Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation
Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation
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DOI：
10.1007/s00280-006-0205-x
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发表时间：
2006-11-01
影响因子：
3
通讯作者：
Falcone, Alfredo
中科院分区：
文献类型：
--
作者：
Allegrini, Giacomo;Di Paolo, Antonello;Falcone, Alfredo
用途：最近的临床研究已经证明，在诊断为结直肠癌的患者中，当CPT-11与沙利度胺联合给药时，伊立替康（CPT-11）胃肠道毒性降低。本研究的主要目的是研究CPT-11药代动力学和沙利度胺之间可能的相互作用，以解释先前描述的胃肠道毒性降低。方法：在我们的临床试验中，晚期癌症患者接受CPT-11治疗，剂量为350 mg/m2，第1天，每3周1次。仅在第一个周期，CPT-11与沙利度胺联合给药，剂量为400 mg/天，从第1天至第14天给药。从第二个周期开始，以相同剂量继续伊立替康单药治疗。在第1和第2周期进行伊立替康及其代谢产物SN-38和SN-38-葡糖苷酸的药代动力学分析。结果：共有19名患者进入研究。对16例患者进行了药代动力学分析。药代动力学数据表明，当与沙利度胺联合给药时，伊立替康代谢为SN-38和SN-38-葡糖苷酸减少。事实上，SN-38的时间-浓度曲线下面积（AUC）在第一个周期显著低于第二个周期（分别为0.99 +/- 0.45 hx μ g/ml vs 1.34 +/- 0.65，P=0.027），而伊立替康和SN-38-葡萄糖醛酸苷的AUC在第1周期时高于第2周期（分别为34.53 +/- 11.38 hx mug/ml vs. 28.42 +/- 12.23 hx mug/ml，P=0.064和2.39 +/- 1.21 h（mug/ml vs. 1.86 +/- 1.11 hx mug/ml，P=0.018）。结论：我们的研究表明，当CPT-11与沙利度胺联合给药时，CPT-11代谢为活性代谢物SN-38的代谢显著降低。这些观察结果强烈表明沙利度胺与CPT-11代谢的相互作用，至少部分解释了先前描述的耐受性改善。
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/m(2) 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 hx mu g/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 hx mu g/ml vs. 28.42 +/- 12.23 hx mu g/ml, P=0.064 and 2.39 +/- 1.21 h(mu g/ml vs. 1.86 +/- 1.11 hx mu g/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.