PHASE-I AND PHARMACOKINETIC STUDY OF ETOPOSIDE PHOSPHATE

Etoposide phosphate (EP) is a water-soluble derivative of etoposide (V P-16), a semisynthetic podophyllotoxin which is useful in the treatmen t of a wide variety of hematological malignancies and solid tumors. Be cause etoposide is poorly water soluble, it must be dissolved in a var iety of organic solvents and given in relatively large volumes of sali ne. EP is rapidly converted to the parent drug in vivo and has been sh own to be active in animal studies. We performed a phase I pharmacokin etic study in 27 patients. Three patients each received an etoposide-e quivalent dose of 50 or 75 mg/m(2) each day by i.v. bolus (5 min) dail y for 5 days and 21 patients received a dose equivalent to 100 mg/m(2) of etoposide each day for 5 days. Non-compartmental pharmacokinetic d ata were obtained far 22 of the patients. As with previous studies, EP behaves as a prodrug of etoposide. The C-max (25.3-42.5 mu g/ml) incr eased linearly, while AUC(int) (75.8-156 h mu g/ml) of etoposide incre ased proportionately with dose (50-100 mg/m(2) of etoposide equivalent s). Time to achieve C-max corresponded to the end of the 5 min injecti on, indicating a rapid formation of etoposide from EP. Mean etoposide phosphate/etoposide C-max and AUC(int) ratios were 0.08 or less and 0. 003, respectively, indicating that the major circulating moiety in pla sma was etoposide. Parameters such as MRT, T-1/2, CL/F, CL(R), V-SS/F and %UR were dose independent. The toxicities of EP were virtually ide ntical to those seen with etoposide, with dose-related myelosuppressio n, alopecia and stomatitis. Severe neutropenia was the dose-limiting t oxicity. No significant problems with hypotension or allergic reaction s were observed. No problems, difficulties or complications were obser ved as a result of bolus (5 min) administration. On the basis of phase I toxicity data, we recommend an etoposide equivalent starting dose o f 100 mg/m(2)/day far 5 days in previously untreated patients who have an excellent performance status. In patients who have had one or more prior chemotherapy regimens, extensive prior radiation therapy or mod erately impaired performance status, we recommend an etoposide phospha te starting dose of 75 mg/m(2)/day for 5 days with courses repeated at 3 week intervals.