A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

Br J Cancer. 2008 Apr 22;98(8):1312-9. doi: 10.1038/sj.bjc.6604311. Epub 2008 Mar 25.


The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapy-refractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m(-2) day(-1) (n=7), 2.8 mg m(-2) day(-1) (n=5) and 4.2 mg m(-2) day(-1) (n=8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C(ss)) of SN-38 were between 1 and 3.3 ng ml(-1). From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4+/-30.1 and 130.4+/-9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m(-2) day(-1) dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities >grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality
  • Female
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Humans
  • Irinotecan
  • Male
  • Middle Aged
  • Thrombospondin 1 / blood
  • Thrombospondin 1 / genetics
  • Vascular Endothelial Growth Factor A / blood
  • Vascular Endothelial Growth Factor A / genetics


  • Antineoplastic Agents, Phytogenic
  • Thrombospondin 1
  • Vascular Endothelial Growth Factor A
  • Granulocyte Colony-Stimulating Factor
  • Irinotecan
  • Camptothecin