Purpose: To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. Patients and Methods: Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count greater than or equal to 4,000/mu L, and platelet count greater than or equal to 100,000/mu L, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m(2)/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m(2)/d. Results: Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m(2), with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m(2)/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, bur two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peek plasma concentrations at 5 minutes, with a terminal half-life (t(1/2)) of 7 minutes. Etoposide reached peek concentrations at 7 to 8 minutes, with a t(1/2) of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (C-max) and area under the curve (AUC). Conclusion: Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m(2) on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens. (C) 1994 by American Society of Clinical Oncology.
