PHASE-I AND PHARMACOKINETIC STUDY OF ETOPOSIDE PHOSPHATE BY PROTRACTED VENOUS INFUSION IN PATIENTS WITH ADVANCED CANCER

Purpose: Etoposide has schedule-dependent cytotoxic activity, and clin ical resistance may be overcome with prolonged low-dose therapy. Oral bioavailability is variable, and protracted intravenous administration is limited by water insolubility, which requires large infusion volum es. Etoposide phosphate (EP) is a water-soluble prodrug that is rapidl y converted in vivo to etoposide, and may be administered in concentra ted solution. A phase I study was conducted to determine the toxicity, pharmacokinetics, and pharmacodynamics of EP administered as a protra cted venous infusion in the ambulatory setting. Methods: Twenty-three patients with advanced cancer were treated with a continuous infusion of EP using ambulatory pumps for 6 weeks followed by a 2-week rest. Co horts were treated with EP at 10, 20, 25, and 30 mg/m(2)/d. Steady-sta te plasma etoposide levels (Css) and stability of EP in infusion pumps were measured using high performance liquid chromatography (HPLC). Re sults: Myelosuppression, mucositis, and fatigue were dose-limiting. Th e maximum-tolerated dose (MTD) of EP was 20 mg/m(2)/d. The mean Css (/- SD) of etoposide were 0.67 +/- 0.25, 1.14 +/- 0.24, 1.38 +/- 0.64, and 2.19 +/- 0.52 mu g/mL at daily EP doses of 10, 20, 25, and 30 mg/m (2), respectively. Neutropenia correlated with Css (r = 0.65, P = .008 ). EP wets stable in infusion pumps for at least 7 days. Partial respo nses were observed in patients with hepatoma and non-small-cell lung c ancer (one each). Conclusion: EP may be conveniently and safely admini stered as a low-volume protracted venous infusion in the ambulatory se tting. Cytotoxic plasma concentrations of etoposide are obtained at th e MTD. The pharmacodynamic relationships observed suggest the possibil ity of pharmacologically based dosing of EP. (C) 1997 by American Soci ety of Clinical Oncology.