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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-04

AUTHORS

G Allegrini, A Falcone, A Fioravanti, M T Barletta, P Orlandi, F Loupakis, E Cerri, G Masi, A Di Paolo, R S Kerbel, R Danesi, M Del Tacca, G Bocci

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. More... »

PAGES

1312

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.bjc.6604311

DOI

http://dx.doi.org/10.1038/sj.bjc.6604311

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1048648006

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18362940


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