title: A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients.
abstract: 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.
authors: Division of Medical Oncology, General Hospital of Livorno, Department of Oncology, University of Pisa, Pisa, Italy.
authors: G
authors: G
authors: Allegrini
authors: A
authors: A
authors: Falcone
authors: A
authors: A
authors: Fioravanti
authors: M T
authors: MT
authors: Barletta
authors: P
authors: P
authors: Orlandi
authors: F
authors: F
authors: Loupakis
authors: E
authors: E
authors: Cerri
authors: G
authors: G
authors: Masi
authors: A
authors: A
authors: Di Paolo
authors: R S
authors: RS
authors: Kerbel
authors: R
authors: R
authors: Danesi
authors: M
authors: M
authors: Del Tacca
authors: G
authors: G
authors: Bocci
mesh_terms: 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
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D002166:Camptothecin