Pharmacokinetics and Bioequivalence of Two Formulations of S-1 (Tegafur/Gimeracil/Oxonate) Capsule in Chinese Cancer Subjects under Fasting and Fed Conditions: a Multicenter, Randomized, Open, Single-dose, Double-Cycle Crossover Study

Junli Lu ¹ Yuyan Lei ^1,2 Yuanyuan Mo ¹ Xiangping Wang ¹ Wanying Liu ¹ Yu Yan ¹ Hongying Yang ¹ Canxia Li ¹ Lifeng Huang ¹ Qiuxia Shen ¹ Caihong Wang ¹ Jingjie Chen ³ Lulu Chen ^4* Xiaohui Li ^2,4*

• ¹ Nanning Second People's Hospital, Nanning, China
• ² Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan Province, China
• ³ Qilu Pharmaceutical Co., Ltd, Shandong, China
• ⁴ Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, Anhui Province, China

Objective: S-1, an oral multicomponent capsule containing tegafur, gimeracil, and potassium oxonate, has demonstrated efficacy in various tumour types. This study aimed to assess the pharmacokinetics, bioequivalence (BE), and safety of a newly developed generic S-1 capsule compared to the original brand-name formulation in Chinese cancer patients under fasting and fed conditions. Methods: A multicenter, randomized, open-label, single-dose, double-cycle crossover study was conducted in Chinese cancer patients. The study involved 120 subjects, with 60 assigned to the fasting group and another 60 to the fed group. In each study cycle, subjects were randomly assigned to receive either the reference or test S-1 capsule at a 5-day interval. Blood samples were collected for analysis within 48 hours after ingestion. The plasma concentrations of tegafur, 5-fluorouracil, gimeracil, and potassium oxonate were determined by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The main pharmacokinetic (PK) parameters were calculated using the non-compartmental approach. BE was assessed through the geometric mean ratios (GMRs) between the two formulations and their respective 90% confidence intervals (CIs). The safety of the two formulations was also evaluated.The pharmacokinetics of the two formulations were similar under both fasting and fed conditions. The 90% CIs of the GMRs for the maximum observed serum concentration (Cmax), AUC0-t, and AUC0-∞ ratios were observed to lie within the BE acceptance range of 80% to 125%.Both formulations of the S-1 capsule exhibited similar adverse events (AEs), primarily including decreased white blood cell count and hypertension. These AEs were generally mild and transient. The safety profiles of the two formulations were found to be good and comparable, with no serious adverse events (SAEs) reported.The newly developed generic S-1 and reference formulation exhibit comparable PK in Chinese cancer patients during the fasting and fed states. The formulations of S-1 showed good tolerability and a similar safety profile.This trial is registered at the Chinese Clinical Trial website (http://www. chinadrugtrials.org.cn/index.html), identifier CTR20171562.