Cancer Chemotherapy and Pharmacology

, Volume 58, Issue 5, pp 585–593

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

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

DOI: 10.1007/s00280-006-0205-x

Cite this article as:
Allegrini, G., Di Paolo, A., Cerri, E. et al. Cancer Chemother Pharmacol (2006) 58: 585. doi:10.1007/s00280-006-0205-x

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.

Keywords

Metastatic disease Diarrhea Pharmacokinetics Irinotecan Thalidomide 

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

Cmax

Maximal plasma concentration

Tmax

Time to reach Cmax

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

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Giacomo Allegrini
    • 1
  • Antonello Di  Paolo
    • 2
  • Elisa Cerri
    • 1
  • Samanta Cupini
    • 3
  • Federica Amatori
    • 2
  • Gianluca Masi
    • 1
  • Romano Danesi
    • 2
  • Lorenzo Marcucci
    • 1
  • Guido Bocci
    • 2
  • Mario Del Tacca
    • 2
  • Alfredo Falcone
    • 1
    • 4
  1. 1.U. O. Oncologia medica, Presidio OspedalieroLivornoItaly
  2. 2.Division of Pharmacology and Chemotherapy, Department of Internal MedicineUniversity of Pisa PisaItaly
  3. 3.Division of Internal Medicine Hospital “F. Lotti” of PontederaPisaItaly
  4. 4.Cattedra di Oncologia MedicaUniversity of PisaPisaItaly

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