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.
|Autori interni:||DI PAOLO, ANTONELLO|
|Autori:||ALLEGRINI G; DI PAOLO A; CERRI E; CUPINI S; AMATORI F; MASI G; DANESI R; MARCUCCI L; BOCCI G; DEL TACCA M; FALCONE A|
|Titolo:||Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation|
|Anno del prodotto:||2006|
|Digital Object Identifier (DOI):||10.1007/s00280-006-0205-x|
|Appare nelle tipologie:||1.1 Articolo in rivista|