A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO).
使用口服环孢素对晚期结直肠癌进行伊立替康药代动力学生物调节的随机 III 期试验: 帕尼图单抗、伊立替康和环孢素在结直肠癌治疗试验 (PICCOLO) 中的结果。

摘要

BACKGROUND:The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan.
METHODS:Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation.
RESULTS:The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference.
INTERPRETATION:The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC.
FUNDING:The trial was funded by Cancer Research UK and supported by Amgen Pharma.

译文

背景: 伊立替康治疗晚期结直肠癌的主要毒性是迟发性腹泻。肠 SN-38,通过去除母体葡萄糖醛酸苷排泄到胆汁中或通过肠羧酸酯酶原位产生,对肠上皮细胞有毒。伊立替康和 SN-38G 的小管转运是由 ABCC2 (MRP2) 和 ABCB1 (MDR1) 介导的,它们都受到环孢素的抑制。我们测试了与单剂伊立替康相比,伊立替康和环孢素的抗癌功效是否不逊色,毒性是否优越。
方法: 672 名先前接受含氟嘧啶化疗的晚期、可测量的 CRC 患者被随机分为伊立替康每周 350 mg/m (2) (或 300 mg/m (2)) 如果年龄> 70 或性能状态 (PS) = 2) 或每周 140 毫克/米 (2) 的伊立替康 (120 毫克/米 (2),如果年龄> 70 或 PS = 2) 用环孢素 3 mg/kg t。 d. s。从伊立替康之前的早上开始,用嘴呼吸三天。主要终点是 12 周时存活和无进展患者的比例。关键的次要终点是随机分组 12 周内 ≥ 3 级腹泻的发生率。
结果: 使用伊立替康 12 周的无进展患者比例为 53.4%,而使用伊立替康加环孢素的患者比例为 47.2% (差异 =-6.3%,95% 置信区间 (CI) [-13.8%, 1.3%])。由于 95% CI 的下限超过了预先指定的-10.6% 的非劣效界限,因此没有统计证明伊立替康加环孢素与单独伊立替康相比的非劣效界限。15.0% 的患者使用伊立替康出现严重腹泻,而使用伊立替康加环孢素的患者为 13.8%,差异不显著。
解读: 伊立替康使用口服环孢素的药代动力学生物调节并未改善伊立替康在晚期 CRC 中的治疗指数。
资助: 该试验由英国癌症研究中心资助,并由安进制药公司支持。

Ciclosporin

内分泌 免疫抑制剂 治疗药物
概述  :  

环孢素是一种免疫抑制剂和天然产物,对于类风湿性关节炎,牛皮癣,克罗恩病,肾病综合症以及器官移植,可通过口服或静脉注射来预防,以防止排斥反应。它也可以用来作为滴眼剂治疗干燥性角膜结膜炎(干眼)。 作用机制 主要作用是降低T细胞的活性。它可以通过抑制钙调磷酸酶-磷酸酶途径中的钙调磷酸酶和阻止线粒体通透性转换孔打开来实现。环孢菌素与淋巴细胞特别是T细胞的胞浆蛋白亲环蛋白(免疫亲和素)结合。这种环孢菌素-亲环蛋白复合物抑制钙调神经磷酸

Ciclosporin

释    义   环孢素

例    句   On treatment, the oral medication mainly include anti-tumor drug, CyA, VA, anti-bacterium drug, biological products and blood vessel formation antigeon and so on.治疗方面,内用药物主要有抗肿瘤药物、环孢素A、维甲酸、抗菌药、生物制品、血管生成拮抗剂等。

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