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

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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 h×μg/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 h×µg/ml vs. 28.42±12.23 h×µg/ml, P=0.064 and 2.39±1.21 h(μg/ml vs. 1.86±1.11 h×μg/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.

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Abbreviations

CPT-11:

Irinotecan

CRC:

Colorectal cancer

5-FU:

5-Fluorouracil

LV:

Leucovorin

NCI:

National Cancer Institute

ECOG:

Eastern Cooperative Oncology Group

SN-38:

7-Ethyl-10-hydroxycamptothecin

SN-38 glucuronide:

7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]-camptothecin (the β-glucuronide conjugate of SN-38)

AUC:

Area under the time versus plasma concentration curve

t1/2β:

Elimination half-life

CL:

Total body clearance

C max :

Maximal plasma concentration

T max :

Time to reach C max

REC:

Relative extent of conversion

MR:

Metabolic ratio

BI:

Biliary index

GR:

Glucuronidation ratio

RECIST:

Response evaluation criteria in solid tumor

APC:

7-Ethyl-10 (4-N-5-aminopentanoic acid)-(1-piperidino)-carbonyloxycamptothecin

NPC:

7-Ethyl-10 (4-(1-piperidino)-1-amino)-carbonyloxycamptothecin

AEDs:

Antiepileptic drugs

CYP450:

Cytochrome P-450

ABC:

ATP binding cassette

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Acknowlegments

The authors thanks Mr. Michele Andreuccetti for technical assistance.

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Authors and Affiliations

  1. U. O. Oncologia medica, Presidio Ospedaliero, Viale Alfieri 36, 57124, Livorno, Italy

    Giacomo Allegrini, Elisa Cerri, Gianluca Masi, Lorenzo Marcucci & Alfredo Falcone

  2. Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy

    Antonello Di Paolo , Federica Amatori, Romano Danesi, Guido Bocci & Mario Del Tacca

  3. Division of Internal Medicine, Hospital “F. Lotti” of Pontedera, Pisa, Italy

    Samanta Cupini

  4. Cattedra di Oncologia Medica, University of Pisa, Pisa, Italy

    Alfredo Falcone

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  1. Giacomo Allegrini
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  2. Antonello Di Paolo
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  3. Elisa Cerri
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  4. Samanta Cupini
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Correspondence to Giacomo Allegrini.

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Grant support: The work was partially supported by Associazione Italiana Ricerca Cancro (AIRC) and Fondazione A.R.C.O.

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Allegrini, G., Di Paolo , A., Cerri, E. et al. Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation. Cancer Chemother Pharmacol 58, 585–593 (2006). https://doi.org/10.1007/s00280-006-0205-x

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