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 chemotherapyrefractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m À2 day À1 (n ¼ 7), 2.8 mg m À2 day À1 (n ¼ 5) and 4.2 mg m À2 day À1 (n ¼ 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 À1 . 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 À2 day À1 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 4grade 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.

Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer

“…Moreover, the possible antiangiogenic mechanism of our combination therapy in responder patients is also suggested by the simultaneous significant decrease of plasma VEGF, as also described by Colleoni et al (43), and the increase of the endogenous inhibitor of angiogenesis TSP-1, which would suggest a shift to an antiangiogenic state. Similar findings were previously described by our group in colorectal cancer patients treated with metronomic irinotecan (19).…”

“…Before drug administration and at day 14, 28, 42, 56, 70, and 84, 10 mL of blood were drawn from the antecubital vein of patients. Peripheral blood mononuclear cell (PBMC) were collected as previously published (19) and the cell suspension was centrifuged at 800 × g for 10 min and washed with PBS; the resulting pellet was immediately frozen in liquid nitrogen and stored at -80°C. Total RNA was extracted from cells using the TRI REAGENT LS (Sigma).…”

Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin

“…The use of irinotecan in a metronomic dosing regimen in a preclinical model of colorectal cancer (HT-29) was recently described (41); the authors indicate that metronomic dosing with irinotecan alone significantly inhibited tumor growth and also decreased microvessel density. The same group has now examined the pharmacokinetic and pharmacodynamic effects of metronomic irinotecan in metastatic colorectal patients, although the study did not include an examination of antivascular effects in the tumor tissue (42). Irinophore C, which behaves as a circulating drug depot that maintains low doses of active drug in the circulation for extended periods, may in fact be fundamentally akin to metronomic chemotherapy.…”

Metronomic anti-cancer therapy – an ongoing treatment option for advanced cancer patients

“…Furthermore, known cytotoxic/-static drugs which are only available for intravenous application are of current interest. In colorectal cancer patients drugs such as irinotecan were given in a metronomic fashion as low dose continuous infusion for 3 weeks (1,4 to 4,2 mg/d) followed by a 1 week rest [29]. The treatment was well tolerated without toxicity and resulted in a disease stabilization of 20%.…”