PHARMACOKINETICS OF INTRALUMBAR DTC-101 FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES

Purpose: To study the results of intralumbar administration of chemotherapeutic agents for the treatment of neoplastic meningitis and to determine how these results relate to the variable and often subtherapeutic drug concentrations in the ventricular cerebrospinal fluid (CSF) compartment. Ventricular and lumbar pharmacokinetic studies were done following intralumbar administration of DTC-101, an extended-release formulation of cytarabine. Patients and Methods: Nine patients (age range, 23 to 67 years; median age, 42 years) with leptomeningeal metastases were treated with 18 courses of intralumbar DTC-101. Eight patients who were treated with 14 courses underwent pharmacokinetic CSF sampling from the lumbar sac and lateral ventricle. Cytarabine concentrations were determined by using high-pressure liquid chromatography. Results: Following intralumbar administration of DTC-101, therapeutic free cytarabine concentrations were achieved rapidly in both of the ventricular and lumbar CSF compartments and maintained for 2 weeks. The mean pharmacokinetic parameters of free cytarabine in the lumbar and ventricular CSF compartments were as follows: maximum concentration, 226 and 6.06 mg/L; half-life, 277 and 130 hours; and area under the concentration vs time curve, 4120 and 598 mu g/h per milliliter, respectively. Conclusions: Intralumbar administration of DTC-101 results in extended cytotoxic free cytarabine concentrations in both of the lumbar and ventricular regions of CSF and allows an every-other-week drug-dosing schedule.