Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases
M. C. Chamberlain, P. Kormanik, S. B. Howell and S. Kim
Department of Neurosciences, University of California-San Diego, La Jolla, USA.
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 micrograms/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.