Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing.

Abstract

Despite the clinical experience with Ommaya reservoir-facilitated intraventricular methotrexate (MTX) therapy, established age-related dosage guidelines do not exist. In an attempt to design such a schedule, 49 courses of intra-Ommaya MTX (median dose, 6 mg) administered to 12 patients were studied. Using a fluorescence polarized immunoassay (TDx; Abbott, Dallas, TX), the median peak intraventricular CSF MTX concentration (CSF [MTX]) was 423 mumol/L. Median CSF [MTX] at 24 hours was 4.6 mumol/L, and at 48 hours was 1.05 mumol/L. Median MTX half-life (t1/2) was 5.7 hours. A CSF [MTX] greater than 1 mumol/L was maintained for 24 hours in all but one course and for 48 hours in half of the courses. No correlations were found between MTX dose, patient age, [MTX], t1/2 or prior therapy. Considerable intra- and interpatient variability was seen in MTX disposition, emphasizing the need to monitor [MTX] with each course. A schedule for intraventricular MTX with an initial dose of 6 mg and supplemental doses of 6, 4, or 2 mg at 24 and 48 hours according to serial measurements of intraventricular [MTX] should be initiated to provide a minimum CSF [MTX] of 1 mumol/L for 72 hours.

Development of the Metronomic Biofeedback Pump for leptomeningeal carcinomatosis: technical note

“…As shown in Fig. 9D, high concentrations of the drug could be documented in the CSF at levels that compared favorably to what has been reported in patients (e.g., Strother et al 22 ). After initial buildup, MTX concentrations remained fairly constant for several hours, consistent with metronomic delivery.…”

Intrathecal topotecan in adult patients with neoplastic meningitis

“…7,8 The effectiveness of intrathecal chemotherapy is also limited because of the short half-life within the CSF of the commonly used chemotherapeutic agents such as methotrexate, cytarabine, and thiotepa as well as the cell-cycle specific mechanism of action of most available agents. 9 Therefore, development of new agents for intrathecal administration with more suitable pharmacokinetic and pharmocodynamic characteristics is essential.…”

Safety and Efficacy of Liposomal Cytarabine in the Treatment of Neoplastic Meningitis

“…Chemotherapy usually consists of methotrexate (MTX) and cytarabine as a single-agent or combination therapy. The major disadvantages of the cytotoxic agents mentioned above are their rapid clearance from the CSF after intrathecal injection, which therefore requires frequent injection schedules of usually 3 times per week [7,8]. This intrathecal injection schedule is burdensome for the patient and increases the risk of injection-related infections.…”