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

Kuwahara,Akiko; Kobuchi,Shinji; Tamura,Takao

doi:10.3892/ol.2018.9586

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

Authors:
- Akiko Kuwahara
- Shinji Kobuchi
- Takao Tamura
View Affiliations

Affiliations: School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyōgo 663‑8179, Japan, Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607‑8414, Japan, Department of Medical Oncology, Kindai University Nara Hospital, Ikoma, Nara 630‑0293, Japan
Published online on: October 16, 2018 https://doi.org/10.3892/ol.2018.9586
Pages: 668-675

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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/(m2·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.

View Figures

View References

1	Saif MW, Choma A, Salamone SJ and Chu E: Pharmacokinetically guided dose adjustment of 5-fluorouracil: A rational approach to improving therapeutic outcomes. J Natl Cancer Inst. 101:1543–1552. 2009. View Article : Google Scholar : PubMed/NCBI
2	Lee JJ, Beumer JH and Chu E: Therapeutic drug monitoring of 5-fluorouracil. Cancer Chemother Pharmacol. 78:447–464. 2016. View Article : Google Scholar : PubMed/NCBI
3	Kuwahara A, Yamamori M, Kadoyama K, Nishiguchi K, Nakamura T, Miki I, Tamura T, Okuno T, Omatsu H and Sakaeda T: Effects of plasma concentrations of 5-fluorouracil on long-term survival after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 30:942011. View Article : Google Scholar : PubMed/NCBI
4	Kuwahara A, Yamamori M, Nishiguchi K, Okuno T, Chayahara N, Miki I, Tamura T, Kadoyama K, Inokuma T, Takemoto Y, et al: Effect of dose-escalation of 5-fluorouracil on circadian variability of its pharmacokinetics in Japanese patients with Stage III/IVa esophageal squamous cell carcinoma. Int J Med Sci. 7:48–54. 2010. View Article : Google Scholar : PubMed/NCBI
5	Fleming GF, Schumm P, Friberg G, Ratain MJ, Njiaju UO and Schilsky RL: Circadian variation in plasma 5-fluorouracil concentrations during a 24 h constant-rate infusion. BMC Cancer. 15:692015. View Article : Google Scholar : PubMed/NCBI
6	Kobuchi S, Ito Y, Nakano Y and Sakaeda T: Population pharmacokinetic modelling and simulation of 5-fluorouracil incorporating a circadian rhythm in rats. Xenobiotica. 46:597–604. 2016. View Article : Google Scholar : PubMed/NCBI
7	Kobuchi S, Yazaki Y, Ito Y and Sakaeda T: Circadian variations in the pharmacokinetics of capecitabine and its metabolites in rats. Eur J Pharm Sci. 112:152–158. 2018. View Article : Google Scholar : PubMed/NCBI
8	Kaldate RR, Haregewoin A, Grier CE, Hamilton SA and McLeod HL: Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6. Oncologist. 17:296–302. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cisplatin (BRIPLATIN^®) [Drug information]. Bristol-Myers Squibb. 2017.
10	Kitajima K, Fukuoka M, Kobayashi S, Kusunoki Y, Takada M, Negoro S, Matsui K, Sakai N, Ryu S and Takifuji N: Studies on the appropriate administration of cisplatin based on pharmacokinetics and toxicity. Gan To Kagaku Ryoho. 14:2517–2523. 1987.(In Japanese). PubMed/NCBI
11	Mould DR and Upton RN: Basic concepts in population modeling, simulation and model-based drug development-part 2: Introduction to pharmacokinetic modeling methods. CPT Pharm Syst Pharmacol. 17:e382013. View Article : Google Scholar
12	Yang QJ, Bukuroshi P, Quach HP, Chow ECY and Pang KS: Highlighting vitamin D receptor-targeted activities of 1α, 25-dihydroxyvitamin D (3) in mice via physiologically based pharmacokinetic-pharmacodynamic modeling. Drug Metab Dispos. 46:75–87. 2018. View Article : Google Scholar : PubMed/NCBI
13	Kobuchi S, Ito Y, Okada K, Imoto K, Kuwano S and Takada K: Pre-therapeutic assessment of plasma dihydrouracil/uracil ratio for predicting the pharmacokinetic parameters of 5-fluorouracil and tumor growth in a rat model of colorectal cancer. Biol Pharm Bull. 36:907–916. 2013. View Article : Google Scholar : PubMed/NCBI
14	Kobuchi S, Kuwano S, Imoto K, Okada K, Nishimura A, Ito Y, Shibata N and Takada K: A predictive biomarker for altered 5-fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer. Biopharm Drug Dispos. 34:365–376. 2013.PubMed/NCBI
15	Jiang H, Lu J and Ji J: Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: A potential biomarker for dihydropyrimidine dehydrogenase levels. Br J Pharmacol. 141:616–623. 2004. View Article : Google Scholar : PubMed/NCBI
16	Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A and Boisdron-Celle M: Individual fluorouracil dose adjustment based on pharmacokinetic followup compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 26:2099–2105. 2008. View Article : Google Scholar : PubMed/NCBI
17	Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A and Gamelin E: Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: A phase II, proof-of-concept study. Clin Colorectal Cancer. 11:263–267. 2012. View Article : Google Scholar : PubMed/NCBI
18	Buchi KN, Moore JG, Hrushesky WJ, Sothern RB and Rubin NH: Circadian rhythm of cellular proliferation in the human rectal mucosa. Gastroenterology. 101:410–415. 1991. View Article : Google Scholar : PubMed/NCBI
19	Zhang R, Lu Z, Liu T, Soong SJ and Diasio RB: Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: Possible relevance to fluoropyrimidine chemotherapy. Cancer Res. 53:2816–2822. 1993.PubMed/NCBI
20	Jilma B, Hergovich N, Stohlawetz P, Eichler HG, Bauer P and Wagner OF: Circadian variation of granulocyte colony stimulating factor levels in man. Br J Haematol. 106:368–370. 1999. View Article : Google Scholar : PubMed/NCBI
21	Abolmaali K, Balakrishnan A, Stearns AT, Rounds J, Rhoads DB, Ashley SW and Tavakkolizadeh A: Circadian variation in intestinal dihydropyrimidine dehydrogenase (DPD) expression: A potential mechanism for benefits of 5FU chrono-chemotherapy. Surgery. 146:269–273. 2009. View Article : Google Scholar : PubMed/NCBI
22	Kobuchi S, Ito Y and Sakaeda T: Population pharmacokinetic-pharmacodynamic modeling of 5-fluorouracil for toxicities in rats. Eur J Drug Metab Pharmacokinet. 42:707–718. 2017. View Article : Google Scholar : PubMed/NCBI
23	Hsieh CH, Hou ML, Chiang MH, Tai HC, Tien HJ, Wang LY, Tsai TH and Chen YJ: Head and neck irradiation modulates pharmacokinetics of 5-fluorouracil and cisplatin. J Transl. 11:2312013. View Article : Google Scholar