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

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Br J Cancer. 2008 Apr 22;98(8):1312-9. Epub 2008 Mar 25.

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients.
Allegrini G, Falcone A, Fioravanti A, Barletta MT, Orlandi P, Loupakis F, Cerri E, Masi G, Di Paolo A, Kerbel RS, Danesi R, Del Tacca M, Bocci G.Division of Medical Oncology, General Hospital of Livorno, Department of Oncology, University of Pisa, Pisa, Italy.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.