Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours

Abstract

SummaryAs the systemic administration of etoposide is effective in the treatment of relapsed and metastatic brain tumours, a pilot trial was designed to study the feasibility of intraventricular administration of etoposide in such patients. 14 patients aged 2.1 to 33.2 years were treated with intraventricular etoposide simultaneously with either oral or intravenous chemotherapy with trofosfamide or carboplatin and etoposide. In 59 courses (1-12/patient) 0.5 mg etoposide was administered daily via an indwelling subcutaneous reservoir for 5 consecutive days every 2-5 weeks over a period of 0-11 months. During 15 courses in 5 patients serial CSF samples were obtained and etoposide levels were determined by reversed-phase HPLC. Side effects included transient headache and bacterial meningitis, each during 2 courses. Pharmacokinetic data analysis in the CSF (11 courses, 4 patients) revealed a terminal half-life of 7.4±1.2 hours and an AUC of 25.0 ± 9.5 µg h ml -1 (mean ± standard deviation). The volume of distribution at steady state and total clearance exhibited a large interindividual variability with mean values of 0.16 l and 0.46 ml min -1 respectively. Intraventricularly administered etoposide is well tolerated. CSF peak levels exceed more than 100-fold those achieved with intravenous infusions. Further studies should be focused on optimizing the dose and schedule and on determining the effectiveness of intraventricularly administered etoposide.

CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective

“…Pharmacokinetics in CSF has also been studied for etoposide in patients with metastatic brain tumors [91]. Following intraventricular administration (0.5 mg), the ventricular etoposide concentration decreased in a biexponential fashion, with a mean initial ( -phase) half-life of 1.4 hr and a terminal ( -phase) half-life of 7.4 hr.…”

Intracerebroventricular drug administration

“…Fleischhack et al [55] studied etoposide CSF pharmacokinetics in 4 patients with metastatic brain tumors who ranged in age from 12 to 32 years. They administered a 0.5 mg etoposide TCP Transl Clin Pharmacol dose via an Ommaya or Rickham reservoir and observed a biphasic CSF distribution pattern.…”

Drug delivery approaches for the treatment of glioblastoma multiforme

“…Another strategy for bypassing the BBB is to deliver the drug directly within the ventricular system of the brain (Fleischhack et al 2001). In this approach, drugs are injected into the cerebrospinal fluid (CSF) through the use of reservoirs implanted subcutaneously and connected to the ventricles via a catheter (Misra et al 2003).…”