating 24-h 5-FU and LV levels showed systemic fluctuations in drug concentrations depending on the time of day despite a constant rate infusion [26]. These geneticbased circadian rhythms modulate metabolism and distribution in normal tissues.…”