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.

Figure 1

Actuarial PFS and OS curves calculated by the Kaplan–Meier method from the first day of metronomic irinotecan chemotherapy.

Figure 2

Plasma levels of irinotecan (CPT-11) (A), SN-38 (B) and SN-38 glucuronide (C) in 20 mCRC patients receiving an i.v. continuous infusion of CPT-11 at three different dose levels. Symbols and bars represent mean and s.d.

Figure 3

TSP-1 (A) and VEGF (B) plasma concentrations and TSP-1 (C) and VEGF (D) gene expression in PBMC of patients administered with three different metronomic irinotecan (CPT-11) doses. Symbols and bars represent mean and s.d. The data are presented as a percentage of the concentration at day 0 (before the beginning of CPT-11 infusion) of each individual patient or as the percentage of 2^−ΔΔC_t at day 0 of each single patient.