A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients.
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.
Allegrini
G
G
Division of Medical Oncology, General Hospital of Livorno, Department of Oncology, University of Pisa, Pisa, Italy.
Falcone
A
A
Fioravanti
A
A
Barletta
M T
MT
Orlandi
P
P
Loupakis
F
F
Cerri
E
E
Masi
G
G
Di Paolo
A
A
Kerbel
R S
RS
Danesi
R
R
Del Tacca
M
M
Bocci
G
G
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D019700:Thrombospondin 1 / Q000097:blood / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D002166:Camptothecin