INTRATHECAL ADMINISTRATION OF TOPOTECAN IN NONHUMAN-PRIMATES

The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studi ed in a nonhuman primate model following intraventricular administrati on of 0.1 mg. Lactone and total drug concentrations were measured usin g a reverse-phase HPLC method with fluorescence detection. The mean pe ak concentrations of lactone and total drug in ventricular CSF were 83 +/- 18 mu M and 88 +/- 25 mu M, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3 h. Th e mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (A UC) to lactone was 450-fold greater following intraventricular adminis tration of 0.1 mg topotecan than after systemic intravenous administra tion of a 40-fold higher dose (10 mg/m(2)). Peak lumbar concentrations (n = 1), which occurred 2 h after intraventricular drug administratio n, were 0.98 mu M and 2.95 mu M for the lactone and total drug, respec tively. A transient CSF pleocytosis was observed in one animal followi ng intraventricular topotecan administration and in one animal followi ng intralumbar topotecan administration. No other acute or chronic neu rologic or systemic toxicities were observed following a single intrav entricular dose or weekly (x4) intralumbar topotecan. Compared with sy stemic topotecan, intrathecal administration provided a significant ph armacokinetic advantage in terms of CSF drug exposure and did not prod uce any significant neurotoxicity in a nonhuman primate model. Intrath ecal topotecan should be evaluated clinically as a potential alternati ve therapy for refractory meningeal tumors.