伊立替康联合沙利度胺治疗晚期实体瘤患者：一项具有药效学和药代动力学评估的临床研究。

Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation.

作者信息

Allegrini Giacomo, Di Paolo Antonello, Cerri Elisa, Cupini Samanta, Amatori Federica, Masi Gianluca, Danesi Romano, Marcucci Lorenzo, Bocci Guido, Del Tacca Mario, Falcone Alfredo

机构信息

U. O. Oncologia medica, Presidio Ospedaliero, Viale Alfieri 36, 57124, Livorno, and Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Italy.

出版信息

Cancer Chemother Pharmacol. 2006 Nov;58(5):585-93. doi: 10.1007/s00280-006-0205-x. Epub 2006 May 6.

DOI:10.1007/s00280-006-0205-x

PMID:16680463

Abstract

PURPOSE

Recent clinical studies have demonstrated a reduction of irinotecan (CPT-11) gastrointestinal toxicities when the CPT-11 is administered in combination with thalidomide in patients with diagnosis of colorectal cancer. The main purpose of this study was to investigate possible interactions between CPT-11 pharmacokinetics and thalidomide to explain the previously described gastrointestinal toxicity reduction.

METHODS

In our clinical trial, advanced cancer patients were treated with CPT-11 on a dose of 350 mg/m2 at day 1 every 3 weeks. Only at the first cycle, CPT-11 was administered in association with thalidomide on a dose of 400 mg/day given from day 1 to day 14. From the second cycle, the treatment was continued with irinotecan alone at the same dose. Pharmacokinetics analysis of irinotecan and its metabolites, SN-38 and SN-38-glucuronide, were performed at the first and second cycle.

RESULTS

A total of 19 patients entered the study. The pharmacokinetic analysis were performed on 16 patients. Pharmacokinetic data suggested a decreased metabolism of irinotecan into SN-38 and SN-38-glucuronide when it was administered with thalidomide. Indeed, area under the time-concentration curve (AUC) of SN-38 was significantly lower at the first cycle than the second cycle (0.99+/-0.45 hxmicrog/ml vs 1.34+/-0.65, respectively, P=0.027) whereas AUC of irinotecan and SN-38-glucuronide were higher at first cycle than second cycle (34.53+/-11.38 hxmicrog/ml vs. 28.42+/-12.23 hxmicrog/ml, P=0.064 and 2.39+/-1.21 h(microg/ml vs. 1.86+/-1.11 hxmicrog/ml, P=0.018, respectively).

CONCLUSIONS

Our study demonstrates a significant decreased metabolism of CPT-11 into the active metabolite SN-38 when CPT-11 is administered in association with thalidomide. These observations strongly suggest an interaction of thalidomide with CPT-11 metabolism and, at least in part, it might explain the previously described improvement in tolerability.

摘要

目的

近期临床研究表明，在诊断为结直肠癌的患者中，当伊立替康（CPT - 11）与沙利度胺联合使用时，其胃肠道毒性有所降低。本研究的主要目的是调查CPT - 11药代动力学与沙利度胺之间可能存在的相互作用，以解释先前所述的胃肠道毒性降低现象。

方法

在我们的临床试验中，晚期癌症患者每3周于第1天接受350mg/m²剂量的CPT - 11治疗。仅在第一个周期，CPT - 11与沙利度胺联合使用，沙利度胺剂量为400mg/天，从第1天至第14天给药。从第二个周期开始，继续单独使用相同剂量的伊立替康进行治疗。在第一个和第二个周期对伊立替康及其代谢产物SN - 38和SN - 38 - 葡糖醛酸进行药代动力学分析。

结果

共有19名患者进入该研究。对16名患者进行了药代动力学分析。药代动力学数据表明，当CPT - 11与沙利度胺联用时，其代谢为SN - 38和SN - 38 - 葡糖醛酸的过程减缓。实际上，第一个周期SN - 38的时间 - 浓度曲线下面积（AUC）显著低于第二个周期（分别为0.99±0.45 h×μg/ml和1.34±0.65，P = 0.027），而CPT - 11和SN - 38 - 葡糖醛酸的AUC在第一个周期高于第二个周期（分别为34.53±11.38 h×μg/ml对28.42±12.23 h×μg/ml，P = 0.064；2.39±1.21 h×μg/ml对1.86±1.11 h×μg/ml，P = 0.018）。