Phase I and pharmacokinetic study of etoposide phosphate by protracted venous infusion in patients with advanced cancer.

PURPOSEEtoposide has schedule-dependent cytotoxic activity, and clinical 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 volumes. Etoposidephosphate (EP) is a water-soluble prodrug that is rapidly converted in vivo to etoposide, and may be administered in concentrated solution. A phase I study was conducted to determine the toxicity, pharmacokinetics, and pharmacodynamics of EP administered as a protracted venous infusion in the ambulatorysetting.METHODSTwenty-three patients with advanced cancer were treated with a continuous infusion of EP using ambulatorypumps for 6 weeks followed by a 2-week rest. Cohorts were treated with EP at 10, 20, 25, and 30 mg/m2/d. Steady-state plasma etoposidelevels (Css) and stability of EP in infusion pumpswere measured using high performance liquid chromatography (HPLC).RESULTSMyelosuppression, mucositis, and fatigue we...