Original Article

Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients

Zhi-xiang Zhuang, Hong Zhu, Ji Wang, Min-gao Zhu, Hui Wang, Wang-yang Pu, Hua-hui Bian, Lei Chen, Hong Zhang
DOI: 10.1038/aps.2012.169


Zhi-xiang ZHUANG#, Hong ZHU#, *, Ji WANG, Min-gao ZHU, Hui WANG, Wang-yang PU, Hua-hui BIAN, Lei CHEN, Hong ZHANG
Department of Oncology, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China

Aim: S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.
Methods: A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m2, po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0–t, and AUC0–∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and Cmax of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews.

Results: The mean values of Cmax, AUC0–t, and AUC0–∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t, and AUC0–∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found.

Conclusion: The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m2) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.

Keywords: anticancer drug; S-1; tegafur; 5-fluorouracil; 5-chloro-2,4-dihydroxypyridine; potassium oxonate; pharmacokinetics

The authors would like to thank the volunteers and staff who participated in this study. The authors would like to thank the sponsor, Minsheng Pharmaceutical Co, Ltd, China (Hangzhou, China), for providing financial support. Mr Qin WAN and Xiu-gui CHEN who are employees of Minsheng Pharmaceutical Co, Ltd of China provided significant assistance during the clinical trials. This work was supported by grants from Suzhou City Research Foundation for Applied Basic Research (No YJS0930 and No SYS201129), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No 10KJB320020), National Natural Science Foundation of China (No 81000944) and Research Foundation for “Reserved Academic Leader” from the Second Affiliated Hospital of Soochow University.
# These authors contributed equally to this article.
* To whom correspondence should be addressed.
E-mail zhoncology@suda.edu.cn
Received 2012-10-08 Accepted 2012-11-07

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