Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors
Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors
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DOI：
10.1200/jco.2000.18.14.2772
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发表时间：
2000-07-01
影响因子：
45.3
通讯作者：
Giaccone, G
中科院分区：
文献类型：
--
作者：
van Groeningen, CJ;Peters, GJ;Giaccone, G
目的：研究S-1的副作用，确定最大耐受剂量（MTD），并研究S-1的药代动力学，S-1是一种口服氟尿嘧啶类药物，由氟尿嘧啶（5-FU）前体药物替加氟与两种调节剂5-氯-2，4-二羟基吡啶和氧嗪酸钾组合而成。晚期实体瘤患者接受S-1 bid治疗28天，随后休息1周。结果：28例患者接受了25、45、35和40 mg/m2四个连续剂量的S-1，最初发现的MTD为45 mg/m2，腹泻为剂量限制性毒性（DLT）。腹泻也是40 mg/m2剂量下的DLT，这是暴露于广泛既往化疗的患者的MTD。其他毒性一般为轻度。两名患者的肿瘤尺寸缩小超过50%。5-FU的血浆药代动力学呈线性;在最高S-1剂量水平下，5-FU血浆峰浓度达到1 - 2 μ mol/L，5-FU的半衰期为3 - 4小时。腹泻严重程度与5-FU的药代动力学参数之间存在显著相关性。结论：S-1在化疗初治或化疗暴露最少的患者中的推荐剂量为40 mg/m2 bid，连续28 d，每5周1次。在大量预治疗的患者中，推荐剂量为35 mg/m2 bid，II期试验在已知对5-FU治疗有反应的肿瘤中进行。(C)2000年，美国临床肿瘤学会。
Purpose: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate.Patients and Methods: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter.Results: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2), The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m2, which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 mu mol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU.Conclusion: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m2 bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid, Phase II trials are warranted in tumors known to be responsive to 5-FU treatment. (C) 2000 by American Society of Clinical Oncology.