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.
A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients.
FALCONE, ALFREDO;FIORAVANTI, ANNA;ORLANDI, PAOLA;G. Masi;DI PAOLO, ANTONELLO;DANESI, ROMANO;BOCCI, GUIDO
2008-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
