A 4-HOUR TOPOTECAN INFUSION ACHIEVES CYTOTOXIC EXPOSURE THROUGHOUT THE NEURAXIS IN THE NONHUMAN PRIMATE MODEL - IMPLICATIONS FOR TREATMENT OF CHILDREN WITH METASTATIC MEDULLOBLASTOMA

The purpose of this study was to define the length of topotecan (TPT) i.v. infusion necessary to attain a cytotoxic exposure for medulloblas toma cells throughout the neuraxis. In vitro studies of human medullob lastoma cell lines (Daoy, SJ-Med3) were used to estimate the length an d extent of TPT systemic exposure associated with inhibition of tumor cell growth or the exposure duration threshold (EDT). We evaluated TPT systemic and cerebrospinal fluid (CSF) disposition in six male rhesus monkeys (8-12 kg) that received TPT 2.0 mg/m(2) i.v. as a 30-min or 4 -h infusion. Plasma and CSF samples were assayed for TPT lactone by hi gh-performance liquid chromatography, and the CSF exposures were compa red with the estimated EDT. Results of the in vitro studies defined an EDT as a TPT lactone concentration of >1 ng/ml for 8 h (IC99) daily f or 5 days. The mean +/- SD for systemic clearance (CLSYS), penetration into fourth ventricle (%CSF4th), and penetration into lumbar space (% CSFLUM) were similar for the 30-min and the 4-h infusions. At a TPT la ctone systemic exposure (AUC(PL)) of 56.7 +/- 19.9 ng/ml.h, time above 1 ng/ml in the fourth ventricle was 1.4-fold greater for a 4-h infusi on compared with a 30-min infusion. At a TPT lactone AUC(PL) of 140 ng /ml.h, the 4-11 infusion achieved the desired TPT exposure throughout the neuraxis (lateral and fourth ventricles and lumbar space), whereas the 30-min infusion failed to achieve it in the lumbar space. In conc lusion, prolonging TPT i.v. infusion from 30-min to 4-h at a targeted AUC(PL) achieves the EDT throughout the neuraxis and represents an alt ernative method of TPT administration that will be tested prospectivel y in patients with high-risk medulloblastoma.